CANNABIS SATIVA 29

2 sativa L.

Common Names Almindelig hamp Denmark Harilik kanep Slovenia Asa Japan Haschischpflanze Germany Bang Egypt Hash United Kingdom Bhaang India Hashas Turkey Bhaango Nepal Hashish Morocco Canamo indico Spain Hemp United Kingdom Canapa indica Italy Hennep Netherlands Canhamo Portugal Hind kinnabi Turkey Cares Nepal Huo ma cao China Chanvre cultive France Huo ma China Chanvre de l’Inde France Indian hemp United Kingdom Chanvre France Indische hennep Netherlands Chanvrier sauvage France Indischer hanf Germany Charas India Indisk hamp Sweden Churras India Kannabis Finland Da ma cao China Kannabisu Japan Da ma ren China Kerp Albania Da ma China Kinnab Turkey Dagga South Africa Konopie siewne Poland Dansk pot Denmark Konopie Poland Echter hanf Germany Konoplja Slovenia Esrar Turkey Kultur hanf Germany Gaanjaa Nepal Maconha Portugal Gajiimaa Nepal Marihana Netherlands Ganja Guyana Marihouava Greece Ganja India Marihuana Poland Grifa Spain Marihuana Bulgaria Hachis Spain Marihuana Croatia Hamp Denmark Marihuana Czech Republic Hamp Norway Marihuana Denmark Hampa Sweden Marihuana France Hampjurt Iceland Marihuana Germany Hamppu Finland Marihuana Hungary Hanf Germany Marihuana Mexico

From: Medicinal Plants of the World, vol. 3: Chemical Constituents, Traditional and Modern Medicinal Uses By: I. A. Ross © Humana Press Inc., Totowa, NJ 29 30 MEDICINAL PLANTS OF THE WORLD

Marihuana Russia Porkanchaa Thailand Marihuana Serbia Pot Denmark Marihuana Spain Qinnib Arabic countries Marihuana Ukraine Riesen hanf Germany Marihuana United States Seruma erva Portugal Marijuana France Taima Japan Marijuana Italy Til Arabic countries Marijuana Mexico Vrai chanvre France Marijuana Portugal Weed Guyana Marijuana Sweden Xian ma China Mashinin Japan Ye ma China Navadna konoplja Slovenia

BOTANICAL DESCRIPTION types of plants are numerous varieties that Cannabis sativa is an annual herb of the differ from the main one in height, extent MORACEAE family that grows to 5 m tall. of branching, and other characteristics. It is usually erect; stems variable, with res- ORIGIN AND DISTRIBUTION inous pubescence, angular, sometimes hol- Native to Central Asia and long cultivated low, especially above the first pairs of true in Asia, Europe, and China. Now a wide- leaves; basal leaves opposite, the upper spread tropical, temperate, and subarctic leaves alternate, stipulate, long petiolate, cultivar. Cannabis sativa has been cultivated palmate, with 3–11, rarely single, lan- for more than 4500 years for different pur- ceolate, serrate, acuminate leaflets up to 10 poses, such as fiber, oil, or narcotics. The cm long, 1.5 cm broad. Flowers are monoe- oldest use of hemp is for fiber, and later the cious or dioecious, the male in axillary and seeds were used for culinary purposes. Plants terminal panicles, apetalous, with five yel- yielding the drug were discovered in India, lowish petals and five poricidal stamens; the cultivated for medicinal purposes as early as female flowers germinate in the axils and 900 BC. In medieval times, it was brought to terminally, with one single-ovulate ovary. North Africa, where currently it is culti- Fruit is brown, shining achene, variously vated exclusively for hashish or kif. marked or plain, tightly embraces the seed with its fleshy endosperm and curved TRADITIONAL MEDICINAL USES embryo; late summer to early fall; year- Afghanistan. Hot water extract of the resin round in tropics. Drug-producing selections is taken orally to induce abortionCS235. grow better and produce more drugs in the China. Hot water extract of the inflores- tropics; oil- and fiber-producing plants cence is taken orally for wasting diseases, to thrive better in the temperate and subtropi- clear the blood, to cool the temperature, to cal areas. The form of the plant and the relieve fluxes, for rheumatism, to discharge yield of fiber from it vary according to cli- pus, and to stupefy and produce hallu- mate and particular variety. Varieties culti- cinationsCS035. The seed is taken orally as an vated for their fibers have long stalks, emmenagogueCS014. Decoction of the seed is branch very little, and yield only small taken orally as an anodyne, an emmenag- quantities of seed. Oil seed varieties are ogue, a febrifuge, for migraine, and for small, mature early, and produce large quan- cancerCS112. It is taken orally as a hallucino- tities of seed. Varieties grown for the drugs gen and externally for rheumatismCS109. are small, much branched with smaller dark- Guatemala. The leaves are used externally green leaves. Between these three main to relieve muscular painsCS106. CANNABIS SATIVA 31

India. Hot water extract of the dried entire unripe fruit is taken orally to induce plant is taken orally as a narcotic and to sleepCS192. relieve pain of dysmenorrheaCS210. Hot water Iran. Fluidextract of the dried flowering top extract of the dried flower and leaf is taken or the dried fruit is taken orally for abdomi- orally for dyspepsia and gonorrhea and as a nal pain associated with indigestion, for nerve stimulantCS217. Hot water extract of pain associated with cancer, for rheumatoid the inflorescence of female plants is taken arthritis, for gastric cramps or neuralgia, for orally as an abortifacientCS010. Hot water coughing, and as a hypnotic. Fluidextract of extract of the leaf is taken orally to relieve the dried fruit is taken orally for whooping menstrual painCS086. For cuts, boils, and blis- cough, as a hypnotic, and a tranquilizerCS034. ters, leaf paste is applied topically for 4 The dried seed is taken orally as a diuretic. daysCS098. Hot water extract of the bark is An infusion is taken orally as an analgesic taken orally for hydrocele and other in rheumatism or rheumatoid arthritis, a inflammationCS125. Extract of the leaves is sedative, a diaphoretic, and for hysteric con- used as an insect repellantCS246. Hot water ditions, gout, epilepsy, and cholera. The extract of the seed is taken orally as an seed oil is administered per rectum to reduce emmenagogueCS010. The powdered seed is cramps associated with lead poisoning asso- taken orally as an aid in conception. One ciated with constipation and vomiting. To gram of seeds is powdered, then mixed with reduce breast engorgement or reduce milk water, and given to women in the morning secretion, the seed oil is applied topically. before breakfast for 7 days after menstrua- In some cases, it would completely stop milk tion. The use of pepper and cane sugar is secretion. One to 2 g of seed oil is taken avoided. Paste of dried leaves is applied over orally several times a day for urinary the anus in the morning and evening for incontinencyCS034. pilesCS099. The dried leaf juice is used exter- Jamaica. Hot water extract of the flower, nally on cuts and piles and taken orally as leaf, and twig is taken orally as an antispas- an anthelminticCS143. To eliminate cough, modic and anodyneCS238. Hot water extract bronchitis, and other respiratory ailments, a of the resin is taken orally for diabetesCS198. half tablespoonful of powdered dried leaves Mexico. The aerial parts are smoked as a is mixed with an equal amount of honey and hallucinogenCS117. taken orally three times dailyCS193. Seed oil Morocco. The aerial parts are taken orally is used externally for burns. The oil is as a narcoticCS111. extracted by roasting the seedsCS213. Seeds are Nepal. Decoction of the leaf is taken orally taken orally for diabetes, hysteria, and by adults as an anthelminticCS090. The pow- sleeplessnessCS127. The aerial parts are dered leaf is mixed with cattle feed as a smoked to decrease nausea and vomiting treatment for diarrheaCS105. For headache, induced by anticancer drugsCS061. Hot water the dried leaves are ground with Datura extract of the aerial parts is taken orally by stramonium leaves and Picrorhiza schrophu- males as an aphrodisiacCS123. The dried aerial lariflora stem and water then applied parts are smoked by women to increase their externallyCS222. The leaf juice is used exter- amorous prowessCS181. The fresh leaves are nally as an antiseptic, as a hemostat on cuts taken orally for hemorrhoidsCS108. Hot water and wounds, and to treat swelling of extract of the dried leaf and seed is taken sprained jointsCS110. The seeds are crushed, orally for stomach troubles and indiges- mixed with curd, and taken orally for tionCS217. Fresh leaf juice is administered dysenteryCS090. Decoction of the seed is taken intraural to treat earacheCS143. The fruit is orally as an anthelminticCS104. To aid in par- used externally for skin diseasesCS227. The turition, 2 teaspoonfuls of powdered seeds 32 MEDICINAL PLANTS OF THE WORLD are made into a paste with sesame oil Apigenin glycoside: PlCS172 (Sesamum indicum L.) and applied intra- Apigenin-7-O-para-coumaroyl-glucoside: PlCS172 CS172 vaginally during laborCS100. Arabinic acid: Pl Arabinose: PlCS172 Hot water extract of the entire Pakistan. Arabitol: PlCS172 CS002 plant is taken orally as a parturifacient . Arachidic acid: PlCS172, SdCS134 Infusion of the leaf is taken orally for gen- Arginine: PlCS172 Aromadendrene, allo: PlCS172 eral weaknessCS113. Aspartic acid: PlCS172 Saudi Arabia. The aerial parts, mixed with Azelaic acid: PlCS172 honey, sugar, and nutmeg, are taken orally Behenic acid: PlCS172 CS156 CS172 as a psychotropicCS248. Benzaldehyde, para-ethyl: EO , Pl Benzene, 1-methyl-4-iso-propenyl: PlCS068, Senegal. The seed is taken orally as an CS172 CS011 emmenagogue . Benzo-(A)-anthracene: Lf Smoke 3.3 µg/100 South Africa. Hot water extract of the CigCS088 entire plant is taken orally for asthmaCS107. Benzo-(A)-pyrene: Lf Smoke 4.2 µg/100 Hot water extracts of the root and seed are CigCS088 taken orally to induce abortion, labor, and Benzo-(F)-fluoranthene: Lf Smoke 3 µg/100 CS088 menstruationCS234, CS219. Cig Benzo-(G-H-I-)-perylene: Lf Smoke 0.7 µg/ United States. Fluidextract of the inflores- 100 CigCS088 cence is taken orally as a narcotic, antispas- Benzo-(K)-fluoranthene: Lf Smoke 1.1 µg/100 CS015 modic, analgesic, and aphrodisiac . Hot CigCS088 water extract of the flowering top is taken Benzoic acid, 4-hydroxy methyl ester: PlCS033 orally as a potent antispasmodic, anodyne, Benzoic acid, 4-hydroxy-N-propyl ester: and narcotic. One teaspoon of plant mate- PlCS033 CS172 rial is steeped in 2 cups of boiling water, and Benzoic acid, 4-hydroxy: Pl Benzoxocin-5-methanol, 2-(H)-1, 3-4-5-6- 1 tablespoonful is taken two to four times a α CS247 tetrahydro, 7-hydroxy- -2-trimethyl-9-N- day . The dried aerial parts are smoked by propyl-2-6-methano: PlCS172 CS166 both sexes as an aphrodisiac . Benzyl acetate, para-ethyl: EOCS156, PlCS172 Vietnam. The seeds are taken orally as an Benzyl acetate: EOCS156,CS172 emmenagogueCS013. Bergamotene, α, trans: Lf EOCS062, ResinCS069, West Indies. Hot water extract of the entire InflorescenceCS036, PlCS172 α CS196 plant is taken orally as an antispasmodicCS161. Bergamotene, : Lf EO Betaine, iso-leucine, L-(+): PlCS172 Yugoslavia. Hot water extract of the seed is CS202 CS169 Bibenzyl, 3-4-5-trihydroxy: Resin 596.5 taken orally for diabetes . Bibenzyl, 3-4-dihydroxy-5-5-dimethoxy-3-(3- Zimbabwe. Hot water extract of the aerial methyl-but-2-enyl): AerCS155 parts is taken orally as a treatment for Bibenzyl, 3-4-dihydroxy-5-methoxy: AerCS155, malariaCS238. Lf 2CS157 Bibenzyl,3-3-dihydroxy-4-5-dimethoxy: CHEMICAL CONSTITUENTS Lf 5CS157, AerCS155 (ppm unless otherwise indicated) Bisabolene: PlCS068 Acetaldehyde: PlCS172 Bisabolol, α: PlCS172, Fl EOCS196 Acetone: PlCS172 Borneol acetate: PlCS172, EOCS156 Actinidiolide, dihydro: EOCS156, PlCS172 Borneol, (–): PlCS068 Alanine: PlCS172 Borneol: ResinCS069, EOCS156 Aldotetronic acid, 2-C-methyl: PlCS172 Bornesitol, D, (+): PlCS172 Aldotetronolactone, 2-C-methyl: PlCS172 Butylamine, iso: PlCS172 Anethole, cis: EOCS156, PlCS172 Butylamine, N: PlCS172 Anethole, trans: EOCS156, PlCS172 Butylamine, sec: PlCS172 CANNABIS SATIVA 33

Butyraldehyde, iso: PlCS172 , C-3: ResinCS132 Cadaverine: PlCS172 Cannabielsoin: PlCS172 Cadinene, ∆: PlCS172, EOCS156 Cannabifuran, dehydro: ResinCS239, PlCS172 Cadinene, γ: PlCS172, EOCS156 Cannabifuran: PlCS172, ResinCS239 Calamenene: PlCS172, Lf EOCS062 monomethyl ether: PlCS172 Campest-4-en-3-one: PlCS172 Cannabigerol: ResinCS084, PlCS044 Campest-5-en-3-β-ol-7-one: PlCS172 monoethyl ether: Campestanol: SdCS076 Lf 20CS004, PlCS172 Campesterol: SdCS076, Call TissCS083, RtCS050 Cannabigerolic acid: Lf 40CS032, PlCS172, Camphene hydrate: EOCS156, PlCS172 InflorescenceCS218 Camphene: Inflorescence EOCS036, Lf EOCS062, Cannabigerovarin: PlCS172 ResinCS069 Cannabigerovarinic acid: PlCS172 Camphor: Lf EOCS062, PlCS172 Cannabinerolic acid: Lf 7.6CS032 Canabispiran: Lf CS091 : ResinCS020 Cannabamine B: Lf CS070 Cannabinodivarin: PlCS172 Cannabamine C: Lf CS070 methyl ether: ResinCS018 Cannabamine D: Lf CS070 Cannabinol monomethyl ether: PlCS172 Cannabamine: Lf CS070 Cannabinol, ∆-6(A)-10(A)-tetrahydro, Cannabicclovarin: PlCS172 10-oxo: ResinCS239, PlCS172 Cannabichromanone, C-3: ResinCS132 Cannabinol, ∆-6(A)-10(A)-tetrahydro, Cannabichromanone: Resin 59CS150 8-9-dihydroxy (DL): AerCS158 , propyl: ResinCS137 Cannabinol, ∆-6(A)-10(A)-tetrahydro, Cannabichromene: RtCS145, ResinCS009, 9-10-dihydroxy (DL): AerCS158 AerCS049,CS206 Cannabinol, ∆-6(A)-10(A)-tetrahydro, Cannabichromenic acid: InflorescenceCS218, 9-hydroxy-10-ethoxy: AerCS118 ResinCS055, Lf CS073 Cannabinol, ∆-6(A)-10(A)-tetrahydro, Cannabichromevarin: PlCS172 cis: PlCS172 Cannabichromevarinic acid: PlCS172 Cannabinol, ∆-8-tetrahydro, trans (–): Cannabicitran: PlCS172 AerCS064 Cannabicoumaronic acid: Resin 84CS150 Cannabinol, ∆-8-tetrahydro, trans: PlCS172 Cannabicoumaronone: PlCS172 Cannabinol, ∆-8-tetrahydro: PlCS038, : AerCS064, Lf CS057, FlCS074, ResinCS055, RtCS145, InflorescenceCS218 ResinCS043 Cannabinol, ∆-9-tetrahydro, 6(A)-7-10(A)- Cannabicyclolic acid: InflorescenceCS218 trihydroxy: PlCS172 Cannabidihydrophenanthrene: Lf 20CS001 Cannabinol, ∆-9-tetrahydro, cis: Lf 2CS114, monomethyl ether: PlCS172 Lf/FlCS074 Cannabidiol, C-4: PlCS172 Cannabinol, ∆-9-tetrahydro, methyl ether: Cannabidiol, propyl: ResinCS137 ResinCS137 Cannabidiol: LfCS040, AerCS039, ResinCS045, Cannabinol, ∆-9-tetrahydro, propyl: InflorescenceCS052 ResinCS137 Cannabidiolic acid: PlCS172 Cannabinol, ∆-9-tetrahydro, trans (–): PlCS172 Cannabidiolic acid-tetrahydro-cannabitriol Cannabinol, ∆-9-tetrahydro, trans: Fl/LfCS074, ester: PlCS172 PlCS172, ResinCS137 Cannabidiorcol: PlCS172 Cannabinol, ∆-9-tetrahydro: PlCS041, : PlCS172 ResinCS048, BkCS046, Sd 16.5CS126, Call Tiss Cannabidivarol: PlCS146,CS172 65CS188, Fr 0.5653%CS089, Fl tops 4%CS136, Cannabidivarolic acid: PlCS146 LfCS060, RtCS145 Cannabielsoic acid A: PlCS172, ResinCS056 Cannabinol, ∆-9-tetrahydroxylic acid: Cannabielsoic acid B, C-3: PlCS172, ResinCS132 ResinCS019 Cannabielsoic acid B: PlCS172, ResinCS056 Cannabinol, hexahydro: AerCS064 Cannabielsoic acid, C-3: PlCS172 Cannabinol, propyl: ResinCS137 Cannabielsoin I, dehydro: ResinCS239 Cannabinol, tetrahydro, iso, propyl: ResinCS137 34 MEDICINAL PLANTS OF THE WORLD

Cannabinol, tetrahydro, iso: ResinCS137 Cannabisperenone, iso: PlCS172 Cannabinol, tetrahydro: PlCS133 Cannabispiradienone: Lf 5–6CS185, CS001 Cannabinol: ResinCS009, Sd 8CS148, Cannabispiran, dehydro: Lf 2.3CS091, CS209 Fr 0.1275%CS089, PlCS038 Cannabispiran, iso: LfCS180 Cannabinol-C-4, ∆-9-tetrahydro, trans: Cannabispiran: Lf 20–245.7CS080, CS209 PlCS172 Cannabispiranol, α: Lf 0.3CS185 Cannabinol-C-4: PlCS172 Cannabispiranol, β: Lf 8–80CS209, CS091 Cannabinolic acid A, ∆-9-tetrahydro, trans Cannabispiranol: Lf 18CS157 (–): AerCS064 Cannabispirenone A, (–): Lf 30CS185 Cannabinolic acid A, ∆-9-tetrahydro, trans: Cannabispirenone A, (DL): Lf 30CS185 PlCS172 Cannabispirenone B: Lf CS185 Cannabinolic acid A, ∆-9-tetrahydro: LfCS004 Cannabispirenone: Lf 210CS185 Cannabinolic acid B, ∆-9- tetrahydro, trans Cannabispirenone: Lf 61CS157, Aer 10CS124 (–): AerCS064 Cannabispirol, acetyl: PlCS172 Cannabinolic acid B, ∆-9-tetrahydro, trans: Cannabispirone: Aer 30CS124, PlCS172, PlCS172 Lf 40CS157 Cannabinolic acid B, ∆-9-tetrahydro: Cannabistilbene I: Lf 0.4CS204 ResinCS055 Cannabistilbene II: LfCS204 Cannabinolic acid, ∆-1-tetrahydro: Cannabitetrol: PlCS205 Lf 1.4333%CS032 Cannabithrene I: Lf 4CS185 Cannabinolic acid, ∆-8-tetrahydro, trans: Cannabithrene II: Lf 8CS185 PlCS172 Cannabitriol, (+): AerCS118, PlCS172 Cannabinolic acid, ∆-8-tetrahydro: Cannabitriol, (+): PlCS172 InflorescenceCS218 Cannabitriol, (DL): Lf 2.7CS203 Cannabinolic acid, ∆-9-tetrahydro: Cannabitriol, trans (DL): LfCS194 InflorescenceCS218, LfCS151,CS179 Cannabitriol: Aer 250CS079 Cannabinolic acid, tetrahydro: LfCS179, PlCS041, Cannabivarichromene: ResinCS017 PollenCS067 , ∆-9-tetrahydro, trans (–): Cannabinolic acid: LfCS004, ResinCS055, PlCS172, AerCS064 InflorescenceCS218, PlCS172 Cannabivarin, ∆-9-tetrahydro, trans: PlCS172 Cannabinolic acid-C-4, ∆-9-tetrahydro, trans: Cannabivarin, tetrahydro: Fl/LfCS074 PlCS172 Cannabivarin: PlCS172 Cannabiol, ∆-6(A)-10(A)-tetrahydro, 9-10- Cannabivarinic acid, ∆-9-tetrahydro, trans (–): dihydroxy (DL): PlCS172 AerCS064 Cannabiorcol, ∆-9-tetrahydro, trans: PlCS172 Cannabivarinic acid, ∆-9-tetrahydro, trans: Cannabiorcol: PlCS172 PlCS172 Cannabiorcolic acid, ∆-9-tetrahydro, trans: Cannabivarol, ∆-9-tetrahydro: PlCS146 PlCS172 Cannabivarol, tetrahydro: PlCS041 Cannabipinol: PlCS172 Cannabivarol: Fl topsCS211 Cannabiprene: Lf 26.8CS091 Cannabivarolic acid, tetrahydro: PlCS041 Cannabiripsol: PlCS172, AerCS165 Cannflavin A: Aer 190CS028 Cannabisativine, anhydro: PlCS172 Cannflavin B: Aer 30CS028 Cannabisativine: Rt 2CS085 Cannflavin: Lf 138.5CS027 Cannabiscoumaranone: Resin 140CS150 Cannflavone 2: AerCS226 Cannabisin A: Fr 74CS029 Canniflavone 1: Lf 0.8CS185 Cannabisin B: Fr 812CS030 Canniflavone 2: 6CS185 Cannabisin C: Fr 0.267%CS030 Canniprene: Lf 27-1490CS209, CS182, PlCS172 Cannabisin D: Fr 59.8CS030 Car-3-ene: InflorescenceCS036, EOCS156, PlCS172 Cannabisin E: Fr 120CS031 Car-4-ene: PlCS172, CS068 Cannabisin F: Fr 45CS031 Carbazole: Lf (smoke)CS054 Cannabisin G: Fr 20CS031 Carvacrol: Lf EOCS062, PlCS172 Cannabisiradienone: PlCS172 Carveol acetate, dihydro: PlCS172, EOCS156 CANNABIS SATIVA 35

Carvone, dihydro: RtCS122, EOCS156, PlCS172 Docosane, N: PlCS172 Carvone: RtCS122, EOCS156, PlCS172 Dodecan-1-al: EOCS156, PlCS172 alcohol, α: EOCS156, PlCS068 Dodecan-2-one: PlCS172, EOCS156 Caryophyllene epoxide, β: Lf EO, Fl EOCS196 Dodecane, N: PlCS172 Caryophyllene epoxide: Lf EOCS062 Dotriacontane, 2-methyl: PlCS172 Caryophyllene oxide: Fl topsCS211, Lf EOCS053, Dotriacontane, N: PlCS172 PlCS172 Edestin: PlCS172 Caryophyllene, α: PlCS172, CS068 Edestinase: PlCS172 Caryophyllene, β: PlCS172, ResinCS069, Fl Eicosadienoic acid: PlCS172 EOCS196, InflorescenceCS036 Eicosane, N: PlCS172 Caryophyllene, iso: PlCS172, Inflorescence Eicosenoic acid: PlCS172 EOCS036 Elemene,γ: EOCS156, Fl EO, Lf EOCS196, PlCS172 Caryophyllene: Lf EOCS062 Ereptase (peptidase): PlCS172 Caryophyllenol: PlCS172 Ergostan-3-one, 5-α: Call TissCS083 Castasterone: SdCS071 Ergosterol: PlCS172 Cedrene, α: PlCS172, EOCS156 Erythritol: PlCS172, Cellulose, hemi: PlCS172 Essential oil: Aer 0.09–0.11%CS156, Cholest-4-en-3-one, 24-methyl: SdCS077 Lf 0.15%CS062, InflorescenceCS036 Cholestan-3-one, 5-α, 24-methyl: SdCS077 Ethanol: PlCS172 Cholesterol: SdCS076 Ethanolamine: PlCS172 Choline: Rt, Fl topsCS070, LfCS177, PlCS172 Ethylamine, (DL): PlCS172 Chrysene: Lf (smoke) 5 µg/100 CigCS088 Ethylamine: PlCS172 Cineol, 1-4: PlCS172, Lf EOCS062 Eudesmol,γ: EOCS156, PlCS172 Cineol, 1-8: Lf EOCS062, PlCS172 Eugenol methyl ether: EOCS156, PlCS172 Cinnamic acid, trans: LfCS006, PlCS172 Eugenol, iso: EOCS156, PLCS172 Cinnamide, N-(para-hydroxy-β-phenylethyl)- Eugenol: EOCS156, PlCS172 para-hydroxy-(trans): PlCS172 Farnesene, α trans, trans: EOCS156, PlCS172 Citric acid, iso: PlCS172 Farnesene, α: Fl EO, Lf EOCS196 Citric acid: PlCS172 Farnesene, β, cis: PlCS172 Citronellol: EOCS156, PlCS172 Farnesene, β, trans: Fl EOCS196, Lf EOCS062, CS196 Copaene, α: Lf EOCS062, PlCS172 Farnesene, β: ResinCS069, Inflorescence Cosmosioside: PlCS172 EOCS036, EOCS156, PlCS172 Coumaric acid, para: PlCS172 Farnesene: PlCS172 Cubebene, α: PlCS172, EOCS156 Farnesol: PlCS172, EOCS156 Curcumene, α: PlCS172, Lf EOCS062 Farnesyl-acetone: EOCS156, PlCS172 Curcumene, β: PlCS172,CS068 Fatty acids: SdCS059 Curcumene: EOCS156 Fenchol: Lf EOCS062, PlCS068 Cyclocitral, β: PlCS172, EOCS156 Fenchone: EOCS156, PlCS172 Cyclohex-5-enone, 2-2-6-trimethyl: PlCS172, Fenchyl alcohol: ResinCS069, EOCS156, PlCS172 EOCS156 Ferulic acid: PlCS172 Cyclohexanone, 2-2-6-trimethyl: EOCS156, Flavocannabiside: AerCS121 PlCS172 Flavone, 4-5-7-trihydroxy-3-methoxy-6- Cyclolanost-24-methylene-3-β-acetate: PlCS033 geranyl: Lf 6CS182 Cymen-8-ol, para: EOCS156, PlCS172 Flavosativaside: AerCS121 Cymene, para: PlCS172, CS068, EOCS156, Friedelanol, epi: PlCS172, CS068 InflorescenceCS036 Friedelin: PlCS172, CS033, CS068, RtCS122 Cystine: PlCS172 Friedelinol, epi: PlCS172, RtCS122 Dec-3-en-5-one: EOCS156, PlCS172 Fructose: PlCS172 Decan-1-al: PlCS172, EOCS156 Furfural, 5-methyl: EOCS156 Decan-2-one: EOCS156, PlCS172 Furo-(1,2,A)-4-N-pentyl-7-7-10-trimethyl- Decane, N: PlCS172 dibenzopyran, 2-methyl: Lf (smoke)CS195 Dibenz-(A-1)-anthracene: Lf (smoke) 0.3 µg/ Furo-(1,2,A)-4-N-pentyl-7-7-10-trimethyl- CigCS088 dibenzopyranyl: Lf (smoke)CS195 36 MEDICINAL PLANTS OF THE WORLD

Furo-(1,2-A)-4-N-pentyl-7-7-10-trimethyl- Hexyl acetate: EOCS156 dibenzopyran, 2-3-dimethyl: Hexyl iso-butyrate: EOCS156 Lf (smoke)CS195 Histamine: PlCS172 Galactitol: PlCS172 Histidine: PlCS172 Galactosamine: PlCS172, Lf/St 1.9%CS081 Hordenine: LfCS051, PlCS172 Galactose: PlCS172 Humulene oxide I: PlCS172 Galacturonic acid: PlCS172 Humulene oxide II: PlCS172 Geraniol: Lf EOCS062, PlCS172 Humulene oxide: EOCS156 Geranyl acetone: PlCS172, EOCS156 Humulene, α: Lf EO, Fl EOCS196 Glucaric acid: PlCS172 Humulene, β: PlCS172, Inflorescence EOCS036, Gluconic acid: PlCS172 EOCS156 Glucosamine: PlCS172 Humulene: Lf EOCS062, ResinCS069 Glucose, α (D): PlCS172 Indan-1-spiro-cyclohexane, 5-7-dihydroxy: Glucose, β(D): PlCS172 ResinCS026 Glutamic acid: PlCS172 Indan-1-spiro-cyclohexane, 5-hydroxy-7- Glyceric acid: PlCS172 methoxy: ResinCS026 Glycerol, (D), D-manno-octulose: PlCS172 Indan-1-spiro-cyclohexane, 7-hydroxy-5- Glycerol: PlCS172 methoxy: ResinCS026 Glycine: PlCS172 Indole: Lf (smoke)CS054 Glycoprotein (Cannabis sativa): Lf CS119 Inositol, (+): PlCS172 Grossamide: Fr 8CS029 Inositol, myo: PlCS172, Fl/LfCS082 Guaiol: PlCS172 Ionone, β: EOCS172, PlCS172 Gurjunene,α: Fl EOCS196, ResinCS069, PlCS172 : AerCS241 Heneicosane, 3-methyl: PlCS172 Ledol: PlCS172, EOCS156 Heneicosane, N: PlCS172 Leucine, iso: PlCS172 Hentriacontane, 2-methyl: PlCS172 Leucine: PlCS172 Hentriacontane, 3-methyl: PlCS172 Lignanamide I: FrCS093 Hentriacontane, N: PlCS172 Limonene: PlCS172, Fl EOCS196, ResinCS069, Hept-2-3n-6-one, 2-methyl: PlCS172 Inflorescence EOCS036 Hept-5-en-2-one, 6-methyl: EOCS156 Linalool, cis, oxide: EOCS156, PlCS172 Heptacosane, 3-methyl: PlCS172 Linalool, trans, oxide: PlCS172 Heptacosane, N: AerCS063, PlCS172 Linalool: PlCS172, ResinCS069, Lf EOCS062 Heptadecane, 3-6-dimethyl: PlCS172 Linoleic acid methyl ester: PlCS172 Heptadecane, 3-7-dimethyl: PlCS172 Linoleic acid: PlCS172, SdCS134 Heptadecane, N: PlCS172 Linolenic acid methyl ester: EOCS156 Heptan-1-al: PlCS172, EOCS156 Linolenic acid: PlCS172, SdCS134 Heptan-2-one: EOCS156, PlCS172 Longifolene, (+): PlCS068 Heptatriacontane, N: PlCS172 Longifolene: PlCS172, EOCS156, Inflorescence Heptulose, sedo: PlCS172 EOCS036 Hexacosane, 2-methyl: PlCS172 Lysine: PlCS172 Hexacosane, N: PlCS172 Malic acid: PlCS172 Hexadecanamide: ResinCS116 Malonic acid: PlCS172 Hexadecane, N: PlCS172 Maltose: PlCS172 Hexadecane-1-ol: PlCS172, EOCS156 Mannitol: PlCS172 Hexan-1-al: EOCS156, PlCS172 Mannose: PlCS172 Hexan-1-ol acetate: PlCS172 Mentha-1-8(9)-dien-5-ol, meta: PlCS172 Hexan-1-ol butyrate: PlCS172 Methanol: PlCS172 Hexan-1-ol caproate: PlCS172 Methionine: PlCS172 Hexan-1-ol iso-butyrate: PlCS172 Methyl acetate: PlCS172 Hexatriacontane, N: PlCS172 Methylamine, di: PlCS172 Hex-cis-3-en-1-ol caproate: EOCS156 Methylamine: PlCS172 Hex-cis-3-enol caproate: PlCS172 Muscarine: PlCS172 CANNABIS SATIVA 37

Myrcene: Fl EOCS196, ResinCS069, Inflorescence Perillene: EOCS156, PlCS172 EOCS036, PlCS068 Peroxidase: PlCS172 Myristic acid: PlCS172, EOCS156 Perylene: Lf (smoke) 0.9 µg/CigCS088 Nerol: EOCS062, PlCS172 Phellandrene, α: Inflorescence EOCS036, PlCS172 Nerolidol: Lf EOCS062, PlCS172 Phellandrene, β: Lf EOCS062, PlCS172 Neurine: PlCS172, RtCS070 Phenethylamine, β: PlCS172 Nonacosane, N: AerCS063, PlCS172 Phenol, 2-6-di-tert-butyl-4-methyl: EOCS156 Nonadecane, N: PlCS172 Phenol, 3-[2-(3-hydroxy-4-methoxy-phenyl)- Nonan-1-al: PlCS172, EOCS156 ethyl]-5-methoxy: PlCS172 Nonan-1-ol: PlCS172, EOCS156 Phenol, 3-[2-(3-hydroxy-4-methoxy-phenyl)- Nonane, N: PlCS172 ethyl]-ethyl-5-methoxy: PlCS172 Nonatriacontane, N: PlCS172 Phenol, 3-[2-(3-iso-prenyl-4-hydroxy-5- Ocimene, β, cis: PlCS172, EOCS156 methoxy-phenyl)-ethyl]-5-methoxy: PlCS172 Ocimene, β, trans: Lf EOCS062, PlCS172, CS068 Phenol, 3-[2-(4-hydroxy-phenyl)-ethyl]-5- Ocimene, cis: Inflorescence EOCS036 methoxy: PlCS172 Ocimene, trans: Inflorescence EOCS036 Phenol, 4-vinyl: AerCS159 Oct-1-en-3-ol: PlCS172, EOCS156 Phenol, 5-methoxy-3-[2-(3-hydroxy-4- Octacosane, 2-methyl: PlCS172 methoxy-phenyl)-ethyl]: Lf 1.9CS209 Octacosane, 9-methyl: PlCS172 Phenylalanine: PlCS172 Octacosane, N: PlCS172 Phloriglucinol, β-D-glucoside: StCS102 Octadecane, 3-6-dimethyl: PlCS172 Phosphatase, adenosine-5: PlCS172 Octadecane, 3-7-dimethyl: PlCS172 Phosphoric acid: PlCS172 Octadecane, N: PlCS172 Phthalate, N-butyl: EOCS156 Octan-1-al: EOCS156, PlCS172 Phthalate, N-propyl: EOCS156 Octan-1-ol caproate: PlCS172 Phytol: EOCS156, PlCS172 Octan-1-ol: EOCS156, PlCS172 Pinene, α, oxide: EOCS172, PlCS172 Octan-3-ol: EOCS156, PlCS172 Pinene, α: ResinCS069, Inflorescence EOCS036, Octan-3-one: EOCS156, PlCS172 Lf EOCS062, PlCS172 Octatriacontane, N: PlCS172 Pinene,β: Lf EOCS062, ResinCS069, Inflorescence Octyl caproate: EOCS156 EOCS036, PlCS172 Oleic acid methyl ester: Call TissCS083 Pinocarveol: EOCS156, PlCS172 Oleic acid: PlCS172, SdCS134 Pinocarvone: EOCS156, PlCS172 Olivetol: AerCS226 Piperidine: Fl top, LfCS070, PlCS172 Orientin: AerCS121, PlCS172 Piperitenone oxide: EOCS156, PlCS172 Orientin-2-O-β-D-glucoside: PlCS172, Piperitenone: ResinCS069, EOCS156, PlCS172 Aer 4.2CS131 Piperitone oxide: EOCS156, PlCS172 Orientin-7-O-α-L-rhamnosyl glucoside: PlCS172 Proline, L: RtCS070 Orientin-7-O-β-D-glucoside: PlCS172 Proline: PlCS172 Oxidase, polyphenol: PlCS172 Prop-1-ene, 3-phenyl-2-methyl: PlCS172, Palmitic acid methyl ester: Call TissCS083, EOCS156 EOCS156, PlCS172 Prospylamine, N: PlCS172 Palmitic acid: SdCS134, PlCS172 Pulegone: EOCS156, PlCS172 Palmitoleic acid: PlCS172 Pyrano-(3-4-B)-benzofuran, 1-4 5-hydroxy-7- Pectin: PlCS172 pentyl-1-(A)-α-3-3-trimethyl-ethano-1- Pentacosane, 3-methyl: PlCS172 (H): AerCS115 Pentacosane, N: PlCS172 Pyrene: Lf (smoke) 6.6 µg/CigCS088 Pentadecan-2-one, 6-10-14-trimethyl: PlCS172, Pyroglutamic acid: PlCS172 EOCS156 Pyrrolidine: PlCS172 Pentadecan-2-one: EOCS156, PlCS172 Quebrachitol, (+): PlCS172 Pentadecane, N: PlCS172 Querachitol: Fl/LfCS082 Pentan-1-al: EOCS156, PlCS172 Quercetin: AerCS241 Pentatriacontane, N: PlCS172 Raffinose: PlCS172 38 MEDICINAL PLANTS OF THE WORLD

Rhamnose: PlCS172 Terpineol, α: PlCS172, ResinCS069, Lf EOCS062, Ribitol: PlCS172 EOCS068 Ribose: PlCS172 Terpineol, β: EOCS156, PlCS172 Sabinene, trans: PlCS172, EOCS156 Terpinolene: Fl EOCS062, Lf EOCS062, Inflores- Sabinene: EOCS156, PlCS172 cence EOCS036, PlCS172 Safranal: EOCS156, PlCS172 Tetracosane, 2-methyl: PlCS172 Salicyclic acid methyl ester: EOCS156, PlCS172 Tetracosane, N: PlCS172 Santalene, β, epi: PlCS172, EOCS156 Tetradecane, 2-6-dimethyl: PlCS172 Sativic acid: PlCS172 Tetradecane, N: PlCS172 Scyllitol: Fl/LfCS082 Tetratriacontane, N: PlCS172 Selina-3-7(11)-diene: PlCS172, Inflorescence Threonic acid: PlCS172 EOCS036 Threonine: PlCS172 Selina-4(14)-7(11)-diene: Inflorescence Thujene, α: PlCS172, CS068, EOCS156 EOCS036, PlCS172 Thujol alcohol: PlCS172, EOCS156 Selinene,α: PlCS172, Inflorescence EOCS036, Triacontane, 3-methyl: PlCS172 EOCS156 Triacontane, N: PlCS172 Selinene,β: Inflorescence EOCS036, PlCS172, Tricosane, 3-methyl: PlCS172 EOCS156 Tricosane, N: PlCS172 Serine: PlCS172 Tridecan-1-al: EOCS156, PlCS172 Sitostanol: SdCS076 Tridecane, 3-6-dimethyl: PlCS172 Sitosterol, β: RtCS122, SdCS076, Call TissCS083, Tridecane, N: PlCS172 PlCS172 Trigonelline: PlCS172, FL topCS070 Skatole: Lf (smoke)CS054 Tritriacontane, N: PlCS172 Sorbitol: PlCS172 Tryptophan: PlCS172 Spiro-(cyclohexane-1-3-(4-6-dihydroxy)- Tyramine, feruloyl: Sd 2.5, Rt, Resin, indan): Fl topCS135 LfCS149,CS230 Spiro-(cyclohexane-1-3-(4-hydroxy-6- Tyramine, N-(para-coumaroyl): Fr 111CS029, methoxy)-indan): Fl topCS135 Sd 111CS092 Spiro-(cyclohexane-1-3-(6-hydroxy-4- Tyramine, N-trans-caffeoyl: Fr 47.1CS029 methoxy)-indan): Fl topCS135 Tyramine, N-trans-feruloyl: Fr 78.5CS029 Stearic acid methyl ester: Call TissCS083 Tyramine, para-coumaroyl: Sd 0.5CS230, Rt, Lf, Stearic acid: PlCS172, SdCS134 ResinCS149,CS230 Stigmast-22-en-3-one, 5-α: Call TissCS083 Tyramine: PlCS172 Stigmast-4-en, 3-one: PlCS172, RtCS050 Tyrosine: PlCS172 Stigmast-5-en-3-β-ol-7-one: RtCS050, PlCS172 Undecan-1-al: EOCS156, PlCS172 Stigmasta-4-22-diene-3-one: RtCS050, PlCS172 Undecan-2-one, 6-10-dimethyl: EOCS156, Stigmasta-5-22-dien-3-β-ol-7-one: RtCS050 PlCS172 Stigmasta-7-24(28)-dien-3-β-ol, 5-α: PlCS172 Undecan-2-one: EOCS156, PlCS172 Stigmastan-3-one, 5-α: Call TissCS083 Undecane, N: PlCS172 Stigmasterol: SdCS076, PlCS172 Valine: PlCS172 Stilbene, dihydro 3'-5-dihydroxy-3-4- Vanillic acid: PlCS172 dimethoxy: LfCS185 Vitamin K: PlCS172 Stilbene, dihydro 4’-5-dihydroxy-3-methoxy: Vitexin, iso, 7-O-α-L-rhamnosyl-glucoside: LfCS185 PlCS172 Succinic acid: PlCS172 Vitexin, iso, 7-O-β-D-glucosyl-arabinoside: Sucrose: PlCS172 PlCS172 Terpinen-4-ol, α: PlCS172 Vitexin, iso: PlCS172 Terpinen-4-ol: Lf EOCS062, PlCS172 Vitexin-2-β-D-glucoside: PlCS172, Aer 4CS131 Terpinene, α: Lf EOCS062, PlCS172, Inflores- Vitexin-7-O-β-D-(6-glucoside): PlCS172 cence EOCS036 Vomifoliol, dihydroxylan: PlCS172 Terpinene, γ: PlCS172, ResinCS069, EOCS156, Vomifoliol: PlCS172 Inflorescence EOCS036 Xylitol: PlCS172 CANNABIS SATIVA 39

Xylose: PlCS172 ence of measurable levels of ∆-9-THC in the Zeatin nucleoside: PlCS172 blood of drivers in the absence of alcohol or CS172 Zeatin: Pl other drugs, by surveys of driving under the PHARMACOLOGICAL ACTIVITIES influence of cannabis, and by significantly AND CLINICAL TRIALS higher accident culpability risk of drivers Abortifacient activity. Alcohol extract of using cannabis. Evidence demonstrated that the dried leaf, administered intragastrically cannabis dependence, both behavioral and to pregnant rats at a dose of 125 mg/kg, pro- physical, occurred in about 7–10% of regu- duced teratogenic effectsCS233. Water extract lar users, and that early onset of use—espe- of the dried leaf, administered intragastri- cially of weekly or daily use—is a strong cally to pregnant rats at variable dosage lev- predictor of future dependence. Cognitive els on days 6–15 of pregnancy was activeCS228. impairments of various types are readily Acute cardiovascular fatalities. Six cases demonstrable during acute cannabis intoxi- of possible acute cardiovascular death in cation, but there is no suitable evidence yet young adults were reported where very available to permit a decision as to whether recent cannabis ingestion was documented long-lasting or permanent functional losses by the presence of ∆-9-tetrahydrocannab- can result from chronic heavy use in inol (∆-9-THC) in postmortem blood adultsCS265. The gender effects on progression samples. A broad toxicological blood analy- to treatment entry and on the frequency, sis could not reveal other drugsCS392. severity, and related complications of the Acute panic reaction (Koro). Koro, an Diagnostic and Statistical Manual of Mental acute panic reaction related to the percep- Disorders, 3rd edition revised drug and alco- tion of penile retraction, was once consid- hol dependence among 271 substance- ered limited to specific cultures. Over 70 dependent patients (mean age: 32.6 years; American men responded by telephone to 156 women) was studied. There was no gen- report negative reactions to cannabis. Three der difference among patients in the age at of them (Caucasians aged 22–26 years with onset of regular use of any substance. considerable experience with cannabis) Women experienced fewer years of regular spontaneously mentioned experiencing use of opioids and cannabis and fewer years symptoms of Koro after smoking cannabis. of regular alcohol drinking before entering All three cases occurred after the partici- treatment. Although the severity of drug pants had heard about cannabis-induced and alcohol dependence did not differ by Koro and used the drug in a novel setting or gender, women reported more severe psy- atypical way. Two of the men had body chiatric, medical, and employment com- dysmorphia, which may have contributed to plicationsCS285. In a 3-day, double-blind, symptoms. All three decreased their can- randomized, counterbalanced study, the nabis consumption after the Koro experi- behavioral, cognitive, and endocrine effects ence. Several factors may have interacted to of 2.5 and 5 mg intravenous ∆-9-THC were create the symptoms. These include previ- characterized in 22 healthy individuals, who ous knowledge of cannabis-induced Koro, had been exposed to cannabis but had never the use of cannabis in a way that might been diagnosed with a cannabis abuse disor- heighten a panic reaction, and poor body der. Prospective safety data at 1, 3, and 6 imageCS393. months post-study was also analyzed. ∆-9- Adverse effects. A causal role of acute can- THC produced schizophrenia-like positive nabis intoxication in motor vehicle and and negative symptoms, altered perception, other accidents has been shown by the pres- increased anxiety and plasma cortisol, 40 MEDICINAL PLANTS OF THE WORLD euphoria, disrupted immediate and delayed of CB1 receptor has been shown to block word recall, sparing recognition recall, voluntary alcohol intake in miceCS255. impaired performance on tests of distract- Allergenic effect. An “All India Coordi- ibility, verbal fluency, and working memory, nated Project on Aeroallergens and Human but did not impair orientationCS287. This Health” was undertaken to discover the study examined the behavioral and neuro- quantitative and qualitative prevalence of chemical ( CB1 receptor gene aerosols at 18 different centers in the coun- expression) changes induced by spontane- try. Predominant airborne pollens were ous cannabinoid withdrawal in mice. Ces- Holoptelea, Poaceae, Asteraceae, Eucalyp- sation of CP-55,940 treatment in tolerant tus, Casuarina, Putanjiva, Cassia, Quercus, mice induced a spontaneous time-depen- Cocos, Pinus, Cedrus, Ailanthus, Cheno/Ama- dent behavioral withdrawal syndrome ranth, Cyperus, Argemone, Xanthium, Parthen- consisting of marked increases (140%) in ium, and others. Clinical and immunological motor activity, number of rearings (170%), evaluations revealed some allergenically decreases in grooming (57%), wet-dog important taxa. Allergenically important shakes (73%), and rubbing behaviors (74%) pollens were Prosopis juliflora, Ricinus com- on day 1, progressively reaching values simi- munis, Morus, Mallotus, Alnus, Querecus, lar to vehicle-treated mice on day 3. This Cedrus, Argemone, Amaranthus, Chenopo- spontaneous cannabinoid withdrawal dium, Holoptelea, Brassica, Cocos, Cannabis, resulted in CB1 gene expression up-regula- Parthenium, Cassia, and grassesCS317. In the tion (20–30%) in caudate-putamen, ventro- multitest routine skin-test battery, 78 of 127 medial hypothalamic nucleus, central patients tested (61%) were cannabis-test amygdaloid nucleus, and CA1, whereas in positive. Thirty of the 78 patients were ran- the CA3 field of hippocampus, a significant domly selected to determine if they had decrease (15–20%) was detectedCS293. allergic rhinitis and/or asthma symptoms Alcohol interaction. The complementary during the cannabis pollination period. By DNA and genomic sequences encoding G history, 22 (73%) claimed respiratory symp- protein-coupled cannabinoid receptors toms in July through September. All 22 of (CB1 and CB2) from several species were these subjects were also skin test-positive to cloned. This has facilitated discoveries of weeds pollinating during the same period as endogenous ligands (endocannabinoids). cannabis (ragweed, pigweed, cocklebur, Two fatty acid derivatives characterized to Russian thistle, marsh elder, or kochia)CS411. be arachidonylethanolamide and 2-arachi- Alkaline phosphatase stimulation. Etha- donylglycerol isolated from both nervous nol (95%) extract of the dried resin, admin- and peripheral tissues mimicked the phar- istered intraperitoneally to toads at a dose macological and behavioral effects of ∆-9- of 10 mg/day for 14 days, was active. The THC. The down-regulation of CB1 receptor results were significant at p < 0.01 levelCS216. function and its signal transduction by Aminopyrene-N-demethylase induction. chronic alcohol was demonstrated. The ob- Ethanol (95%) extract of the dried aerial served down-regulation of CB1 receptor- parts, administered intraperitoneally to rats binding and its signal transduction resulted at a dose of 2 mg/kg for 15 days, was active. from the persistent stimulation of receptors A dose of 20 mg/kg for 7 days was also by the endogenous CB1 receptor agonists activeCS141. arachidonylethanolamide and 2-arachi- Amnesic syndrome. A 26-year-old woman donylglycerol, whose synthesis is increased suffered disseminated intravascular coagula- by chronic alcohol treatment. The deletion tion (DIC) and a brief respiratory arrest fol- CANNABIS SATIVA 41

lowing recreational use of 3,4-methylene- effective dose (ED)50 35.5 mg/kg and hot CS052 dioxymethamphetamine (MDMA, or “ec- plate method, ED50 53 mg/kg . Petroleum stasy”) together with amyl nitrate, lysergic ether and ethanol (95%) extracts of the acid (LSD), cannabis, and alcohol. She was dried aerial parts, administered intragastri- left with residual cognitive and physical cally to mice, was active vs phenylbenzo- deficits, particularly severe anterograde quinone-induced writhing, inhibitory memory disorder, mental slowness, severe concentration (IC)50 0.013 mg/kg and 0.045 ataxia, and dysarthria. Follow-up investiga- mg/kg, respectivelyCS140. tions have shown that these have persisted, Analgesic effect. (AJA, although there has been some improvement CT-3, or IP-751), administered to healthy in verbal recognition memory and in social human adults and patients with chronic functioning. Magnetic resonance imaging neuropathic pain, demonstrated a complete and quantified positron emission tomogra- absence of psychotropic actions. It proved phy investigations revealed severe cerebel- to be more effective than placebo in reduc- lar atrophy and hypometabolism accounting ing this type of pain as measured by the for the ataxia and dysarthria; thalamic, visual analog scale. Signs of dependency retrosplenial, and left medial temporal were not observed after withdrawal at the hypometabolism to which the anterograde end of the 1-week treatment periodCS274. amnesia can be attributed. There was some Forty women undergoing elective abdomi- degree of frontotemporal–parietal hypome- nal hysterectomy were investigated in a ran- tabolism, possibly accounting for the cogni- domized, double-blind, placebo-controlled, tive slowness. The putative relationship of single-dose trial. Randomization took place these abnormalities to the direct and indi- when postoperative patient-controlled rect effects of MDMA toxicity, hypoxia, and analgesia was discontinued on the second ischemia was consideredCS394. postoperative day. When patients requested Amyotrophic lateral sclerosis. One hun- further analgesia, they received a single, dred thirty one respondents with amyo- identical capsule of either 5 mg of oral ∆-9- trophic lateral sclerosis—13 of whom THC (n = 20) or placebo (n = 20) in a reported using cannabis in the last 12 double-blind fashion. The primary outcome months—were examined. The results indi- measure was summed pain intensity differ- cated that cannabis might be moderately ence (SPID) at 6 hours after administration effective at reducing symptoms of appetite of the study medication derived from visual loss, depression, pain, spasticity, and drool- analog pain scores on movement and at rest. ing. Cannabis was reported ineffective in Secondary outcome measures were time-to- reducing difficulties with speech and swal- rescue medication and adverse effects of lowing, and sexual dysfunction. The long- study medication. Mean (standard devia- est relief was reported for depression (approx tion [SD]) visual analog scale pain scores 2–3 hours)CS296. before medication in the placebo and ∆-9- Analgesic activity. Ethanol (50%) extract THC groups were 6.3(2.6) and 6.4(1.3) cm of the entire plant, administered intraperi- on movement, and 3.2(1.9) and 3.3(0.9) at toneally to mice at a dose of 250 mg/kg, was rest, respectively. There were no significant active vs tail pressure methodCS007. Flavonoid differences in mean (95% confidence inter- fraction of the leaf, administered intraperi- val [CI] of the difference) SPID at 6 hours toneally to mice, was activeCS242. The inflo- between the groups (placebo 7.9, ∆-9-THC rescence, administered orally to male rats, 4.3[–1.8 to 9] cm per hour on movement; produced weak activity vs paw pressure test, placebo 8.8, ∆-9-THC 4.9[–0.2 to 8.1] cm 42 MEDICINAL PLANTS OF THE WORLD per hour at rest) and time to rescue analge- were studied. Seventy-two (35%) subjects sia (placebo 217, ∆-9-THC 163[–22 to 130] reported ever having used cannabis. Thirty- minutes). Increased awareness of surround- two (15%) subjects reported having used ings was reported more frequently in pa- cannabis for pain relief (pain users), and 20 tients receiving ∆-9-THC (40 vs 5%, p = (10%) subjects were currently using can- 0.04). There were no other significant dif- nabis for pain relief. Thirty-eight subjects ferences with respect to adverse eventsCS326. denied using cannabis for pain relief (recre- THC, morphine, and a THC–morphine ational users). Compared with nonusers, combination were administered to 12 pain users were significantly younger (p = healthy subjects using experimental pain 0.001) and were more likely to be tobacco models (heat, cold, pressure, and single and users (p = 0.0001). The largest group of repeated transcutaneous electrical stimula- patients using cannabis had pain caused by tion). THC (20 mg), morphine (30 mg), trauma and/or surgery (51%), and the site THC–morphine (20 mg THC + 30 mg mor- of pain was predominantly neck/upper body phine), or placebo were given orally as and myofascial (68 and 65%, respectively). single dose. Reaction time, side effects (vi- The median duration of pain was similar in sual analog scales), and vital functions were both pain users and recreational users (8 vs monitored. For the pharmacokinetic profil- 7 years; p = 0.7). There was a wide range of ing, blood samples were collected. THC did amounts and frequency of cannabis use. Of not significantly reduce pain. In the cold the 32 subjects who used cannabis for pain, and heat tests, it even produced hyperalge- 17 (53%) used four puffs or less at each dos- sia, which was completely neutralized by ing interval, eight (25%) smoked a whole THC–morphine. A slight additive analge- cannabis cigarette (joint), and four (12%) sic effect was observed for THC–morphine smoked more than one joint. Seven (22%) in the electrical stimulation test. No anal- of these subjects used cannabis more than gesic effect resulted in the pressure and heat once daily, five (16%) used it daily, eight test, with neither THC nor THC–mor- (25%) used it weekly, and nine (28%) used phine. Psychotropic and somatic side effects it rarely. Pain, sleep, and mood were most (sleepiness, euphoria, anxiety, confusion, frequently reported as improving with can- nausea, dizziness, etc.) were common, but nabis use, and “high” and dry mouths were usually mildCS330. Three cannabis-based the most commonly reported side effectsCS351. extracts ∆-9-THC, cannabidiol [CBD], and Patients with chronic pain completed a a 1:1 mixture of them both) were given over questionnaire about the type of cannabis a 12-week period in a randomized, double- used, the mode of administration, the blind, placebo-controlled, crossover trial. amount used and the frequency of use, and Extracts, which contained THC, proved their perception of the effectiveness of most effective in symptom control. Regi- cannabis on a set of pain-associated symp- mens for the use of the sublingual spray toms and side effects. Fifteen patients (10 emerged and a wide range of dosing require- males) were interviewed (median age, 49.5 ments was observed. Side effects were com- years; range, 24–68 years). All patients mon, reflecting a learning curve for both smoked herbal cannabis for therapeutic patient and study team. These were gener- reasons (median duration of use, 6 years; ally acceptable and little different to those range, 2 weeks–37 years). Seven patients seen when other psychoactive agents are only smoked at night (median dose eight used for chronic painCS294. Over a 6-week puffs, range two to eight puffs), and eight period 209 chronic noncancer pain patients patients used cannabis mainly during the CANNABIS SATIVA 43 day (median dose of three puffs; range, two that a flare might last anywhere from a few to eight puffs); the median frequency of use days to a few weeks and relief from flare were was four times per day (range, 1 to 16 times/ by analgesic injections (including opiates), day). Twelve patients reported improve- relaxation, sleep, and cannabis (three indi- ment in pain and mood, whereas 11 viduals). Three-quarters of the groups reported improvement in sleep. Eight agreed that there was no long-term effect on patients reported a “high;” six denied a the ankylosing sponylitis following a “high.” Tolerance to cannabis was not flareCS378. reportedCS368. THC was administered to six Anti-anaphylactic activity. Water extract patients with chronic pain at doses 5–20 of the dried fruit, at a concentration of 1 µg/ mg/day. A sufficient pain relief had been mL, produced weak activity on the rat achieved in three patients. The other three Leuk-RBL 2H3 vs biotinyl immunoglobulin suffered from intolerable side effects, such E-avidin complex-induced degranulation as nausea, dizziness, and sedation without a of β-hexosaminidaseCS103. reduction of pain intensity. In these cases, Anti-androgenic effect. Ethanol (95%) the treatment was continued with other extract of the aerial parts, administered analgesicsCS391. intraperitoneally to castrated mice at a dose Anaphrodisiac effect. Tincture of the of 2 mg/animal, produced strong activityCS012. resin, administered intraperitoneally to The dried leaf, smoked by 13 male adults for male mice at a dose of 12.5 mg/kg, produced 21 days, was inactiveCS208. a significant reduction in mounts and Anti-arthritic effect. Oral administration attempted mounts. Other behaviorial of AJA, a cannabinoid acid devoid of activities were unaffectedCS153. psychoactivity, reduced joint tissue damage Angiotensin-converting enzyme inhibi- in rats with adjuvant arthritis. Peripheral tion. Ethanol (100%) extract of the dried blood monocytes (PBM) and synovial leaf at a concentration of 333.3 µg/mL pro- fluid monocytes (SFM) were isolated from duced weak activity, and the water extract healthy subjects and patients with inflam- was inactiveCS129. matory arthritis, respectively, treated with Ankylosing spondylitis. Ankylosing spon- AJA (0–30 mM) in vitro, and then stimu- dylitis is a systemic disorder occurring in lated with lipopolysaccharide. Cells were genetically predisposed individuals. The dis- harvested for messenger RNA (mRNA), ease course appears to be characterized by and supernatants were collected for bouts of partial remission and flares. There cytokine assay. Addition of AJA to PBM were 214 patients questioned (169 men, 45 and SFM in vitro reduced both steady-state women; average disease duration, 25 years; levels of interleukin-1γ (IL-1γ) mRNA and age of disease onset, 22 years). The main secretion of IL-1γ in a concentration-de- symptoms of flare were pain (all groups), pendent manner. Suppression was maximal immobility (90%), fatigue (80%), and emo- (50.4%) at 10 mM AJA (p < 0.05 vs un- tional symptoms, such as depression, with- treated controls, n = 7). AJA did not drawal, and anger, (75%). All of patients influence tumor necrosis factor-α (TNF-α) experienced between one and five localized gene expression in or secretion from flares per year. Fifty-five percent of the PBMCS358. groups contained patients (n = 85) who Antibacterial activity. Essential oil, on experienced a generalized flare. The main agar plate, was active on Staphylococcus perceived triggers of flare were stress (80%) aureus and Streptococcus faecalis, minimum and “overdoing it” (50%). Patients reported inhibitory concentration (MIC) 0.5 mg/mL, 44 MEDICINAL PLANTS OF THE WORLD and produced weak activity on Pseudomonas perazine, haloperidol, domperidone, or fluorescens and Escherichia coli, MIC 10 mg/ alizapride. Relative risk was 1.38 (95% CI mL and 5 mg/mL, respectivelyCS152. 1.18–1.62), number-needed-to-treat (NNT) Anticonvulsant activity. Ethanol (95%) was 6 for complete control of nausea; rela- extract of the entire plant, administered tive risk was 1.28 (CI 1.08–1.51), NNT 8 subcutaneously to male mice and rats at a for complete control of vomiting. Cannab- dose of 2–4 mL/kg, was active vs metrazole inoids were not more effective in patients and electroshock, respectively. A dose of 4 receiving very low or very high emetogenic mL/kg was inactive vs strychnine convul- chemotherapy. In crossover trials, patients sions in miceCS005. The entire plant, smoked preferred for future chemo- by 29 patients with epilepsy under the age therapy cycles: relative risk 2.39 (2.05– of 30 years, was active. It must be noted that 2.78), NNT 3. Some potentially beneficial in some species, cannabinoids can precipi- side effects occurred more often with can- tate epileptic seizuresCS120. Tincture of the nabinoids: “high” 10.6 (6.86–16.5), NNT 3; resin, administered intraperitoneally to sedation or drowsiness 1.66 (1.46–1.89), mice at a dose of 25 mg/kg, produced 80% NNT 5; euphoria 12.5 (3–52.1), NNT 7. protection vs pentylenetetrazole convul- Harmful side effects also occurred more of- sionsCS058. ten with cannabinoids: dizziness 2.97 (2.31– Antidiuretic activity. After ingesting the 3.83), NNT 3; dysphoria or depression 8.06 aerial parts, a 55-year-old man developed (3.38–19.2), NNT 8; hallucinations 6.10 urinary retention that required catheteriza- (2.41–15.4), NNT 17; paranoia 8.58 (6.38– tion for reliefCS154. 11.5), NNT 20; and arterial hypotension Anti-emetic activity. In a qualitative study 2.23 (1.75–2.83), NNT 7. Patients given of self-care in pregnancy, birth, and lacta- cannabinoids were more likely to withdraw tion within a nonrandom sample of 27 because of side effects (relative risk 4.67 women in British Columbia, Canada, 20 [3.07–7.09]; NNT 11)CS400. women (74%) experienced pregnancy- Anti-estrogenic effect. Ethanol (95%) induced nausea. Ten of these women used extract of the dried aerial parts, adminis- antiemetic herbal remedies, which included tered intragastric to rats at variable doses ginger, peppermint, and cannabis. Only gin- was inactiveCS231. Petroleum ether extract of ger has been subjected to clinical trials the dried leaf, administered intraperito- among pregnant women, although the three neally to female rats at a dose equivalent to herbs were clinically effective against nau- 10 mg/kg (THC) on sea and vomiting in other contexts, such as 11–21 days of age, was activeCS175. chemotherapy-induced nausea and post- Antifertility effect. Petroleum ether ex- operative nauseaCS311. CBD, a major non- tract of the entire plant, administered by psychoactive cannabinoid administered by gastric intubation to female mice at doses oral infusion to rats with nausea elicited by of 75 mg/kg and 150 mg/kg, was active. A lithium chloride, and with conditioned nau- dose of 3 mg/kg, produced weak activityCS170. sea elicited by a flavor paired with lithium Resin, administered by gastric intubation to chloride, was activeCS382. Oral , oral male mice at variable dosage levels, was (THC), and intramuscular inactiveCS189. were administered to 1366 Antifungal activity. Ethanol (50%) extract patients. Cannabinoids were more effec- of the dried leaf was active on Rhizoctonia tive antiemetics than prochlorperazine, solani, mycelial inhibition was 65.99%CS229. metoclopramide, chlorpromazine, thiethyl- Water extract of the fresh leaf on agar plate CANNABIS SATIVA 45 at a concentration of 1:1 was active on ity, production of oxygen-derived free radi- Fusarium oxysporumCS096. The water extract cals, and nitric oxide ([NO], nitrite/nitrate also produced strong activity on Ustilago content) after three doses of CBD. The maydis and Ustilago nudaCS212. Water extract effect on NO seemed to depend on a lower of the fresh shoot on agar plate was inactive expression of the endothelial isoform of NO on Helminthosporium turcicumCS237. synthaseCS303. Antiglaucomic activity. Water extract of Antimalarial activity. The dried leaf was the dried entire plant, administered intra- inactive on Plasmodium falciparum D-6 and CS095 venously to Rhesus monkeys and rabbits at W-2, IC50 greater than 1000 nmols . a dose of 0.01 µg/animal, was active. The Antimycobacterial activity. Essential oil, intraocular pressure rose for 24 hours on agar plate, was active on Antimyco- postinjection, then fell for 3 days. A dose of bacterium smegmatis, MIC 0.1 mg/mLCS152. 25 µg/animal, administered intravenously to Anti-nematodal activity. Water extract of rabbits, was also active. The effect was not the dried leaf at variable concentrations influenced by atropine, scopolamine, produced strong activity on Meloidogyne methysergide, haloperidol, chlorpromazine, incognitaCS200. spironolactone, yohimbine or dexametha- Antioxidant activity. Methanol extract of sone. Partial inhibition was seen when the stem, at concentration 50 µL, produced galactose, glucose or mannose were admin- strong activityCS101. istered intravenously, concurrentlyCS232. Antispasmodic activity. Ethanol (50%) Water extract of the dried leaf and stem, ap- extract of the entire plant was active on the plied opthalmically to rabbits was activeCS072. guinea pig ileum vs acetylcholine and hista- Antigonadotropin effect. Ethanol (80%) mine-induced spasmsCS007. The resin antago- extract of the dried aerial parts, adminis- nized serotonin contractions of the rat tered intragastrically to male langurs at a intestine and non-pregnant uterusCS003. dose of 14 mg/kg daily for 90 days produced Antispermatogenic effect. Sixteen healthy equivocal effectCS173. chronic marijuana smokers were associated Anti-inflammatory activity. Petroleum with a decline in sperm concentration and ether and ethanol (95%) extracts of the total sperm count during the fifth and sixth dried aerial parts, applied externally on mice weeks after 4 weeks of high-dose smoking at a dose of 100 µg/ear, was active vs tissue (8–20 cigarettes/day)CS164. The dried aerial plasminogen activator-induced erythema of part, taken by inhalation daily, decreases the earCS140. CBD was administered orally to the quantity as well as quality of sper- rats at doses of 5–40 mg/kg daily for 3 days matozoaCS181. Ethanol (80%) extract of the after the onset of acute inflammation in- dried aerial parts, administered intra- duced by intraplantar injection of 0.1 mL gastrically to langurs at a dose of 14 mg/kg carrageenan (1% w/v in saline). CBD had a daily for 90 days, was equivocalCS173. Ethanol time- and dose-dependent antihyperalgesic (95%) extract of the dried aerial parts, effect after a single injection. Edema follow- administered intraperitoneally to mice at a ing carrageenan peaked at 3 hours and lasted dose of 2 mg/animal daily for 45 days, pro- 72 hours. A single dose of CBD reduced duced a complete arrest of spermatogenesis. edema in a dose-dependent fashion and sub- The effect was reversibleCS244. sequent daily doses produced further time- Antistress activity. The leaf smoke, in and dose-related reductions. There were combination with hashish smoke, adminis- decreases in prostaglandin E2 (PGE2) tered to rats housed in a wire cage inside a plasma levels, tissue cyclo-oxygenase activ- larger cage with a cat, was equivocal. The 46 MEDICINAL PLANTS OF THE WORLD rats’ brains were dissected and measured Cannabinoids are usually well tolerated, and for protein and catecholamine levelsCS214. do not produce the generalized toxic effects Anti-tumor activity. Arachidonyl ethanol- of conventional chemotherapiesCS328. amide, in three cervical carcinoma (CxCa) Anti-ulcer activity. Petroleum ether extract cell lines at increasing doses with or with- of the dried aerial parts, administered intra- out antagonists to receptors to arachidonyl peritoneally to male rats, was activeCS097. ethanolamide, induced apoptosis of CxCa Antiviral activity. Hot water extract of the cell lines via aberrantly expressed vanilloid dried fruit, in vero cell culture at a concen- receptor-1. Arachidonyl ethanolamide- tration of 0.5 mg/mL, was inactive on her- binding to the classical CB1 and CB2 can- pes simplex 1 virus, measles virus, and nabinoid receptors mediated a protective poliovirus 1CS094. effect. A strong expression of the three Anxiolytic activity. AEA, a primary endo- forms of arachidonyl ethanolamide recep- genous ligand of the brain cannabinoid tors was observed in ex vivo CxCa biop- receptors, is released in selected regions of siesCS297. Three cannabis constituents, CBD, the brain and is deactivated through a two- ∆-8-THC, and cannabinol displayed anti- step process consisting of transport into cells proliferative activity in several human can- followed by intracellular hydrolysis. Phar- cer cell lines in vitro. They were oxidized to macological blockade of the enzyme fatty their respective paraquinones 2, 4, and 6. acid amide hydrolase (FAAH), which is Quinone 2 significantly reduced cancer responsible for intracellular AEA degrada- growth of HT-29 cancer in nude miceCS275. tion, produced anxiolytic-like effects in rats ∆-9-THC binds and activates membrane without causing the wide spectrum of receptors of the 7-transmembrane domain, behavioral responses typical of direct-acting G protein-coupled superfamily. Several cannabinoid agonists. These findings sug- putative endocannabinoids have been iden- gest that AEA contributes to the regulation tified, including (AEA), 2- of emotion and anxiety, and that FAAH arachidonyl glycerol, and noladin ether. might be the target for a novel class of Synthesis of numerous cannabinomimetics anxiolytic drugsCS323. has expanded the repertoire of cannabinoid Aphrodisiac activity. The leaf, smoked by receptor ligands with the pharmacodynamic adults of both sexes, was activeCS171. properties of agonists, antagonists, and Attention deficit hyperactivity disorder. inverse agonists. These ligands have proven Attention defict hyperactivity disorder has to be powerful tools both for the molecular been considered a mental and behavioral characterization of cannabinoid receptors disorder of childhood and adolescence. It is and the delineation of their intrinsic signal- being increasingly recognized in adults, who ing pathways. Much of the understanding of may have psychiatric comorbidity with sec- the signaling mechanisms activated by can- ondary depression, or a tendency to drug nabinoids has been derived from studies of and alcohol abuse. A 32-year-old woman receptors expressed by tumor cellsCS318. Can- known for years as suffering from borderline nabinoids and their derivatives exerted personality disorder and drug dependence palliative effects in cancer patients by pre- (including cannabis, LSD, and ecstasy) and venting nausea, vomiting, and pain and by alcohol abuse that did not respond to treat- stimulating appetite. These compounds ment was reported. Only when correctly have been shown to inhibit the growth of diagnosed as attention defict hyperactivity tumor cells in culture and animal models by disorder and appropriately treated with the modulating key cell-signaling pathways. psychotropic stimulant methylphenidate CANNABIS SATIVA 47

(Ritalin®), was there significant improve- took ecstasy, 10% took tranquillizers, 9% ment. She succeeded academically, which used hypnotics, 4% used creatine, and 41% had not been possible previously, her crav- used vitamins against fatigue. Beliefs about ing for drugs diminished, and a drug-free doping did not differ among doping agent state was reachedCS446. users and nonusers, except for the associated Auditory function. Eight male subjects health risks, which were minimized by users. (aged 22–30 years) who had previously used Users of doping agents stated that the cannabis were investigated. They performed quality of the relations that they main- air conduction pure tone audiometry in tained with their parents was sharply both ears over 0.5–8 kHz. A simple test of degraded, and they reported that they were frequency selectivity by detecting a 4-kHz susceptible to influence and difficult to live tone under two masking noise conditions with. More often than nondoping-agent was also carried out in one ear. Three test users, these adolescents were neither happy, sessions at weekly intervals were carried out, nor healthy, although paradoxically, they at the start of which they ingested a capsule seemed less anxious and were more self- containing either placebo, 7.5, or 15 mg of confidentCS302. Maternal exposure to ∆-9- THC. These were administered in a ran- THC in rats resulted in alteration in the domized cross-over, double-blind manner. pattern of ontogeny of spontaneous locomo- Auditory testing was carried out 2 hours tor and exploratory behavior in the off- after ingestion. Blood samples were also spring. Adult animals exposed during obtained at this time point and assayed for gestational and lactational periods exhib- ∆-9-THC and 11-hydroxy-THC levels. No ited persistent alterations in the behavioral significant changes in threshold or fre- response to novelty, social interactions, quency resolution were seen with the dos- sexual orientation, and sexual behavior. ages employed in this studyCS367. They also showed a lack of habituation and Barbiturate potentiation. Flavonoid frac- reactivity to different illumination condi- tion of the leaf, administered intraperito- tions. Adult offspring of both sexes also neally to mice, was activeCS242. Petroleum displayed a characteristic increase in spon- ether extract of the dried entire plant, taneous and water-induced grooming administered intraperitoneally to pigs at a behavior. Some of the effects were depen- dose of 250 mg/kg, was inactiveCS022. dent on the sex of the animals being studied, Behavioral effect. A four-page, self-com- and the dose of cannabinoid administered pleted questionnaire was designed to deter- to the mother during gestational and lacta- mine the drugs used (licit, illicit, and doping tional periods. Maternal exposure to low substances) along with beliefs about doping doses of THC sensitized the adult offspring and the psychosociological factors associ- of both sexes to the reinforcing effects of ated with their consumption. The question- morphine, as measured in a conditioned naire was distributed to high school students place preference paradigmCS462. enrolled in a school sports association in β-Endorphin interaction. ∆-9-THC ad- eastern France. The completed forms were ministered to rats produced large increases received from 1459 athletes: 4% stated that in extracellular levels of β-endorphin in they had used doping agents at least once in the ventral tegmental area and lesser their life (their main source of supply being increases in the shell of the nucleus peers and health professionals). Thirty-four accumbens (Nac). In rats that had learned percent of the sample smoked some tobacco, to discriminate injections of THC from 66% used alcohol, 19% used cannabis, 4% injections of vehicle, the opioid agonist 48 MEDICINAL PLANTS OF THE WORLD morphine did not produce THC-like dis- ketocannabinoid, CBD, and a combined criminative effects, but markedly increased oral application of both substances on bin- discrimination of THC. The opioid antago- ocular depth inversion and behavioral states nist naloxone reduced the discriminative were investigated in nine healthy male vol- effects of THC. Bilateral microinjections of unteers. A significant impairment of bin- β-endorphin directly into the ventral teg- ocular depth perception was found when mental area, but not into the shell of the nabilone was administered, but combined Nac, markedly increased the discriminative application with CBD revealed reduced effects of ineffective threshold doses of effects on binocular depth inversionCS414. THC, but had no effect when given alone. Birth-weight effect. A total of 32,483 can- The increase was blocked by naloxoneCS280. nabis-using women giving birth to live-born Binocular depth inversion reduction. A infants were investigated. The largest reduc- study to assess whether the binocular depth tion in mean birth-weight for any cannabis inversion illusion (BDII) could detect subtle use during pregnancy was 48 g (95% CI, 83– cognitive impairment owing to regular can- 14 g), with considerable heterogeneity nabis use was conducted. Ten regular can- among the five studies. Mean birth-weight nabis users and 10 healthy controls from the was increased by 62 g (95% CI, 8-g reduc- same community sources, matched for age, tion – 132-g increase; p heterogeneity, 0.59) sex, and premorbid intelligence quotient among infrequent users (Յ weekly), (IQ) were evaluated. The subjects were also whereas cannabis use at least four times per compared on measures of executive func- week had a 131-g reduction in mean birth- tioning, memory, and personality. Regular weight (95% CI 52–209-g reduction; p het- cannabis users were found to have signifi- erogeneity, 0.25). From the five studies of cantly higher BDII scores for inverted low birth-weight, the pooled odds ratio for images. This was not to the result of a prob- any use was 1.09 (95% CI 0.94–1.27; p het- lem in the primary processing of visual erogeneity, 0.19)CS437. In a cohort study con- information, as there was no significant sisted of a multiethnic population of 7470 difference between the groups for depth pregnant women. Information on the use of perception of normal images. There was drugs was obtained from personal interviews no relationship between BDII scores for at entry to the study and assays of serum inverted images and time since the last dose, obtained during pregnancy. Pregnancy suggesting that the measured impairment of outcome data (low birth-weight [<2500 g], BDII more closely reflected chronic than pre-term birth [<37 weeks gestation], and acute effects of regular cannabis use. There abruptio placentae) were obtained with a were no significant differences between the standardized study protocol. A total of 2.3% groups for other neuropsychological mea- of the women used cocaine and 11% used sures of memory or executive function. A cannabis during pregnancy. Cannabis use positive relationship was found between was not associated with low birth-weight psychoticism as defined by the revised (1.1, 0.9–1.5), pre-term delivery (adjusted Eysenck Personality Questionnaire and can- odds ratio [OR] 1.1, CI 0.8–1.3), or abrup- nabis, tobacco, and alcohol use. Cannabis tio placentae (1.3, 0.6–2.8)CS465. users also used significantly larger amounts Bladder dysfunction. Two whole-plant of alcohol. No relationship was found extracts of Cannabis sativa were adminis- between BDII scores and drug use other tered to patients with advanced multiple than cannabis or psychoticismCS332. Nabi- sclerosis (MS) and refractory troublesome lone, a psychoactive synthetic 9-trans- lower urinary tract symptoms. The patients CANNABIS SATIVA 49 took the extracts containing ∆-9-THC and lower caffeine consumption group exhib- CBD (2.5 mg of each per spray) for 8 weeks ited AA protection during both phases. followed by THC-only (2.5 mg THC per Covariates (neuroticism, extraversion and spray) for a further eight weeks, and then depression scores, age, sex, body mass index) into a long-term extension. Assessments were not significantCS377. included urinary frequency and volume Blood-borne sexually transmitted infec- charts, incontinence pad weights, cysto- tions. Substance use, including alcohol and metry, and visual analog scales for second- illicit drugs, increases the risk for the acqui- ary troublesome symptoms. Twenty-one sition and transmission of sexually transmit- patients were recruited and data from 15 ted infection (STI). The prevalence of were evaluated. Urinary urgency, the num- blood-borne STI including human immuno- ber and volume of incontinence episodes, deficiency virus (HIV), human T-cell frequency, and nocturia all decreased lymphotrophic virus type 1, hepatitis B significantly following treatment (p < virus, and syphilis in residents of a detoxifi- 0.05, Wilcoxon’s signed rank test). Daily cation and rehabilitation unit in Jamaica total voided, catheterized and urinary were investigated. The demographic char- incontinence pad weights also decreased acteristics and the results of laboratory significantly for both extracts. Patient self- investigations for STI in 301 substance assessment of pain, spasticity, and quality abusers presented during a 5-year period of sleep improved significantly (p < 0.05, were reviewed. The laboratory results were Wilcoxon’s signed rank test) with pain im- compared with those of 131 blood donors. provement continuing up to a median of 35 The substances used by participants were weeks. There were few troublesome side alcohol, cannabis, and cocaine. None of effects, suggesting that cannabis-based the clients was an intravenous drug user. medicinal extracts are a safe and effective Female substance abusers were at higher risk treatment for urinary and other problems in for STI. The prevalence of STI in substance patients with advanced MSCS269. abusers did not differ significantly from that Blood pressure stress reactivity effect. in blood donors (12% vs 10%). The preva- Data from an ascorbic acid (AA) trial lence of syphilis in substance abusers was (Cetebe 3 g/day for 14 days, n = 108) were significantly higher than that in blood compared by substance use level regarding donors (6% vs 3%, p < 0.05). The preva- systolic blood pressure (SBP) stress reactiv- lence of syphilis was dramatically increased ity to the anticipation and actual experience in female substance abusers and female phases of a standardized psychological stres- blood donors (30%, p < 0.001 and 13%, p < sor (10 minutes of public speaking and 0.05, respectively). An excess of human arithmetic). Self-reported never users of T-cell lymphotrophic virus type 1 was also cannabis, persons not currently smoking to- observed in female compared with male sub- bacco, and persons consuming three or more stance abusers. Unemployment was identi- caffeine beverages daily all exhibited AA fied also as a risk factor for sexually SBP stress reactivity protection to the actual transmitted disease in substance abusersCS401. stressor, but not during the anticipation Brain aging effect. The impact of duration phase. Self-reported ever cannabis users, of education, cannabis addiction and smok- current tobacco smokers, and persons con- ing on cognition and brain aging was stud- suming less than three caffeine beverages ied in 211 healthy Egyptian volunteers with daily exhibited the AA SBP protection dur- mean age of 46.4 ± 3.6 years (range, 20–76 ing the anticipation phase, but only the years). The subjects were classified into two 50 MEDICINAL PLANTS OF THE WORLD groups: Gr I (n = 174; mean age, 49.9 ± 3.8 etic cells and has only 44% overall nucle- years; range, 20–76 years), nonaddicts, otide sequence identity with the CB1 recep- smokers, and nonsmokers, educated and tor. The existence of this receptor provided noneducated, and Gr II cannabis addicts the molecular basis for the immunosuppres- (n = 37; mean age, 43.6 ± 2.6 years; range, sive actions of cannabis. The CB1 receptor 20–72 years) all smokers, educated and mediates inhibition of adenylate cyclase, noneducated. Outcome measures included inhibition of N- and P/Q-type calcium the Paced Auditory Serial Addition test for channels, stimulation of potassium chan- testing attention and the Trailmaking test nels, and activation of mitogen-activated A and Trailmaking test B (TMb) for testing protein kinase. The CB2 receptor mediates psychomotor performance. Age corre- inhibition of adenylate cyclase and activa- lated positively with score of TMb in the tion of mitogen-activated protein kinase. nonaddict group and in the addict group The discovery of endogenous cannabinoid (Trailmaking test A and TMb). Years of receptor ligands, AEA (N-arachidonyl- education correlated negatively with scores ethanolamine), and 2-arachidonylglycerol of TMb in the nonaddict group (Gr I) but made the notion of a central cannabinoid not the addict group (Gr II). Cannabis neuromodulatory system plausible. AEA is addicts (Gr II) had significantly poorer released from neurons on depolarization attention than nonaddict normal volun- through a mechanism that requires calcium- teers (Gr I). It was determined that impair- dependent cleavage from a phospholipid ment of psychomotor performance is age precursor in neuronal membranes. The related whether in normal nonaddicts or in release of AEA is followed by rapid uptake cannabis addicts. A decline in attention into the plasma and hydrolysis by fatty-acid was detected in cannabis addicts and has amidohydrolase. The psychoactive cannab- been considered a feature of pathological inoids increase the activity of dopaminergic agingCS448. neurons in the ventral tegmental area– Brain . In humans, mesolimbic pathway. Because these dopam- psychoactive cannabinoids produce eupho- inergic circuits are known to play a pivotal ria, enhancement of sensory perception, role in mediating the reinforcing (reward- tachycardia, antinociception, difficulties in ing) effects of the most drugs of abuse, the concentration, and impairment of memory. enhanced dopaminergic drive elicited by The cognitive deficiencies persist after the cannabinoids is thought to underlie the withdrawal. The toxicity of cannabis has reinforcing and abuse properties of can- been underestimated for a long time, since nabis. Thus, cannabinoids share a final com- recent findings revealed that ∆-9-THC- mon neuronal action with other major drugs induced cell death with shrinkage of neu- of abuse such as morphine, ethanol, and rons and DNA fragmentation in the nicotine in producing facilitation of the hippocampus. The acute effects of cannab- mesolimbic dopamine systemCS423. Hippoc- inoids, as well as the development of toler- ampal slices from humans, guinea pigs, rats, ance, are mediated by G protein-coupled and mice, and cerebellar, cerebrocortical, cannabinoid receptors. The CB1 receptor and hypothalamic slices from guinea pigs and its splice variant, CB1A, are found pre- were incubated with [3H] noradrenaline and dominantly in the brain with highest densi- then superfused. Tritium overflow was ties in the hippocampus, cerebellum, and evoked either electrically (0.3 or 1 Hz) or striatum. The CB2 receptor is found pre- by introduction of Ca2+ ions (1.3 µM) into dominantly in the spleen and in hemopoi- Ca2+-free, K+-rich medium (25 µM) contain- CANNABIS SATIVA 51 ing 1 µM of tetrodotoxin. The cyclic adeno- 141716 (0.1 µM; apparent pA2 8.3), that sone monophosphate (cAMP) accumula- by itself did not affect cAMP accumulation. tion stimulated by 10 µM of forskolin was In conclusion, cannabinoid receptors of the determined in guinea pig hippocampal CB1 subtype occur in the human hippoc- membranes. The following drugs were used: ampus, where they may contribute to the the cannabinoid receptor-agonists (-)-cis- psychotropic , and in the 3-[2-hydroxy-4-(1,1- dimethylheptyl)phen- guinea pig hippocampus, cerebellum, cere- yl]-trans-4-(3-hydroxypropyl)cyclo-hexanol bral cortex, and hypothalamus. The CB1 (CP-55,940) and R(+)-[2,3-dihydro-5-me- receptor in the guinea pig hippocampus is thyl-3-[(morpholinyl)methyl]pyrrolo[1,2, located presynaptically, was activated by 3-de]-1,4-benzoxazinyl]-(1-naphthalen- endogenous cannabinoids, and may be yl)methanone (WIN 55,212-2 [WIN]), the negatively coupled to adenylyl cyclaseCS442. inactive S(-)-enantiomer of the latter (WIN The acute administration of AEA or THC 55,212-3) and the CB1 receptor antagonist in rats increased the maximum binding ca-

N-piperidino-5-(4-chlorophenyl)-1-(2,4- pacity (Bmax) of cannabinoid receptors in the dichlorophenyl)-4-methyl-3-pyrazole- cerebellum and, particularly, in the hippoc- carboxamide (SR 141716). The electrically ampus. This effect was also observed after 5 evoked tritium overflow from guinea pig days of a daily exposure to AEA or THC. hippocampal slices was reduced by WIN The increase in the Bmax after the acute (peak inhibitory concentration 30%, 6.5) treatment seemed to be caused by changes but not affected by WIN 55,212-3 up to 10 in the receptor affinity (high Kd). The mM. The concentration–response curve of increase after the chronic exposure may be WIN was shifted to the right by SR 141716 attributed to an increase in the density of (0.032-µM) (apparent pA2 8.2), which by receptors. The [3H]CP-55,940 binding to itself did not affect the evoked overflow. cannabinoid receptors in the striatum, the WIN (1 µM) also inhibited the Ca2+-evoked limbic forebrain, the mesencephalon, and tritium overflow in guinea pig hippocampal the medial basal hypothalamus was not slices and the electrically evoked overflow altered after the acute exposure to AEA or in guinea pig cerebellar, cerebrocortical, THC. The chronic exposure to THC sig- and hypothalamic slices, as well as in hu- nificantly decreased the Bmax of these recep- man hippocampal slices, but not in rat and tors in the striatum and nonsignificantly in mouse hippocampal slices. SR 141716 (0.32 the mesencephalon. This effect was not µM) markedly attenuated the WIN-induced elicited after the chronic exposure to AEA inhibition in guinea pig and human brain and was not accompanied by changes in the µ CS463 slices. SR 141716 (0.32 M) by itself Kd . increased the electrically evoked tritium Bronchoconstrictor activity. Water extract overflow in guinea pig hippocampal slices, of seed, administered by inhalation to human but failed to do so in slices from the other adults, was activeCS147. brain regions of the guinea pig and in Bronchodilator activity. Petroleum ether human hippocampal slices, but failed to do extract of the aerial parts, administered so in slices from the other brain regions of orally to adults of both sexes, was inac- the guinea pig and in human hippocampal tiveCS078. slices. The cAMP accumulation stimulated Cannabinoid hyperemesis. Nineteen pa- by forskolin was reduced by CP-55,940 and tients were identified with chronic cannabis WIN. The concentration-response curve of abuse and a cyclical vomiting illness. Fol- CP-55,940 was shifted to the right by SR low-up was provided with serial urine drug 52 MEDICINAL PLANTS OF THE WORLD screen analysis and regular clinical consul- amygdala, periaqueductal gray, and the tation to chart the clinical course. Of the paraventricular nucleus of the hypothala- 19 patients, five refused consent and were mus) and reward-related sites (Nac and lost to follow-up, and five were excluded pedunculopontine tegmental nucleus). In a based on cofounders. In all cases, chronic further experiment, Wistar rats and Lewis cannabis abuse predated the onset of the rats did not differ in the amount of Fos im- cyclical vomiting illness. Cessation of can- munoreactivity produced by cocaine (15 nabis abuse led to cessation of the cyclical mg/kg). These results indicate that Lewis vomiting illness in seven cases. Three cases rats are less sensitive to the behavioral, did not abstain and continued to have physiological and neural effects of canna- recurrent episodes of vomiting. Three cases binoidsCS396. rechallenged themselves after a period of Cannabis withdrawal effect. A 35-year- abstinence and suffered a return to illness. old male was cognitively assessed prior to Two of these cases abstained again and cessation of 18 years of daily cannabis use became, and remain, well. The third case and monitored for several weeks post- did not and remains ill. A novel finding was cessation. Brain event-related potential that 9 of the 10 patients, including the pre- measures of selective attention reflecting a viously published case, displayed an abnor- difficulty in filtering out complex irrel- mal washing behavior during episodes of evant information showed no indication of active illnessCS258. improvement over 6 weeks of abstinence. Cannabinoid-induced Fos expression. When tested in the acutely intoxicated state Cannabinoid CB1 receptor agonist CP- prior to cessation of use, a dramatic normal- 55,940 in Lewis and Wistar rats was investi- ization of the event-related potential signa- gated. A moderate (50 µg/kg) and a high ture was observed. A treatment program (250 µg/kg) dose level were used. The 250- based on supportive–expressive psycho- µg/kg dose caused locomotor suppression, therapy was administered and depression, hypothermia, and catalepsy in both strains, anxiety, and general psychological health but with a significantly greater effect in were monitored over the course of with- Wistar rats. The 50-µg/kg dose provoked drawal from cannabisCS466. moderate hypothermia and locomotor sup- Cannabis–amphetamine interaction. Can- pression but in Wistar rats only. CP-55,940 nabinoid–amphetamine interactions were caused significant Fos immunoreactivity in studied as follows: 24 out of 33 brain regions examined. The 1. 30 minutes after acute injection of (-)-∆- most dense expression was seen in the 9-THC (0.1 or 6.4 mg/kg, intraperito- paraventricular nucleus of the hypothala- neally). mus, the islands of Calleja, the lateral sep- 2. 30 minutes after the last injection of 14- tum (ventral), the central nucleus of the daily treatment with (-)-∆-9-THC (0.1 or amygdala, the bed nucleus of the stria 6.4 mg/kg). terminalis (lateral division), and the vent- 3. 24 hours after the last injection of 14- rolateral periaqueductal gray. Despite daily treatment with (-)-∆-9-THC (6.4 having a similar distribution of CP-55,940- mg/kg). induced Fos expression, Lewis rats showed Acute cannabinoid exposure antagonized less overall Fos expression than Wistar rats the amphetamine-induced dose-dependent in nearly every brain region counted. This increase in locomotion, exploration, and held equally true for anxiety-related brain the decrease in inactivity. Chronic treat- structures (e.g., central nucleus of the ment with (-)-∆-9-THC resulted in toler- CANNABIS SATIVA 53 ance to this antagonistic effect on locomo- conservative wound dressings and second- tion and inactivity but not on exploration, ary prostacyclin therapy a complete healing and potentiated amphetamine-induced ste- of digital necrosis was observed. There was reotypes. Lastly, 24 hours of withdrawal no recurrence during the 6-month follow- after 14 days of cannabinoid treatment upCS336. Young men were presented with dis- resulted in sensitization to the effects of tal arteriopathy of the lower limbs in three D-amphetamine on locomotion, explora- cases, and of the left upper limb in the tion, and stereotypesCS431. remaining patient. Symptoms occurred pro- Cannabis-induced coma. Two cases of gressively, distal pulses had disappeared, and cannabis-induced coma were reported fol- distal necrosis was constant. Three patients lowing accidental ingestion of cannabis suffered from Raynauld’s phenomenon, cookies. The possibility of cannabis inges- none of them presented with venous throm- tion should be considered in cases of unex- bosis. Radiological evaluation revealed dis- plained coma in a previously healthy young tal abnormalities in all cases, and proximal child if signs of conjunctival hyperemia, arterial thrombosis in one case. The four pupillary dilatation, and tachycardia were patients were cannabis smokers for at least present and other causes, such as central four years. With cannabis interruption and nervous system infection or trauma were symptomatic treatment, lesions improved unlikelyCS458. for three patients. For one of them, recur- Cannabis-related arteritis. A 19-year-old rence of arteriopathy occurred when he man who presented with plantar claudica- resumed smoking cannabis. For the fourth tion associated with necrosis in a toe under- who never stopped cannabis, an amputation went diagnostic arteriography and surgery was necessaryCS349. Ten male moderate for popliteal artery entrapment type III was tobacco smokers and regular cannabis users studied. Surgical clearance resolved the with a median age of 23.7 years, developed popliteal artery entrapment but left the subacute distal ischemia of the lower or clinical symptoms unchanged. Closer ques- upper limbs, leading to necrosis in the toes tioning disclosed a history of cannabis con- and/or fingers and sometimes to distal limb sumption and intravenous vasodilatory gangrene. Two of the patients also pre- therapy was started. After the 21-day course sented with venous thrombosis and three of vasodilator agents, the pain disappeared patients were suffering from a recent and the toe necrosis regressed. The patient Raynauld’s phenomenon. Biological test stopped taking cannabis and had no signs of results did not show evidence of the classi- recurrenceCS308. A 24-year-old woman who cal vascular risk factors for thrombosis. was a heavy cannabis smoker with progres- Arteriographic evaluation in all of the cases sive Raynauld’s phenomenon and digital revealed distal abnormalities in the arteries necrosis, was investigated. Systemic sclero- of feet, legs, forearms, and hands resembling sis and other connective tissue disorders, as those of Buerger’s disease. A collateral cir- well as arteriosclerosis and arterial emboli culation sometimes with opacification of were excluded with appropriate laboratory the vasa nervorum was noted. In some cases, examinations. Arteriography revealed mul- arterial proximal atherosclerotic lesions and tiple forearm, palmar and digital occlusions venous thrombosis were observed. Despite with corkscrew-shaped vessels. Based on the treatment with ilomedine and heparin in all characteristic arteriography and clinical cases, five amputations were necessary in findings, the diagnosis of cannabis arteritis four patients. The vasoconstrictor effect of was retained. With careful necrectomy, cannabis on the vascular system has been 54 MEDICINAL PLANTS OF THE WORLD known for a long time. It has been shown patients were current tobacco smokers, 19 that ∆-8-THC and ∆-9-THC may induce were current cannabis users, and none were peripheral vasoconstrictor activity. Can- currently using opioids other than pre- nabis arteritis resembles Buerger’s disease, scribed methadone. Abnormalities of respi- but patients were moderate tobacco smok- ratory function were defined as those results ers and regular cannabis usersCS406. outside the 95% confidence interval of ref- Cannabis-related flashback. A young erence values for normal subjects adjusted man who offended a friend without any for age, weight, height, and sex. Thirty-one objective reason was reported. The report of (62%) MMT patients had reduced carbon the forensic psychiatrist demonstrated that monoxide transfer factor; 17 (34%) had el- the offense was committed under the influ- evated single breath alveolar volume, and ence of a cannabis flashback. The last time 43 (86%) had a reduced carbon monoxide the offender had consumed cannabis was 2 transfer factor–alveolar volume ratio. Six weeks before the acts. A plasmatic detection patients (12%) had reduced forced expira- was realized and showed a level of 6 ng/mL, tory volume in 1 second (FEV1); one (2%) 30 minutes after the beginning of the had reduced forced vital capacity (FVC); flashbackCS383. and nine (18%) had an obstructive ventila- Capgras syndrome. A report describes an tory defect. Ten (20%) patients had arterial apparently greater incidence of Capgras syn- CO2 pressure higher than 45 mmHg and 14 drome among the Maori population com- (28%) had alveolar to arterial oxygen gradi- pared with the European population. Five ent higher than 15 mmHg. Chest X-ray, cases of Capgras syndrome were identified echocardiography, and electrocardiogram in the eastern catchment area where 19% of showed no significant abnormalitiesCS256. the population identified as Maori, 75% as The potent cannabinoid receptor agonists European, and 6% as other or nonspecified. WIN55,212-2 (0.05, 0.5, or 5 pmol/50 nL) All of the cases occurred in Maori patients. and HU-210 (0.5 pmol/50 nL) or the CB1 No cases were identified in the western receptor antagonist/inverse agonist AM281 catchment area where 12% of the popula- (1 pmol/100 nL) were microinjected into tion identified as Maori, 87% as European, the rostral ventrolateral medulla oblongata and 1% as other or nonspecified. Four of five (RVLM) of urethane-anesthetized, immobi- cases were females. Two cases had a history lized and mechanically ventilated male of cannabis use. Three cases had exhibited Sprague–Dawley rats (n = 22). Changes in dangerous behavior towards family mem- splanchnic nerve activity, phrenic nerve bersCS410. activity, mean arterial pressure, and heart Carcinogenic activity. The dried leaf, rate in response to cannabinoid administra- administered intraperitoneally to rats of tion were recorded. The CB1 receptor gene both sexes at a dose of 7 mg/kg/week, was was expressed throughout the ventrolateral active. The animals were irradiated with γ medulla oblongata. Unilateral microinjec- radiation between 40 and 50 days of age and tion of WIN 55,212-2 into the RVLM observed for 78 weeks. There was a greater evoked short-latency, dose-dependent in- incidence of tumors in animals given mari- creases in splanchnic nerve activity (0.5 juana extract and γ radiation than either pmol; 175 ± 8%, n = 5) and mean arterial marihuana or γ radiation aloneCS223. pressure (0.5 pmol; 26 ± 3%, n = 8), and Cardiorespiratory effect. Fifty stable abolished phrenic nerve activity (0.5 pmol; patients (25 males, 25 females) with me- duration of apnea: 5.4 ± 0.4 seconds, n = 8), thadone maintenance treatment (MMT) with little change in heart rate (p < 0.005). programs were investigated. Forty-six MMT HU-210, structurally related to ∆-9-THC, CANNABIS SATIVA 55 evoked similar effects when microinjected layers of the membrane, with particularly into the RVLM (n = 4). Prior microinjec- strong expression in the amniotic epithe- tion of AM281 produced agonist-like lium and reticular cells and cells of the effects, and significantly attenuated the maternal decidua layer. Moderate expres- response to subsequent injection of WIN sion was observed in the chorionic cyto- (0.5 pmol, n = 4)CS331. trophoblasts. The expression of FAAH was Cardiovascular effects. The leaf, smoked highest in the amniotic epithelial cells, by adults of both sexes, at a dose of 600 mg/ chorionic cytotrophoblast, and maternal person (1–1.5% THC), produced no decidua layer. The results suggest that the adverse effects on blood pressure, electrocar- human placenta is a likely target for cannab- diogram, and the heartCS065. Cannabis and ∆- inoid action and metabolism. This is con- 9-THC increase heart rate, slightly increase sistent with a placental site of action of supine blood pressure, and on occasion pro- endocannabinoids and cannabis being duced marked orthostatic hypotension. Car- responsible, at least in part, for the poor out- diovascular effects in animals are different, comes associated with cannabis consump- with bradycardia and hypotension the most tion and pathology in the endocannabinoid typical responses. Cardiac output increases, system during pregnancyCS327. and peripheral vascular resistance and maxi- Central nervous system depressant activ- mum exercise performance decrease. Toler- ity. Fluidextract of the aerial parts, admin- ance to most of the initial cardiovascular istered intraperitoneally to rats at a dose of effects appears rapidly. With repeated expo- 25 mg/kg, was active. The fluidextract, sure, supine blood pressure decreases administered orally to dogs, produced slightly, orthostatic hypotension disappears, ataxiaCS240. The leaf, smoked by human blood volume increases, heart rate slows, adults, produced a decrease in psychomotor and circulatory responses to exercise and performanceCS066. Valsalva maneuver are diminished, consis- Central nervous system effect. ∆-9-THC tent with centrally mediated, reduced sym- activates the two G protein-coupled recep- pathetic, and enhanced parasympathetic tors CB1 and CB2. The endogenous ligands activity. Receptor-mediated and probably of these receptors were identified as lipid nonneuronal sites of action account for can- metabolites of arachidonic acid, named nabinoid effects. The endocannabinoid sys- endocannabinoids. The two most studied tem appears important in the modulation of endocannabinoids are AEA and 2-arachi- many vascular functions. Cannabis’ cardio- donyl-glycerol. The CB1 receptor is mas- vascular effects are not associated with sively expressed throughout the central serious health problems for most young, nervous system, whereas CB2 expression healthy users, although occasional myocar- seems restricted to immune cells. Following dial infarction, stroke, and other adverse endocannabinoid binding, CB1 receptors cardiovascular events are reportedCS362. modulate second messenger cascades (inhi- Cataleptic effect. Petroleum ether extract bition of adenylate cyclase, activation of of the dried entire plant, administered mitogen-activated protein kinases and of intraperitoneally to guinea pigs at a dose of focal-adhesion kinases), as well as ionic 100 mg/kg, was activeCS022. conductances (inhibition of voltage-depen- CB1 cannabinoid receptor in human pla- dent calcium channels, activation of several centa. CB1 (G protein-coupled) receptor potassium channels). Endocannabinoids and FAAH expression in human term pla- transiently silenced synapses by decreasing centa were investigated by immunohis- neurotransmitter release. They play major tochemistry. CB1 receptor was found in all roles in various forms of synaptic plasticity 56 MEDICINAL PLANTS OF THE WORLD because of their ability to behave as retro- increases correlated with regional cerebral grade messengers and activate noncanna- blood flow in the cerebellum. Results indi- binoid receptors (such as vanilloid receptor cate that smoking cannabis appears to type-1)CS305. Mice strain with a disrupted accelerate a cerebellar clock-altering self- CB1 gene (CB1 knockout mice) appeared paced behaviorsCS343. healthy and fertile, but they had a signifi- Clinical endocannabinoid deficiency. cantly increased mortality rate. They also Clinical endocannabinoid deficiency, and displayed reduced locomotor activity, the prospect that it could underlie the increased ring catalepsy, and hypoalgesia in pathophysiology of migraine, fibromyalgia, hotplate and formalin tests. ∆-9-THC- irritable bowel syndrome, and other func- induced ring catalepsy, hypomobility, and tional conditions alleviated by clinical can- hypothermia were completely absent in nabis were studied. Migraine has numerous CB1 mutant mice. In contrast, ∆-9-THC- relationships to endocannabinoid function. induced analgesia in the tail-flick test and AEA potentiated 5-hydroxytrayptamine other behavioral (licking of the abdomen) (HT1A) and inhibited 5-HT2A receptors and physiological (diarrhea) responses supporting therapeutic efficacy in acute and after ∆-9-THC administration were found. preventive migraine treatment. Cannab- Results indicate that most, but not all, cen- inoids also demonstrated dopamine-block- tral nervous system effects of ∆-9-THC are ing and anti-inflammatory effects. AEA is mediated by the CB1 receptorCS425. tonically active in the periaqueductal gray Central nervous system stimulant activ- matter, a migraine generator. THC modu- ity. The resin, ingested by a 4-year-old girl, lated glutamatergic neurotransmission via showed signs of stupor alternating with brief N-methyl-D-aspartic acid-receptors. Fibro- intervals of excitation and foolish laughing myalgia is now conceived as a central sensi- with atactic movements. Her temperature, tization state with secondary hyperalgesia. blood pressure, pulse, hemoglobin, leuko- Cannabinoids have similarly demonstrated cytes, serum electrolytes, and serum urea the ability to block spinal, peripheral and were normal. Respiratory rate was 12 beats gastrointestinal mechanisms that promote per minute. Blood sugar elevated. Recovery pain in headache, fibromyalgia, irritable was complete within 24 hours with no bowel syndrome and related disordersCS288. treatmentCS047. Cognitive functioning. Cognitive perfor- Cerebellar clock-altering effect. Twelve mance was examined in 145 adolescents volunteers who smoked cannabis recrea- aged 13–16 years for whom prenatal expo- tionally about once weekly, and 12 volun- sure to cannabis and cigarettes had been teers who smoked daily for a number of ascertained. The subjects were from a low- years performed a self-paced counting task risk, predominantly middle-class sample during positron emission tomography im- participating in an ongoing, longitudinal aging, before and after smoking cannabis study. The assessment battery included tests and placebo cigarettes. Smoking cannabis of general intelligence, achievement, increased regional cerebral blood flow in the memory, and aspects of executive function- ventral forebrain and cerebellar cortex in ing. Consistent with results obtained at ear- both groups, but resulted in significantly less lier ages, the strongest relationship between frontal lobe activation in chronic users. prenatal maternal cigarette smoking and Counting rate increased after smoking can- cognitive variables was seen with overall nabis in both groups, as did a behavioral intelligence and aspects of auditory func- measure of self-paced tapping, and both tioning, whereas prenatal exposure to mari- CANNABIS SATIVA 57 juana was negatively associated with tasks tual performance. On the second day, sub- that required visual memory, analysis, and jects received a regular cigarette or one con- integrationCS344. A multisite, retrospective, taining 290 mg/kg body weight of THC. cross-sectional, neuropsychological study Physical and psychological assessments were was conducted among 102 near-daily can- performed immediately (15 minutes) after nabis users (51 long-term users: mean, 23.9 subjects smoked their cigarettes. Twenty- years of use; 51 shorter-term users: mean, four hours later, physical and psychological 10.2 years of use), compared with 33 non- examinations were repeated. Results suggest user controls. Measures from nine standard that perceptual motor speed and accuracy, neuropsychological tests that assessed atten- two very important parameters of driving tion, memory, and executive functioning ability, seem to be impaired immediately were administered prior to entry into a after cannabis consumptionCS420. The analy- treatment program following a median 17- ses included 1318 participants under age 65 hour abstinence. Long-term cannabis users years who completed the Mini-Mental State performed significantly less well than Examination (MMSE) during three study shorter-term users and controls on tests of waves in 1981, 1982, and 1993–1996. Indi- memory and attention. On the Rey Audi- vidual MMSE score differences between tory Verbal Learning Test, long-term users waves two and three were calculated for recalled significantly fewer words than each study participant. After 12 years, study either shorter-term users (p = 0.001) or con- participants’ scores declined a mean of 1.20 trols (p = 0.005). There was no difference points on the MMSE (standard deviation, between shorter-term users and controls. 1.90), with 66% having scores that declined Long-term users showed impaired learning by at least one point. Significant numbers (p = 0.007), retention (p = 0.003), and of scores declined by three points or more retrieval (p = 0.002) compared with con- (15% of participants in the 18–29-year-old trols. Both user groups performed poorly on age group). There were no significant dif- a time estimation task (p < 0.001 vs con- ferences in cognitive decline between heavy trols). Performance measures often corre- users, light users, and nonusers of cannabis. lated significantly with the duration of There were also no male–female differences cannabis use, being worse with increasing in cognitive decline in relation to cannabis years of use, but were unrelated to with- useCS426. From 250 individuals consuming drawal symptoms and persisted after con- cannabis regularly, 99 healthy, free of any trolling for recent cannabis use and other other past or present drug abuse, or history drug useCS388. A patient with a history of trau- of neuropsychiatric disease cannabis users matic brain injury along with current mood were selected. After an interview, physical disorder and cannabis use was reported. The examination, analysis of routine laboratory impact of cannabis use appeared to have a parameters, plasma/urine analyses for drugs, detrimental effect on his mood. Treatment and Minnesota Multiphasic Personality of the mood disorder resulted in larger cog- Inventory testing, users and respective con- nitive gainsCS415. Sixty healthy volunteers (a trols were subjected to a computer-assisted negative urine drug-screening test was pre- attention test battery comprising visual requisite) were investigated. On the first scanning, alertness, divided attention, flex- day, baseline data were obtained from a ibility, and working memory. Of the poten- physical examination and a psychological tial predictors of test performance within test battery for the investigation of visual the user group, including present age, age of and verbal memory and cognitive percep- onset of cannabis use, degree of acute 58 MEDICINAL PLANTS OF THE WORLD intoxication (THC + THC–OH plasma lev- abuse/dependence. The results indicated els), and cumulative toxicity (estimated that patients with dysthymia and SRD have total life dose), an early age of onset turned exposure to most substances of abuse that out to be the only predictor, predicting was comparable to patients with SRD only. impaired reaction times exclusively in visual They selectively use certain substances less scanning. Early-onset users (onset before often than patients with SRD onlyCS433. A age 16; n = 48) showed a significant impair- course and severity of SRD among 642 ment in reaction times in this function, patients with comorbid major depressive whereas late-onset users (onset after age 16; disorder (MDD) was analyzed by means of n = 51) did not differ from controls (n = both retrospective and concurrent data. 49)CS428. Male volunteers (n = 5) with histo- Data on course included lifetime use, age at ries of moderate alcohol and cannabis use first use, years of use, use in the last year, were administered three doses of alcohol periods of abstinence, and current diagno- (0.25, 0.5, or 1 g/kg), three doses of cannabis sis. Data on severity included two measures (4.8, or 16 puffs of 3.55% ∆-9-THC), and of SRD-associated problems, substance placebo in random order under double blind abuse vs dependence, self-help activities, conditions in seven separate sessions. Blood and number of substances being abused. alcohol concentration (10–90 mg/dL) and SRD-MDD patients tended to manifest THC levels (63–188 ng/mL) indicated that lower levels of cannabis, opiate, and cocaine active drug was delivered to subjects dose use, and more SRD-only patients were abus- dependently. Alcohol and cannabis pro- ing three or more substances. Men with duced dose-related changes in subjective SRD-MDD demonstrated longer mean measures of drug effect. Ratings of perceived durations of abstinence compared with men impairment were identical for the high with SRD-only, whereas SRD-MDD women doses of alcohol and cannabis. Both drugs demonstrated shorter mean durations of produced comparable impairment in digit– abstinence, compared with women with symbol substitution and word recall tests, SRD-only. MDD-SRD patients showed but had no effect in time perception and slightly less substance abuse, but SRD reaction time tests. Alcohol, but not can- severity was comparable with SRD-only nabis, slightly impaired performance in a patientsCS441. number recognition testCS444. Covariation among risk behaviors. A Comorbid dysthymia and substance dis- sample of 913 sexually active high school order. A total of 642 patients were assessed. students completed a self-administered Thirty-nine had substance-related disorder questionnaire that required mainly “yes” or and dysthymia (SRD-dysthymia) and 308 “no” answers to questions involving par- had SRD only. Data on past use were ticipation in a range of risk behaviors. Con- collected by a research associate using a traceptive nonuse was not significantly questionnaire. The patients with SRD- associated with use of cigarettes, alcohol, or dysthymia and SRD did not differ with re- inhalants; perpetration or being a victim of gard to use of alcohol, tobacco, and violence; exposure to risk of physical injury; benzodiazepines. The patients with SRD- and suicidality. For males only, there was a dysthymia started caffeine use at an earlier significant inverse association between age, had shorter “use careers” of cocaine, contraceptive nonuse and use of cannabis amphetamines, and opiates, and had fewer in the previous month. This was not the days of cocaine and cannabis use in the last case for lifetime cannabis use for either year. They also had a lower rate of cannabis genderCS404. CANNABIS SATIVA 59

Cyclo-oxygenase inhibition. Ethanol such as cisplatin. THC-induced cell death (100%) extract and essential oil of the aerial was preceded by significant changes in the parts were active, IC50 6.7 mg/L and 7.5 mg/ expression of genes involved in the mito- L, respectivelyCS226. gen-activated protein kinase signal trans- Cytochrome P450 and 2C6 expression. duction pathways. Both apoptosis and gene Hashish (cannabis) and heroin effect on the expression changes were altered indepen- expression of cytochrome P450 2E1 (CYP dent of p53 and the cannabinoid 1 and 2 2E1) and cytochrome P450 2C6 (CYP 2C6) receptors (CB1-R and CB2-R)CS261. was measured after single (24 hours) and re- Depressant activity. Heavy cannabis use peated-dose treatments (four consecutive and depression are associated and evidence days). The expression of CYP 2E1 was from longitudinal studies suggests that slightly induced after single-dose treatments heavy cannabis use may increase depressive and markedly induced after repeated-dose symptoms among some usersCS321. Partici- treatments of mice with hashish (10 mg/kg pants (n = 1920) were reassessed as part of a body weight). It is believed that N-nitro- follow-up study. The analysis focused on samines are activated principally by CYP two cohorts: those who reported no depres- 2E1 and the activity of N-nitrosodime- sive symptoms at baseline (n = 849) and thylamine was found to be increased after those with no diagnosis of cannabis abuse at single- and repeated-dose treatments of baseline (n = 1,837). Symptoms of depres- mice with hashish by 23 and 41%, respec- sion, cannabis abuse, and other psychiatric tively. Hashish treatments of mice increased disorders were assessed with the Diagnostic the total hepatic content of CYP by 112 and Interview Schedule. In participants with no 206%, respectively; aryl hydrocarbon baseline depressive symptoms, those with a hydroxylase activity by 110 and 165%, diagnosis of cannabis abuse at baseline were respectively; nicotinamide adenine dinucle- four times more likely than those with no otide phosphate–cytochrome c reductase cannabis abuse diagnosis to have depressive activity by 21 and 98%, respectively, and symptoms at the follow-up assessment, after glutathione level by 81 and 173%, respec- adjusting for age, gender, antisocial symp- tively. The level of free radicals (thio- toms, and other baseline covariates. These barbituric acid-reactive substances) was participants were more likely to have expe- potentially decreased after single- or rienced suicidal ideation and anhedonia repeated-dose treatments with either hash- during the follow-up period. Among the ish or heroinCS333. participants who had no diagnosis of can- Cytotoxic activity. Ethanol (50%) extract nabis abuse at baseline, depressive symp- of the entire plant, in cell culture, was inac- toms at baseline failed to significantly µ tive on CA-9KB, ED50 greater than 20 g/ predict cannabis abuse at the follow-up mLCS007. Water extract of the dried seed, in assessmentCS395. The relationship between cell culture at a concentration of 500 µg/ depressive symptoms and polydrug use mL, was inactive on CA-mammary-micro- (alcohol, cannabis, and cocaine) among alveolarCS144. blacks in a high-risk community was stud- Cytotoxic effect. THC, in leukemic cell ied. A street sample (n = 570) from four lines (CEM, HEL-92, and HL60) and in high-risk communities was collected peripheral blood mononuclear cells, 6 hours through personal interviews. Interviewers after exposure induced apoptosis, even at asked respondents about their drug use one times the IC50. THC did not appear to behavior during the past 30 days and their act synergistically with cytotoxic agents, depressive symptoms during the past week. 60 MEDICINAL PLANTS OF THE WORLD

Odds ratios and logistic regressions, adjusted Discriminative stimulus effect. Rhesus for age and sex, were used to assess the rela- monkeys, trained to discriminate ∆-9-THC tionship between depressive symptoms and from vehicle in a two-lever drug discrimina- drug and polydrug use (drug use involving tion procedure, were tested with a variety of cocaine). Results showed that depressive psychoactive drugs, including cannabinoids symptoms are significantly associated with or drugs from other classes. The results indi- polydrug use. Depressive symptoms were not cated that ∆-9-THC discrimination showed associated with alcohol use or with the com- pharmacological specificity, in that none of bination of alcohol and cannabis useCS440. the noncannabinoid drugs fully substituted Diabetic ketoacidosis. One hundred fifty- for ∆-9-THC. The classical cannabinoids, eight young adults, aged 16–30 years, with ∆-9-THC and ∆-8-THC, and the novel type 1 diabetes, attending an urban diabetes cannabinoids, WIN and 1-butyl-2-methyl- clinic, were sent an anonymous confi- 3-(1-naphthoyl)indole, produced full dose- dential postal questionnaire to determine dependent substitution for ∆-9-THC in all the prevalence of street drug use. Eighty- monkeys. A heptyl indole derivative failed five completed responses were received. to substitute for ∆-9-THC, but it also did Twenty-nine percent of respondents admit- not displace [3H] CP-55,940 from its bind- ted to using street drugs. Of those, 68% ing siteCS461. habitually took street drugs more than once DNA synthesis inhibition. Ethanol (95%) a month. Seventy-two percent of users were extract of the dried resin, administered unaware of the adverse effects on diabetes. intraperitoneally to toads at a dose of 10 mg/ Results indicated that the street drug usage day for 14 days, was active. The results were in young adults with type 1 diabetes is com- significant at p < 0.01 levelCS216. mon and may contribute to poor glycemic Dopamine metabolism. The effect of control and serious complications of repeated administrations of THC or WIN, a diabetesCS299. synthetic cannabinoid receptor agonist, on Digital necrosis. An 18-year-old woman, dopamine turnover in the prefrontal cortex, with a history of severe anorexia nervosa of striatum, and Nac in rats, was investi- 5 years’ duration, who acknowledged regu- gated. THC or WIN (twice daily for seven lar use of tobacco and cannabis, was hospi- or 14 days) caused a persistent and selec- talized for necrosis of the left index and tive reduction in medial prefrontal corti- thumb that had occurred shortly after left cal dopamine turnover. No significant radial artery puncture for blood gas analysis. alterations of dopamine metabolism were Acrocyanosis of the four limbs had been observed in the Nac or striatum. These present since the onset of anorexia nervosa. dopaminergic deficits in the prefrontal cor- Arteriography of the upper limbs showed tex were observed after a drug-free period of major spasm of the left radial and cubital up to 14 days. The cognitive dysfunction arteries and thromboses in the left inter- produced by heavy, long-term cannabis use digital arteries of the left index and thumb. may be subserved, in part, by drug-induced The distal portions of the arteries were then alterations in frontal cortical dopamine on the left and on the right. The necrotic turnoverCS346. Two weeks’ administration of lesions healed after intravenous adminis- THC to rats, reduced dopamine transmis- tration of ilomedine and interruption of sion in the medial prefrontal cortex, tobacco and cannabis. Acrocyanosis of the whereas dopamine metabolism in striatal four limbs persistedCS398. regions was unaffectedCS434. CANNABIS SATIVA 61

Dopamine release. A 38-year-old drug- Then a randomized, placebo-controlled free schizophrenic patient took part in a crossover study was performed, in which 19 single photon emission computerized tomo- patients with PD were randomized to graphic study of the brain, and smoked can- receive oral cannabis extract followed by nabis secretively during a pause in the placebo or vice versa. Each treatment phase course of an imaging session. Cannabis had lasted for 4 weeks with an intervening 2- an immediate calming effect, followed by a week washout phase. The primary outcome worsening of psychotic symptoms a few measure was a change in Unified Parkin- hours later. A comparison of the two sets of son’s Disease Rating Scale (UPDRS) (items images, obtained before and immediately 32 to 34) dyskinesia score. Secondary out- after smoking cannabis, indicated a 20% come measures included the Rush scale, decrease in the striatal dopamine D2 recep- Bain scale, tablet arm drawing task, and tor-binding ratio, suggestive of increased total UPDRS score following a levodopa synaptic dopaminergic activityCS399. challenge, as well as patient-completed Dopamine transmission modulation. The measures of a dyskinesia activities of daily endogenous cannabinoid system is a new living scale, the PDQ-39, on–off diaries, and signaling system composed by the central a range of category rating scales. Seventeen (CB1) and the peripheral (CB2) receptors, patients completed the study. Cannabis and several lipid transmitters including was well tolerated and had no pro- or anti- AEA and 2-arachidonylglycerol. Cannab- parkinsonian action. There was no evidence inoid CB1 receptors are present in dopam- for a treatment effect on L-DOPA-induced ine projecting brain areas. In primates and dyskinesia as assessed by the UPDRS, or certain rat strains it is also located in any of the secondary outcome mea- dopamine cells of the A8, A9, and A10 mes- suresCS259. An anonymous questionnaire encephalic cell groups, as well as in hypo- sent to all patients attending the Prague thalamic dopaminergic neurons controlling Movement Disorder Center revealed that prolactin secretion. CB1 receptors co-local- 25% of 339 respondents had taken cannabis ize with dopamine D1/D2 receptors in and 45.9% of these described some form of dopamine projecting fields. Manipulation of benefitCS262. 2,4,5-Trihydroxyphenethyla- dopaminergic transmission is able to alter mine (6-hydroxydopamine)-lesioned rats the synthesis and release of AEA, as well as were treated with the enantiomers of the the expression of CB1 receptors. CB1 recep- synthetic cannabinoid 7-hydroxy-∆6-THC tors can switch their transduction mecha- 1,1-dimethylheptyl. Treatment with its (-)- nism to oppose to the ongoing dopamine (3R, 4R) enantiomer (code name HU-210), signaling. Acute blockade of CB1 receptor a potent cannabinoid receptor type 1 ago- potentiates the facilitatory role of dopam- nist, reduced the rotations induced by ine D2 receptor agonists on movement. CB1 L-DOPA/carbidopa or apomorphine by 34 stimulation results in sensitization to the and 44%, respectively. Treatment with the motor effects of indirect dopaminergic (+)- (3S, 4S) enantiomer (code name agonistsCS291. HU-211), an N-methyl-D-aspartate antago- Dyskinetic activity. A 4-week dose escala- nist, and the psychotropically inactive can- tion study was performed to assess the nabis constituent: CBD and its primary safety and tolerability of cannabis in six metabolite, 7-hydroxy-cannabinol, did not patients with Parkinson’s disease (PD) with show any reduction of rotational behavior. levodopa (L-DOPA)-induced dyskinesia. The results indicate that activation of the 62 MEDICINAL PLANTS OF THE WORLD

CB1 stimulates the dopaminergic system serum prolactin abruptly. None of the can- ipsilaterally to the lesion, and may have nabinoid receptor agonists affected serum implications in the treatment of PDCS338. growth hormoneCS420. Dystonic activity. The neural mechanisms Environmental stress and cannabinoids underlying dystonia involve abnormalities interaction. Anxiety and panic are the within the basal ganglia—in particular, most common adverse effects of cannabis overactivity of the lateral globus pallidus. intoxication. Data suggest that cannabinoid Cannabinoid receptors are located presyn- CB1 receptor modulation of amygdalar aptically on γ-aminobutyric acid receptor activity contributes to these phenomena. (GABA) terminals within the globus palli- Using Fos as a marker, it was tested the dus internus, where their activation reduces hypothesis that environmental stress and GABA reuptake. Cannabinoid receptor CB1 cannabinoid receptor activity interact stimulation may thus reduce overactivity of in the regulation of amygdalar activation in the globus pallidus, and thereby reduce dys- male mice. Both 30 minutes of restraint and tonia. A double-blind, randomized, pla- CB1 receptor agonist treatment (∆-9-THC cebo-controlled, crossover study using the [2.5 mg/kg]) or CP-55,940 (0.3 mg/kg); by synthetic cannabinoid receptor agonist intraperitoneal injection) produced barely nabilone in patients with generalized and detectable increases in Fos expression segmental primary dystonia showed no sig- within the central amygdala (CeA). The nificant reduction in dystonia following combination of restraint and CB1 agonist treatment with nabiloneCS390. administration produced robust Fos induc- Embryotoxic effect. Resin, administered tion within the CeA, indicating a synergis- orally to pregnant rabbits at a dose of 1 mL/ tic interaction between environmental kg, was activeCS167. stress and CB1 receptor activation. An Endocrine effect. Animal models have inhibitor of endocannabinoid transport, demonstrated that cannabinoid administra- AM404 (10 mg/kg), produced an additive tion acutely altered multiple hormonal sys- interaction with restraint within the CeA. tems, including the suppression of the In contrast, FAAH inhibitor-treated mice gonadal steroids, growth hormone, prolac- (URB597, 1 mg/kg) and FAAH (–/–) mice tin, and thyroid hormone and the activation did not exhibit any differences in amygdalar of the hypothalamic–pituitary–adrenal activation in response to restraint compared (HPA) axis. These effects were mediated by with control mice. In the basolateral binding to the endogenous cannabinoid amygdala (BLA) and medial amygdala, receptor in or near the hypothalamus. restraint stress produced a low level of Fos Despite these findings in animals, the effects induction, which was unaffected by cannab- in humans have been inconsistent, and dis- inoid treatment. The CB1 receptor antago- crepancies were likely owing in part to the nist SR141716 dose-dependently increased development of toleranceCS363. Intravenous Fos expression in the BLA and CeACS272. administration of three cannabinoid ago- Epileptic effect. ∆-9-THC at a dose of 1 µM, nists (AEA, , and WIN) significantly depressed evoked depolariz- to nine castrated male calves under stress- ing postsynaptic potentials (PSPs) in rat free conditions provoked immediate olfactory cortex neurones. A standardized increases of serum cortisol and respiration cannabis extract (SCE) and ∆-9-THC-free rate, and produced rapid hypoalgesia to SCE significantly potentiated evoked PSPs cutaneous pain and thermal stimuli. AEA (all results were fully reversed by the CB1 and methanandamide did not affect serum receptor antagonist SR141716A, 1 µM). prolactin. Administration of WIN increased The potentiation by ∆-9-THC-free SCE CANNABIS SATIVA 63 was greater than that produced by SCE. intubation to rats at a dose of 75 mg/kg for On comparing the effects of ∆-9-THC-free 70 days, was activeCS224. SCE on evoked PSPs and artificial PSPs Estrogen receptors stimulating effect. (aPSPs; evoked electrotonically following THC, CBD, and desacetyllevonantradol, in brief intracellular current injection), PSPs estrogen-induced MCF-7 breast cancer cells were enhanced, whereas aPSPs were unaf- at concentrations of no more than 10 µM, fected, suggesting that the effect was not re- produced no effect. THC failed to antago- sulting from changes in background input nize the response to estradiol under condi- resistance. Similar recordings made using tions in which the antiestrogen LY156758 CB1 receptor-deficient knockout mice and (keoxifene; raloxifene) was effective. The wild-type littermate controls revealed can- phytoestrogen formononetin behaved as an nabinoid or extract-induced changes in estrogen at high concentrations, and this membrane resistance, cell excitability and response was antagonized by LY156758. synaptic transmission in wild-type mice that THC, desacetyllevonantradol, or CBD did were similar to those seen in rat neurones, not stimulate transcription of an EREtkCAT but no effect on these properties were seen reporter gene transiently transfected into in CB1 receptor-deficient knockout mice MCF-7 cellsCS452. cells. Results indicated that the unknown Estrogenic effect. Petroleum ether extract extract constituent(s) effects over-rode the of the resin was active on the rat non-preg- suppressive effects of ∆-9-THC on excita- nant uterusCS130. Resin, in the ration of tory neurotransmitter release, which may immature and ovariectomized rats at a con- explain some patients’ preference for herbal centration equivalent to 250 ppm THC/ani- cannabis rather than isolated ∆-9-THC mal, was inactive CS236,CS162. (owing to attenuation of some of the cen- Estrous cycle disruption effect. Ethanol tral ∆-9-THC side effects) and possibly (95%) extract of the dried aerial parts, account for the rare incidence of seizures in administered intraperitoneally to gerbils at some individuals taking cannabis recrea- a dose of 2.5 mg/animal daily for 60 days, tionallyCS278. A SCE with pure ∆-9-THC, at was activeCS184. Petroleum ether extract of matched concentrations of ∆-9-THC, and a the dried aerial, administered intraperi- ∆-9-THC-free extract (∆-9-THC-free SCE) toneally to mice and rats at doses of 1 and 5 in in vitro rat brain slice model of epilepsy mg/animal, respectively, for 64 days, was were examined. In the in vitro epilepsy activeCS174. Petroleum ether extract of the model, in which sustained epileptiform aerial parts, administered intraperitoneally seizures were induced by the muscarinic to female rats, produced weak activityCS016. receptor agonist oxotremorine-M in imma- Petroleum ether extract of the entire plant, ture rat piriform cortical brain slices, SCE administered by gastric intubation to female was a more potent and again more rapidly- mice at doses of 75 mg/kg and 150 mg/kg, acting anticonvulsant than isolated ∆-9- was active. A dose of 3 mg/kg produced THC. ∆-9-THC-free extract also exhibited weak activityCS170. Petroleum ether extract of anticonvulsant activity. CBD did not the resin, administered intraperitoneally to inhibit seizures, nor did it modulate the female rats at doses of 10 and 20 mg/kg, was activity of ∆-9-THC in this model. These activeCS187. Resin, administered orally to results demonstrated that not all of the female rats at doses of 3, 15, and 75 mg/kg therapeutic actions of cannabis herb might daily for 72 days, was activeCS168. be a result of the ∆-9-THC contentCS312. Familial Mediterranean fever. A patient Estrogen cycle disruption effect. The with familial Mediterranean fever was pre- dried aerial part, administered by gastric sented with chronic relapsing pain and 64 MEDICINAL PLANTS OF THE WORLD inflammation of gastrointestinal origin. restrictive symptoms only, 17 with purging After determining a suitable analgesic dos- symptoms. The rates of drug use between age, a double-blind, placebo-controlled, subjects and their comparison groups were crossover trial was conducted using 50 mg compared by Z-scores, with the level of sig- of ∆-9-THC daily in five doses in the active nificance set at 0.05. During the preceding weeks and measuring effects on parameters year, restrictors used significantly less to- of inflammation and pain. Although no bacco, alcohol, and cannabis than grade- anti-inflammatory effects of ∆-9-THC were and sex-matched comparison populations, detected during the trial, a highly signifi- and purgers used these substances at rates cant reduction (p < 0.001) in additional similar to those of comparison subjects. analgesic requirements was achievedCS447. Other drugs seen frequently in the purgers Fish poison. Ethanol (95%) extract of the included , tranquilizers, dried aerial parts at a concentration of 1:1 stimulants, LSD, phencyclidine, cocaine, was active. The water extract was inac- and ecstasy. Both groups used caffeine and tiveCS243. laxatives, but few used diet pills. Restrictors Follicle-stimulating hormone release said they did not use substances because inhibition. Ethanol (95%) extract of the they were bad for their health, tasted dried resin, administered intraperitoneally unpleasant, were contrary to their beliefs, to toads at a dose of 10 mg/day for 14 days, and were too expensive. Purgers generally was active. The results were significant at used substances to relax, relieve anger, avoid p < 0.01 levelCS216. eating, and “get away” from problems. Food intake modulation. Cannabis sativa Female adolescents with eating disorders stimulates appetite, especially for sweet and who have restrictive symptoms use sub- palatable food. Cannabinoid action has stances less frequently than the general ado- proposed a central role of the cannabinoid lescent population but do not abstain from system in obesityCS352. Dronabinol, a com- their use. Those with purging symptoms use mercially available form of a THC, has been substances with a similar frequency to that used successfully for increasing appetite in found in the general adolescent popu- patients with HIV wasting disease. Cannab- lationCS372. inoid receptor antagonist may reduce Gastric secretory inhibition. Petroleum obesityCS353. To determine the prevalence of ether extract of the dried aerial parts, substance use in adolescents with eating dis- administered intraperitoneally to male rats, orders, the results of a data set of Ontario was activeCS097. high school students were compared. One Gene expression effect. Cannabinoids can hundred and one female adolescents who cross the placental barrier and be secreted met the Diagnostic and Statistical Manual of in the maternal milk. Through this way, Mental Disorders, 4th edition’s criteria for an cannabinoids affect the ontogeny of various eating disorder were followed up in a tertiary neurotransmitter systems leading to changes care pediatric treatment center. They were in different behavioral patterns. Dopamine asked to participate in a cross-sectional and endogenous opioids are among the neu- study using a self-administered question- rotransmitters that result more affected by naire assessing substance use and investigat- perinatal cannabinoid exposure, which, ing reasons for use and nonuse; 95 agreed to when animals mature, produce changes in participate and 77 completed the question- motor activity, drug-seeking behavior, naire (mean age, 15.2 years). The patients nociception, and other processes. These dis- were divided into two groups: 63 with turbances are likely originated by the capa- CANNABIS SATIVA 65 bility of cannabinoids to influence the culture via sustained ceramide accumula- expression of key genes for both neurotrans- tion, extracellular signal-regulated kinase mitters, in particular, the enzyme tyrosine activation and Akt inhibition. Cannab- hydroxylase and the opioid precursor pro- inoid treatment inhibited angiogenesis of enkephalin. Cannabinoids seem to be able gliomas in vivo. Cannabinoids killed glioma to influence the expression of genes encod- cells selectively and could protect ing for neuroglia cell adhesion molecules, nontransformed glial cells from deathCS273. which supports a potential influence of Glucosidase inhibition. Ethyl acetate and cannabinoids on the processes of cell prolif- water-soluble fractions of the dried aerial eration, neuronal migration or axonal elon- parts were inactive on the intestineCS128. gation in which these proteins are involved. Gynecomastic effect. A retrospective CB1 receptors, which represent the major analysis was carried out on 175 men over the targets for the action of cannabinoids, are age of 16 years who were presented with abundantly expressed in certain brain breast enlargement and/or “lumps” during a regions, such as the subventricular areas, 7-year period to a single surgeon. The which have been involved in these pro- patients had complete biochemical assess- cesses during brain development. Cannab- ment (liver function tests, γ-glutamyl inoids might also be involved in the transferase, prolactin, α-fetoprotein, and β- apoptotic death that occurs during brain human chorionic gonadotropin), and development, possibly by influencing the mammography and/or ultrasound with fine- expression of Bcl-2/Bax system. CB1 recep- needle biopsy if indicated. Thirty-nine of tors are transiently expressed during brain the patients had bilateral true gynecomastia development in different group of neurons and 88 had unilateral gynecomastia (53% which do not contain these receptors in the left). Carcinoma of the breast was diagnosed adult brainCS254. in eight, pseudo-gynecomastia in 18, 13 had Glaucoma effect. Nine patients with glau- physiological pubertal changes only, and 9 coma unresponsive to treatment were had other diagnoses. Adverse drug reactions treated with orally administered ∆-9-THC were possibly implicated in the etiology of capsules or inhaled cannabis in addition to 47 patients, alcohol in seven patients, can- their existing therapeutic regimen. An ini- nabis in one patient, testicular malignancy tial decrease in intraocular pressure was in four patients, and hepatocellular carci- observed in all patients, and the investi- noma in one patient. Five patients were gator’s therapeutic goal was met in four of found to have hyperprolactinemia. Twenty- the nine patients. The decreases in intra- four percent of patients were reassured with- ocular pressure were not sustained, and the out intervention; 18% failed to attend patients elected to discontinue treatment follow-upCS348. within 1–9 months for various reasonsCS359. Hair stimulant effect. Ethanol (50%) Gliomatous effect. Gliomas, in particular extract of the dried seed, applied externally glioblastoma multiform or grade IV astrocy- to mice at a dose of 0.33 g/mL for 14 days, toma, are the most frequent class of malig- was inactiveCS139. nant primary brain tumors and one of the Hemagglutinin activity. Saline extract of most aggressive forms of cancer. Cannab- the dried seed at a concentration of 10% was inoids and their derivatives slowed the inactive on the human red blood cell CS207. growth of different types of tumors, includ- Hepatitis C risk factor. The study of a ing gliomas, in laboratory animals. Cannab- dually diagnosed population estimated the inoids induced apoptosis of glioma cells in prevalence of hepatitis C virus (HCV) to be 66 MEDICINAL PLANTS OF THE WORLD

29.7% or 16 times higher than that in the a significantly higher number of women general population. A high correlation was used cannabis for pain management. The found between the use of tobacco and HCV most commonly reported reason for medici- infection. This appears to be beyond the risk nal cannabis use was appetite stimulation/ factor conveyed by intravenous drug use. weight gain. Male gender and history of Of the patients whose primary diagnoses intravenous drug use were predictive of any were cocaine, opiate, amphetamine, or cannabis use. Age, gender, HIV clinical polysubstance dependence (drugs often status, antiretroviral use, and history of used intravenously), 42% of the tobacco intravenous drug use were not significant users were HCV-positive, whereas only predictors of medicinal cannabis use. 20% of the nontobacco using patients with Despite the frequency of medicinal use, similar primary diagnoses were HCV-posi- minimal changes in the pattern of cannabis tive. The association of tobacco use with use on HIV diagnosis were reported with HCV was found to be strong for females 80% of current medicinal users also indicat- with alcohol, sedative/hypnotic, inhalant, ing recreational consumptionCS289. HIV or cannabis dependence, as none of the patients (n = 252) were recruited via 17 nontobacco using female patients with consecutive sampling in public health care these diagnoses were HCV-positive, whereas clinics. Structured interviews assessed pat- 14 of the 45 (31%) tobacco-using females terns of recent cannabis use, including its with these diagnoses did test positive perceived benefit for symptom relief. for HCVCS306. Associations between cannabis use and Hepatotoxic activity. Ethanol (95%) demographic and clinical variables were extract of the dried resin, administered examined using univariate and multivariate intraperitoneally to toads at a dose of 10 mg/ regression analyses. Overall prevalence of day for 14 days, was active. The results were smoked cannabis in the previous month was significant at p < 0.01 levelCS216. 23%. Reported benefits included relief of Histamine release stimulation. Water anxiety and/or depression (57%), improved extract of the seed, administered intrader- appetite (53%), increased pleasure (33%), mally to human adults, was active on human and relief of pain (28%). Recent use of can- basophilsCS147. nabis was positively associated with severe HIV involvement. The prevalence, predic- nausea (OR = 4, p = 0.004) and recent use tors, and patterns of cannabis use—specifi- of alcohol (OR = 7.5, p < 0.001) and nega- cally medicinal cannabis use among patients tively associated with being Latino (OR = with HIV—were examined. Any cannabis 0.07, p < 0.001). No associations between use in the year prior to interview and self- cannabis use and pain symptoms were defined medicinal use were evaluated. A observedCS315. No safety problems specific to cross-sectional multicenter survey and ret- HIV or protease inhibitors were found in a rospective chart review were conducted to study in which volunteers stayed in a evaluate overall drug utilization in HIV, research hospital 24 hours a day and were including cannabis use. HIV-positive adults randomly assigned to either smoke can- were identified through the HIV Ontario nabis, take oral THC, or take an oral Observational Database; 104 consenting placebo. Cannabis and THC use was associ- patients were interviewed. Forty-three per- ated with weight gainCS369. cent of the patients reported cannabis use, Hyperglycemic activity. Ethanol (95%) whereas 29% reported medicinal use. Rea- extract of the leaf, administered intrave- sons for use were similar by gender although nously to rats at a dose of 300 mg/kg, pro- CANNABIS SATIVA 67 duced an increase of 40 mg percentage 2 made, using automated immunoassays, of hours postinjection and a corresponding de- the presence of cannabis, cocaine, amphet- crease in liver glycogenCS163. Ethanol (95%) amine, methamphetamine, MDMA, methyl- extract of the dried leaf, administered by enedioxyethylamphetamine (MDE), and gastric intubation to rabbits, produced an opiates. Positive results were confirmed by increase followed by a gradual decrease in gas chromatography–mass spectrometry. blood sugar levelsCS021. The dried leaves, Eleven US plasma units were found to be smoked by human adults, produced elevated positive for cocaine (14.6%), whereas all glucose levels in two out of four subjects and German samples were cocaine-negative (p no impairment of insulin release or changes = 0.0007). Fifteen US plasma units (20%) in growth hormone levelsCS024. and one German unit (1.3%) were con- Hypertensive activity. Ethanol (95%) and firmed as positive for cannabis (p = 0.0003). water extracts of the dried aerial parts, Three out of 75 US plasma units were posi- administered intravenously to cats, were tive for both cannabis and cocaine. In none inactive. The ethanol extract stimulated of the 150 samples were amphetamine, respiration and the water extract had no methamphetamine, MDMA, MDE, or opi- effect on respirationCS243. ates detected CS355. Hypoglycemic activity. Ethanol (95%) Immunomodulatory effect. The smoking extract of the dried leaf, administered by of cannabis showed a significant local gastric intubation to rabbits, produced an immunosuppression of the bactericidal increase, followed by a gradual decrease, in activity of human alveolar macrophages. In blood sugar levelsCS021. Extract of the dried animal studies, cannabinoids were identi- leaf, administered subcutaneously to rabbits fied as potent modulators of cytokine pro- at a dose of 0.5 mL/kg (approx 0.6 mg THC) duction, causing a shift from T-helper-1 for 9 weeks, further enhanced hypoglycemia (Th1) to Th2 cytokines. In consequence, induced by insulin. No hypoglycemic effect a compromised cellular immunity was was seen in normal animalsCS025. Hot water observed in these animals, resulting in extract of the resin, administered by gastric enhanced tumor growth and reduced intubation to dogs at a dose of 20 g of air- immunity to viral infections. In vitro, dried resin/animal, produced weak immunosuppressive effects were shown activityCS198. The dried leaf, smoked by adults in all immune cells, but only at high micro- at a dose of 2 g/person, was inactiveCS023. molar cannabinoid concentrations not Hypotensive activity. Ethanol (50%) reached under normal clinical conditions. extract of the entire plant, administered In conclusion, there was no evidence that intravenously to dogs at a dose of 50 mg/kg, cannabinoids induce a serious, relevant was activeCS007. Ethanol (95%) and water immunosuppression in humans, with the extracts of the dried aerial parts, adminis- exception of cannabis smoking, which may tered intravenously to cats, were inactive. affect local bronchoalveolar immunityCS279. The ethanol extract stimulated respiration, The immune function in 16 MS patients and the water extract had no effectCS243. treated with oral cannabinoids was mea- Ilicit drug in plasmapheresis donors. Sev- sured. A modest increase of tumor necrosis enty-five US plasma units from 10 different factor (TNF)-α in lipopolysaccharide- states in the United States and 75 German stimulated whole blood was found during plasma units that had been analyzed princi- cannabis plant-extract treatment (p = pally for their protein composition were 0.037), with no change in other cytokines. screened for drugs. Determinations were In the subgroup of patients with high 68 MEDICINAL PLANTS OF THE WORLD adverse event scores, an increase in plasma sudden infant death syndrome (SIDS); 58% IL-12p40 was found (p = 0.002). The results were positive for drugs, predominantly indicate pro-inflammatory disease-modify- cocaine. The odds ratio for SIDS among ing potential of cannabinoids in MSCS347. drug-positive infants was 1.5 (CI = 0.46– THC and their metabolites inhibited pro- 5.01) and 1.9 (CI = 0.58–6.2) among duction of IL-1 and γ-interferon, decreased cocaine-positive infantsCS445. a 33% of the lymphocytes activity and Infant neurobehavioral effect. The sub- inhibited 66% of the lymphocytes adenyl- jects and controls in this study were full- cyclase activity. The consumption of can- term infants of appropriate gestational age nabis decreased immunological competence with no medical problems. At 1–2 days of of macrophages, and alternated their essen- age, 20 infants exposed to cocaine, alcohol, tial role of trophicity of the central nervous cannabis, and cigarettes, 17 infants exposed system. Inhibiting actions of cannabinoids to alcohol and/or cannabis and cigarettes, on the cyclo-oxygenase, promoted produc- and 20 drug-free infants were evaluated by tion of arachidonic acid degradation prod- using the Neonatal Intensive Care Unit ucts. This compound mimics the action of Network Neurobehavioral Scale. Cocaine- histamine, induced a raise of the vascular exposed (CE) infants showed increased tone permeability and bronchospasm, and con- and motor activity, more jerky movements, tributed at delayed reaction of anaphy- startles, tremors, back arching, and signs of laxiaCS427. central nervous system and visual stress than Infant mortality. For a period of 11 months, unexposed infants. They also showed poorer 2964 infants were enrolled and screened at visual and auditory following. There were birth for exposure to cocaine, opiate, or can- no differences in how the examination was nabinoid by meconium analysis. At birth, administered to CE and nonexposed infants. 44% of the infants tested positive for drugs, Reduced birth-weight and length were also 30.5% positive for cocaine, 20.2% for opi- observed in CE infants. Differences attrib- ate, and 11.4% for cannabinoids. Compared utable to CE infants were related to muscle with the drug-negative group, a significantly tone and motor performance, following dur- higher percentage (p < 0.05) of the drug- ing orientation, and signs of stress. CE positive infants had lower weight and infants were not more difficult to test, nor smaller head circumference and length at did they require an alteration in the exami- birth and a higher percent of their mothers nation. Both neurobehavioral patterns of were single, multigravid, multiparous, and excitability and lethargy were observed. The had little to no prenatal care. Within the findings may have been a result of the syn- first 2 years of life, 44 infants died: 26 were ergistic effects of cocaine with alcohol and drug-negative (15.7 deaths per 1000 live cannabisCS456. births) and 18 were drug-positive (13.7 Inflammatory effect. A case of a 17-year- deaths per 1000 live births). The mortality old male regular cannabis user who devel- rate among cocaine, opiate, or cannabinoid- oped a large swollen uvula (uvulitis) and positive infants were 17.7, 18.4, and 8.9 per partial upper airway obstruction after 1000 live births, respectively. Among smoking cannabis was evaluated. Symp- infants with birth-weight of 2500 g or less, toms resolved with the administration of infants who were positive for both cocaine corticosteroids and antihistaminesCS380. A and morphine had a higher mortality rate healthy 17-year-old man who inhaled (OR = 5.9, CI = 1.4–24) than drug-nega- cannabis prior to general anesthesia is tive infants. Eleven infants died from the described. In the recovery room, after an CANNABIS SATIVA 69 uneventful general anesthetic, acute uvular were added prior to ethanol extract of can- edema resulted in postoperative airway nabis to determine their effect on Na+ and obstruction and admission to the hospital. Cl– movement. The results suggested that The uvular edema was treated successfully the extract may affect the Cl– movement with dexamethasoneCS455. more directly than Na+ movement in the Information-processing effect. Informa- intestinal epithelial cellsCS307. tion processes are thought to represent the Intraocular pressure reduction. Polysac- basic building blocks of higher order cogni- charide fraction of the dried entire plant, tive processes. The inspection time task was administered intravenously to rabbits at a used to investigate the effects of acute and dose of 1 µg/animal was activeCS138. Water subacute cannabis use on information pro- extract of the dried aerial parts, adminis- cessing in 22 heavy users compared with 22 tered intravenously to rabbits at a dose of nonusers. The findings indicated that users 250 µg/animal, was activeCS142. A dose of 5 in the subacute state display significantly µg/animal was inactive on Rhesus monkeys slowed information-processing speeds and active on rabbits. A dose of 10 mg/ani- (longer inspection times) compared with mal, administered per rectum to Rhesus controls. This deficit appeared to be nor- monkeys and rabbits, was inactiveCS191. malized while users were in the acute state. IQ effect. Cannabis use for 70 individuals These results may be explained as a with- aged 17–20 years was determined through drawal effect, but may also be owing to tol- self-reporting and urinalysis. IQ scores were erance development because of long-term calculated by subtracting each person’s IQ cannabis useCS276. score at 9–12 years (before initiation of drug Insecticidal activity. Leaf extract, admin- use) from his or her score at 17–20 years. istered to larvae of Chironomus samoensis, The difference in IQ scores of current heavy produced paralysis leading to death. The users (at least five joints per week), current extract brought a drastic change in the mor- light users (less than five joints per week), phology of sensilla trichoidea, the general former users (who had not smoked regularly body cuticle, and a significant reduction in for at least 3 months), and nonusers (who the concentration of magnesium and iron, never smoked more than once per week and whereas manganese showed only slight no smoking in the past 2 weeks) was com- average increase. Because the sensilla pared. Current cannabis use was signifi- trichoidea has nerve connections, it was cantly correlated (p < 0.05) in a dose-related assumed that the toxic principle of the leaf fashion with a decline in IQ over the ages extract has affected the central nervous studied. The comparison of the IQ differ- systemCS267. ence scores showed an average decrease of Intestinal motility activity. Rat intestinal 4.1 points in current heavy users (p < 0.05) epithelia mounted in an Ussing chamber compared with gains in IQ points for light attached with voltage/current clamp were current users (5.8), former users (3.5), and used for measuring changes of the short-cir- nonusers (2.6)CS385. cuit current across the epithelia. The intes- Lactate inhibition. The dried leaf, smoked tinal epithelia were activated with current by adults at a dose of 2 g/person, decreased raised by serosal administration of forskolin blood lactic acidCS023. 5 µM. Ethanol extracts of cannabis aug- Leutinizing hormone-release inhibition. mented the current additively when each The dried aerial part, smoked by meno- was added after forskolin. In subsequent pausal women at a dose of 1 g/person, was experiments, ouabain, and bumetanide inactiveCS225. When administered to normal 70 MEDICINAL PLANTS OF THE WORLD and castrated male rats, at a dose of 75 mg/ years. Cannabis and tobacco smoking were kg, was activeCS215. documented at each age using a standard- Lower limb occlusive arteriopathy. Sev- ized interview. Lung function, as measured enty-three patients (60 males and 13 by the FEV1–vital capacity (VC) ratio, was females less than 50 years of age) were obtained by simple spirometry. A fixed divided into four groups: Buerger’s disease effects regression model was used to analyze (thromboangiitis obliterans [TAO]), the data and to account for confounding atheromatous juvenile peripheral obstruc- factors. When the sample was stratified for tive arterial diseases (POAD), autoimmune cumulative use, there was evidence of a POAD, and arteriopathy of undetermined linear relationship between cannabis use origin. The first symptoms occurred at 38 ± and FEV1–VC (p < 0.05). In the absence of 8 years of age. Fourteen patients (20%) had adjusting for other variables, increasing can- TAO, 51 (70%) atheromatous POAD, 4 nabis use over time was associated with a (5%) POAD with systemic or autoimmune decline in FEV1–VC with time; the mean disease, and 4 (5%) undetermined POAD. FEV1–VC among subjects using cannabis Age of onset was earlier in TAO (35 ± 8 vs on 900 or more occasions was 7.2, 2.6 and 40 ± 8 years, p = 0.046), smoking was greater 5% less than nonusers at ages 18, 21, and in the atheroma group (33 ± 16 vs 24 ± 14 26, respectively. After controlling for pack/years, p = 0.033). Fifty-three patients potential confounding factors (age, tobacco with POAD had dyslipidemia and 26% had smoking, and weight) the negative effect of hypertension. Regular cannabis intake was cumulative cannabis use on mean FEV1– more frequent in the TAO group (21% vs VC was only marginally significant (p < 8%). At the time of medical care, Fontaine’s 0.09). Age (p < 0.001), cigarette smoking stage was more frequently stage II in (p < 0.05), and weight (p < 0.001) were all atheroma patients (57% vs 14%) and stage significant predictors of FEV1–VC. Can- IV in TAO patients (86% vs 35%). TAO nabis use and daily cigarette smoking acted was diagnosed in 43% cannabis users and additively to influence FEV1–VC. Results in 19% nonusers. Results indicated that indicated that longitudinal observations the main etiology of juvenile POAD is over 8 years in young adults revealed a dose- atheroma, followed by TAO. Cannabis dependent relationship between cumula- users accounted for at least 10% of these tive cannabis consumption and decline patients. They were characterized by lower in FEV1–VC. When confounders were tobacco intake, more distal lesions, more accounted for the effect was reduced and frequent involvement of the upper limbs. was only marginally significant, but given They presented more frequently as TAOCS379. the limited time frame over which observa- A case of a 30-year-old woman who smoked tions were made, the trend suggests that cannabis and developed intermittent clau- continued cannabis smoking has the poten- dication of the lower limbs was reported. tial to result in clinically important impair- Results indicated that cannabis could be ment of lung functionCS371. involved not only in the pathogenesis of Luteolytic effect. The aerial parts, smoked juvenile obstructive arteriopathy, but by a chronic high-dose user, were inac- also in the development of atheromatous tiveCS160. lesionsCS409. Memory impairment. The effects of com- Lung function. A group of over 900 young bined exposure to ethanol and ∆-9-THC in adults derived from a birth cohort of 1037 a memory task was investigated in rats. subjects were studied at age 18, 21, and 26 Ethanol, voluntarily ingested in alcohol- CANNABIS SATIVA 71 preferring rats, and THC, given by intrap- enhanced the ability of cell-mediated type eritoneal injection, had a synergic action to hypersensitivity and nonspecific immune impair object recognition when a 15-minute responses in normal miceCS334. interval was adopted between the sample Mitochondrial function disruption. ∆-9- phase and the choice phase of the test. THC in the pulmonary transformed cell line Ingestion of ethanol, or 2 or 5 mg/kg of A549 produced a rapid and extensive THC were not able to modify object recog- depletion of cellular energy stores. Adenos- nition in these experimental conditions. ine 5'-triphosphatase levels declined dose

When voluntary ethanol ingestion was dependently with an IC50 of 7.5 µg/mL of combined with administration of these THC after 24 hours of exposure. Cell death doses of THC, object recognition was mark- was observed only at concentrations greater edly impaired. THC impaired object recog- than 10 µg/mL. Studies using JC-1, a fluo- nition only at the dose of 10 mg/kg, when rescent probe for mitochondrial membrane its administration was not combined with potential, revealed diminished mitochon- that of ethanol. The selective cannabinoid drial function at THC concentrations as CB1 receptor antagonist SR 141716A (N- low as 0.5 µg/mL. At concentrations of (piperidin-1-yl)-5-(4-chlorophenyl)-1(2, 4- 2.5 and 10 µg/mL of THC, a decrease in dichloro-phenyl)-4-methyl-1H-pyrazole mitochondrial membrane potential was ob- carboxamide HCl) at the dose of 1 mg/kg served 1 hour after THC exposure. Mito- reversed the amnesic effect of 10 mg/kg of chondrial function remained diminished THC. This indicated that the effect is for at least 30 hours after THC exposure. mediated by the receptor subtype. The syn- Flow cytometry studies on cells exposed to ergism of ethanol and THC was not particulate smoke extracts indicated that detected when an intertrial interval of 1 JC-1 red fluorescence was fivefold lower in minute was adoptedCS370. cells exposed to cannabis smoke extract Memory improvement. Extract from fruc- compared with tobacco smoke-exposed tus cannabis (EFC), administered intra- cells. Comparison with a variety of mito- gastrically to mice with drug-induced chondrial inhibitors demonstrated that dysmnesia at doses of 0.2, 0.4, and 0.8 g/kg, THC produced effects similar to that of for 7 days, prolonged the latency and carbonyl cyanide p-trifluoromethoxyphe- decreased the number of errors in the step- nylhydrazone, suggesting uncoupling of down test, and enhanced the spatial resolu- electron transport. Loss of red JC-1 fluores- tion of amnesic mice in water maze test. cence by THC was suppressed by cyclo- EFC at the dose of 0.2 g/kg overcame amne- sporin A, suggesting mediation by the sia of three stages of memory process. EFC mitochondrial permeability transition pore. activated calcineurin activity at a concen- This disruption of mitochondrial function tration range of 0.01–100 g/L. The maximal was sustained for at least 24 hours after re- value of EFC on calcineurin activity (35% moval of THC by extensive washingCS360. ± 5 %) appeared at a concentration of 10 g/ Mitogenic effect. The resin was inactive LCS320. EFC with activation of calcineurin, on the human and rat white blood cellsCS037. extracted from Chinese traditional medi- Molluscicidal activity. Ethanol (95%) and cine, was used to determine the effects on water extracts of the dried flowering tops, at memory and immunity in mice. In the step- a concentration of 1000 ppm, produced down-type passive avoidance test, the plant weak activity on Biomphalaria straminea and extract (0.2 g/kg) significantly improved Biomphalaria glabrataCS245. Water saturated amnesia induced by drugs, and greatly with essential oil of the aerial parts, at a con- 72 MEDICINAL PLANTS OF THE WORLD centration of 1:2, produced weak activity on (p = 0.0111)CS257. A cannabis-based medici- Biomphalaria glabrataCS201. nal extract (CBME) was administered to Motor function. Nine cannabis smokers 160 patients with multiple sclerosis experi- and 16 controls were studied to determine encing significant problems from at least the attentional areas related to motor func- one of the following: spasticity, spasms, tion, and primary and supplementary motor bladder problems, tremor, or pain. The cortices. Echo planar images and high-reso- interventions were oromucosal sprays of lution molecular resonance images were ac- matched placebo, or whole plant CBME quired. The challenge paradigm included containing equal amounts of ∆-9-THC and left and right finger sequencing. Group dif- CBD at a dose of 2.5–120 mg of each daily, ferences in cerebral activation were exam- in divided doses. The primary outcome mea- ined for Brodmann areas (BA) 4, 6, 24, and sure was a Visual Analogue Scale (VAS) 32 using region of interests analyses in sta- score for each patient’s most troublesome tistical parametric mapping. Cannabis users, symptom. Additional measures included tested within 4–36 hours of discontinuation, VAS scores of other symptoms, and mea- exhibited significantly less activation than sures of disability, cognition, mood, sleep controls in BA 24 and 32 bilaterally during and fatigue. Following CBME the primary right- and left-sided sequencing and for BA symptom score reduced from mean 74.36 6 in all tasks except for left-sided sequenc- (11.1) to 48.89 (22.0) following CBME and ing in the left hemisphere. There were no from 74.31 (12.5) to 54.79 (26.3) following statistically significant differences for BA 4. placebo. Spasticity VAS scores were signifi- None of these regional activations corre- cantly reduced by CBME (Sativex®) in com- lated with urinary cannabis concentration parison with placebo (p = 0.001). There and verbal IQ for smokers. The results sug- were no significant adverse effects on cog- gested that recently abstinent chronic can- nition or mood and intoxication was gener- nabis smokers produce reduced activation in ally mildCS268. A SCE with pure ∆-9-THC, at motor cortical areas in response to finger matched concentrations of ∆-9-THC, and a sequencing compared with controlsCS250. ∆-9-THC-free extract (∆-9-THC-free SCE) Multiple sclerosis. One hundred fifty- in a mouse model of MS, were examined. seven drug-naïve, first-episode schizophrenic Although SCE inhibited spasticity in the patients were examined. A significantly mouse model of MS to a comparable level, elevated brain-derived neurotrophic factor it caused a more rapid onset of muscle relax- (BDNF) serum concentrations in patients ation and a reduction in the time to maxi- with chronic cannabis abuse (n = 35, p < mum effect compared with ∆-9-THC alone. 0.001) or multiple substance abuse (n = 20, The ∆-9-THC-free extract or CBD caused p < 0.001) prior to disease onset were no inhibition of spasticityCS312. In an found. Drug-naïve schizophrenic patients experimental allergic encephalomyelitis without cannabis consumption showed (EAE), an animal model of MS, it was similar results to normal controls and demonstrated that the cannabinoid sys- cannabis controls without schizophrenia. tem is neuroprotective during EAE. Mice, Elevated BDNF serum levels were not deficient in the cannabinoid receptor CB1, related to schizophrenia and/or substance tolerated inflammatory and excitotoxic abuse itself but may reflect a cannabis- insults poorly, and developed substantial related idiosyncratic damage of the schizo- neurodegeneration following immune phrenic brain. Disease onset was 5.2 years attack in EAE. Exogenous CB1 agonists can earlier in the cannabis-consuming group provide significant neuroprotection from CANNABIS SATIVA 73 the consequences of inflammatory central killer cell activity on the effect of viruses nervous system disease in an experimental were similar to those of infected but can- allergic uveitis modelCS339. nabis-free counterparts, but on the level of Mutagenic activity. Petroleum ether uninfected cells treated with cannabis. The extract of the aerial parts, in the ration of effects of cannabis and retrovirus were addi- Drosophila at concentrations of 0.5, 1, and tive resulting in anergy of natural-killer 5% of the diet, was activeCS190. Petroleum cellsCS432. ether extract of the dried leaf, administered Neonatal abstinence syndrome. The by gastric intubation to male mice at a dose relationship of maternal drug abuse to symp- of 50 mg/kg, was activeCS183. Water and toms, the effectiveness of pharmacological methanol extracts of the seed, on agar plate agents in controlling symptoms, and the at a concentration of 100 mg/mL, were length of in-patient stay were investigated inactive on Bacillus subtilis H-17 (Rec+) and in infants with neonatal abstinence syn- Salmonella typhimurium TA100 and TA98. drome. Pharmacological treatment was oral Metabolic activation had no effect on the morphine sulphate (0.2 mg four to six times resultsCS199. hourly), phenobarbitone (3–7 mg/kg/day), Myocardial infarction. A young man who or combination of the two were adminis- suffered a myocardial infarction after taking tered to infants with a serial Finnegan score Viagra® in combination with cannabis was greater than 8. The average maternal age investigated. Viagra is metabolized pre- was 24.6 years, (18–34 years). Drug use vol- dominantly by the CYP450 3A4 hepatic unteered by the mothers was methadone microsomal isoenzyme. Cannabis is a known alone in 6 cases, methadone and benzodiaz- inhibitor of CYP450 3A4 isoenzyme. The epines in 14, methadone and heroin and effect of the Viagra was thus potentiated by benzodiazepines in 7, methadone and the effect of cannabisCS387. heroin in 10, heroin alone in 2, and other Natural-killer cells effect. Leukemia sus- multiple drug use including oral morphine ceptible BALB/c and resistant C57BL/6 sulphate, dothiepin, and cannabis in 4. mice were infected with Friend leukemia Average gestational age was 40.3 (35–42 virus complex and its helper component weeks). The average birth-weight was 2.81 Rowson-Parr virus. At different time points, kg (1.89–3.91 kg). Time-to-onset of with- their natural-killer cells were separated from drawal symptoms was 2.8 (1–13) days. The spleens and treated with 0–10 µg/mL of duration of pharmacological treatment (oral THC, subsequently mixed with Yac-1 tar- morphine sulphate and/or phenobarbitone) get cells for 4 and 18 hours. The natural- was 21.8 (1–62) days. The total hospital stay killer cell activity in both mouse strains for the 43 infants was 1011 daysCS424. infected by either virus complex or helper Neuroendocrine abnormalities. Prolactin virus weakened on days 2–4 postinfection, response to D-fenfluramine was assessed in normalized by day 8 and enhanced on days abstinent ecstasy (MDMA) users with con- 11–14. Natural-killer cell activity on the comitant use of cannabis only (13 males, 11 effect of low concentration (1–2.5 µg/mL) females) and in two control groups: healthy of THC slightly increased in BALB/c, was nonusers (13 females) and exclusive can- unaffected in C57BL/6, especially in the 18 nabis users (seven males). Prolactin hour assays. In the combined effects of can- response to D-fenfluramine was slightly nabis and retrovirus, damages by cannabis blunted in female ecstasy users. Both male dominated over those of retroviruses. Inhi- user samples exhibited a weak prolactin bition or reactive enhancement of natural- response to D-fenfluramine, but this was 74 MEDICINAL PLANTS OF THE WORLD weaker in the group of cannabis users. less of current analgesic therapy. They Baseline prolactin and prolactin response to entered a baseline period of 2 weeks, fol- D-fenfluramine were associated with the lowed by three, 2-week treatment periods; extent of previous cannabis use. The results during each period they received one of indicated that the endocrinological abnor- three oromucosal spray preparations. These malities of ecstasy users might be closely were placebo and two whole plant extracts related to their coincident cannabis of C. sativa L.: GW-1000-02 (Sativex®), useCS381. containing ∆-9-THC: CBD in an approx 1:1 Neurogenic symptoms alleviation. Whole- ratio and GW-2000-02, containing prima- plant extracts of ∆-9-THC, CBD, 1:1 CBD: rily THC. The primary outcome measure THC, or placebo were self-administered by was the mean pain severity score during the sublingual spray to 24 patients with MS last 7 days of treatment. Secondary outcome (n = 18), spinal cord injury (n = 4), brachial measures included pain related quality of life plexus damage (n = 1), and limb amputa- assessments. The primary outcome measure tion owing to neurofibromatosis (n = 1), at failed to fall by the two points defined in doses determined by titration against symp- our hypothesis. Both this measure and mea- tom relief or unwanted effects within the sures of sleep showed statistically significant range of 2.5–120 mg/24 hours for 2 weeks. improvements. The study medications were The patients recorded symptoms, well- well tolerated with the majority of adverse being, and intoxication scores on a daily events, including intoxication type mild to basis using visual analog scales. At the end moderate in severity and resolving sponta- of each two-week period an observer rated neous reactionsCS251. severity and frequency of symptoms on Neuroprotective effect. The effect of can- numerical rating scales, administered stan- nabidiol on β-amyloid peptide-induced tox- dard measures of disability (Barthel Index), icity in cultured rat pheocromocytoma mood, cognition, and recorded adverse PC12 cells was investigated. Following events. Pain relief associated with both exposure of cells to β-amyloid peptide (1 µg/ THC and CBD was significantly superior to mL), a marked reduction in cell survival was placebo. Impaired bladder control, muscle observed. This effect was associated with spasms, and spasticity were improved by increased reactive oxygen species produc- cannabis medicinal extract (CME) in some tion and lipid peroxidation, and caspase 3 patients with these symptoms. Three (a key enzyme in the apoptosis cell-signal- patients had transient hypotension and ling cascade) appearance, DNA fragmenta- intoxication with rapid initial dosing of tion, and increased intracellular calcium. THC-containing CME. The results indi- Treatment of the cells with CBD (10–7–10–4 cated that cannabis could improve neuro- mol) prior to β-amyloid peptide exposure, genic symptoms unresponsive to standard significantly elevated cell survival, whereas treatments. Unwanted effects were predict- it decreased reactive oxygen species produc- able and generally well toleratedCS354. tion, lipid peroxidation, caspase 3 levels, Neuropathic pain relief. Forty-eight pa- DNA fragmentation, and intracellular tients with at least one avulsed root and calciumCS298. CBD and other cannabinoids baseline pain score of four or more on an were examined as neuroprotectants in rat 11-point ordinate scale participated in a cortical neuron cultures exposed to toxic randomized, double-blind, placebo-con- levels of glutamate. The psychotropic can- trolled, three-period crossover study. The nabinoid receptor agonist ∆-9-THC and patients had intractable symptoms regard- cannabidiol, reduced N-methyl-D-aspartate, CANNABIS SATIVA 75

α-amino-3-hydroxy-5-methyl-4-isoxazole paw tremor, and scratches. In both experi- propionic acid and kainate receptor medi- mental conditions, the global withdrawal ated neurotoxicities. Neuroprotection was score was significantly attenuated by ∆-9- not affected by cannabinoid receptor THC administration. The effect of ∆-9- antagonist, indicating a (cannabinoid) THC was not to the result possible adaptive receptor-independent mechanism of action. changes induced by chronic nicotine on CBD demonstrated a reduction in hydrop- CB1 cannabinoid receptors. The density eroxide toxicity in neurons. In this trial of and functional activity of these receptors the abilities of various antioxidants to pre- were not modified by chronic nicotine vent glutamate toxicity, cannabidiol was administration in the different brain struc- superior to both α-tocopherol and ascorbate tures investigated. The consequences of ∆- in protective capacityCS412. 9-THC administration on c-Fos expression Neuropsychological effect. Cerebral blood in several brain structures after chronic flow was measured in 12 long-term can- nicotine administration and withdrawal nabis users shortly after cessation of can- were examined. c-Fos was decreased in the nabis use (mean 1.6 days). The findings caudate putamen and the dentate gyrus showed significantly lower mean hemi- after mecamylamine precipitated nicotine spheric blood flow values and significantly withdrawal. ∆-9-THC administration did lower frontal values in the cannabis subjects not modify c-Fos expression under these compared with normal controls. The results experimental conditions. ∆-9-THC also indicated that the functional level of the reversed conditioned place aversion associ- frontal lobes was affected by long-term can- ated to naloxone precipitated nicotine nabis useCS397. withdrawal. The results indicated that ∆-9- Neurotransmission inhibition. The BLA THC administration attenuated somatic or the medial prefrontal cortex (PFC) signs of nicotine withdrawal and this effect stimulation in urethane-anesthetized rats was not associated with compensatory induced generation of action potentials in changes on CB1 cannabinoid receptors dur- the Nac neurons. This excitatory effect was ing chronic nicotine administration. ∆-9- strongly inhibited by the synthetic cannab- THC also ameliorated the aversive inoid agonists WIN (0.062–0.25 mg/kg, iv motivational consequences of nicotine [intravenously]) and HU-210 (0.125–0.25 withdrawalCS253. mg/kg, iv), or ∆-9-THC (1 mg/kg, iv). D1 Night vision improvement. In a double- or D2 dopamine receptor antagonists blind study, graduated THC administration (SCH23390 0.5–1 mg/kg, sulpiride 5–10 at doses of 0–20 mg (as Marinol) on mea- mg/kg, iv) or the opioid antagonist nalox- sures of dark adaptometry and scotopic sen- one (1 mg/kg, iv) were not able to reverse sitivity was evaluated. Field studies of night the action of cannabinoids. The selective vision were performed among Jamaican and CB1 receptor antagonist/reverse agonist Moroccan fishermen, and mountain dwell- SR141716A (0.5 mg/kg, iv) fully suppressed ers with the LKC Technologies Scotopic the action of cannabinoid agonists, whereas Sensitivity Tester-1 (SST-1). Improve- per se had no significant effectCS374. ments in night vision measures were noted Nicotine and ∆-9-THC interaction. ∆-9- after THC or cannabis. The effect was dose- THC administration to mice significantly dependent and cannabinoid-mediated at decreased the incidence of several nicotine the retinal levelCS286. withdrawal signs precipitated by mecamy- Nocturnal sleep effect. Eight healthy vol- lamine or naloxone, such as wet-dog-shakes, unteers (four males, four females; aged 21– 76 MEDICINAL PLANTS OF THE WORLD

34 years) were taking placebo, 15 mg ∆-9- preceded his stroke. Except for cigarette THC, 5 mg THC combined with 5 mg smoking and slight dyslipidemia, classical CBD, and 15 mg THC combined with 15 risk factors for stroke/embolism were mg CBD. These were formulated in 50:50 absent. The family history for cerebrovas- ethanol to propylene glycol and adminis- cular events, blood pressure, clotting tests, tered using an oromucosal spray during a examinations for thrombophilia, vasculitis, 30-minute period from 10 PM. Electroen- extracranial and intracranial arteries, and cephalogram was recorded during the sleep cardiac investigations were normal or period (11 PM to 7 AM). Performance, sleep respectively negative; the stroke was attri- latency, and subjective assessments of buted to the chronic cannabis consump- sleepiness and mood were measured from tionCS271. 8:30 AM (10 hours after drug administra- Oral cancer. A study of 116 patients aged tion). There were no effects of 15 mg THC 45 years and younger, diagnosed with squa- on nocturnal sleep. With the concomitant mous cell carcinoma of the mouth was con- administration of the drugs (5 mg THC and ducted. Two hundred and seven controls 5 mg CBD to 15 mg THC and 15 mg CBD), who had never had cancer, matched for age, there was a decrease in stage 3 sleep, and sex, and area of residence, were recruited. with the higher dose combination, wake- The self-completed questionnaire con- fulness was increased. The next day, with a tained items about exposure to the follow- 15-mg THC dose, memory was impaired, ing risk factors: tobacco products, cannabis, sleep latency was reduced, and the subjects alcohol, and diet. Conditional logistic reported increased sleepiness and changes in analyses were conducted adjusting for social mood. With the lower dose combination, class, ethnicity, tobacco, and alcohol hab- reaction time was faster on the digit recall its. All tests for statistical significance were task, and with the higher dose combination, two-sided. The majority of oral cancer subjects reported increased sleepiness and patients reported exposure to the major risk changes in mood. Fifteen milligrams of factors of tobacco and alcohol even at the THC appeared to be sedative, and 15 mg younger age. The estimated risks associated CBD appeared to have alerting properties as with tobacco or alcohol were low (OR it increased waking activity during sleep and range: 0.6–2.5) among both males and counteracted the residual sedative activity females. Only smoking for 21 years or more of the 15 mg THCCS290. produced significantly elevated odds ratios Occipital stroke. A right occipital (OR = 2.1; 95% CI: 1.1–4). Exposure asso- ischemic stroke occurred in a 37-year-old ciated with other major risk factors did not Albanese man with a previously uneventful produce significant risks in this sample. medical history, 15 minutes after smoking a Long-term consumption of fresh fruits and cigarette with approximately 250 mg of can- vegetables in the diet appeared to be pro- nabis. Clinical manifestations of the stroke tective for both males and femalesCS310. were left-sided hemiparesis, hemihypesthe- Oral cytological effect. The effects of can- sia and blurred vision, which vanished spon- nabis, methaqualone, or tobacco smoking taneously and almost completely after 3 on the epithelial cells in 16 patients were days. The patient has been smoking can- evaluated. The site samples included the nabis regularly from the age of 27, with a buccal mucosa (left and right sides), the pos- frequency of two to three cigarettes/can- terior dorsum of the tongue, and the ante- nabis per week during the 6 months that rior floor of the mouth. There was a CANNABIS SATIVA 77 significant prevalence of bacterial cells in with agoraphobia diagnosis did not affect the smears and a greater number of degener- the treatment response in either group. ate and atypical squamous cells in cannabis There were no significant differences in users compared with controls. Epithelial weight gain, sexual side effects, or relapse cells in smears taken from cannabis users rates between patients according to gender and tobacco-smoking controls showed or comorbid diagnosisCS300. koilocytic changesCS376. Paroxysmal atrial fibrillation. A healthy Ovulation inhibition effect. Petroleum young subject was observed for paroxysmal ether extract of the aerial parts, admin- atrial fibrillation following cannabis intoxi- istered orally to rats, produced weak cation. The abuse of this substance was the activityCS087. most possible and identifiable risk factorCS407. Pancreatic effect. Place conditioning effect. THC was A 29-year-old man presented with acute administered to female rats at doses of 1, 5, pancreatitis after a period of heavy cannabis or 20 mg/kg) during gestation and lacta- smoking. Other causes of the disease were tion. Maternal exposure to low doses of ruled out. The pancreatitis resolved itself THC (1 and 5 mg/kg), relevant for human after the cannabis was stopped and this was consumption, produced an increased confirmed by urinary cannabinoid metabo- response to the reinforcing effects of a mod- lite monitoring in the community. There erate dose of morphine (350 µg/kg), as mea- were no previous reports of acute pancreati- sured in the place-preference conditioning tis associated with cannabis use in the gen- paradigm (CPP) in the adult male off- eral population. Drugs of all types are related spring. These animals also displayed an en- to the etiology of pancreatitis in approxi- hanced exploratory behavior in the mately 1.4–2% of casesCS313. defensive withdrawal test. Only females Pancreatic toxicity. The dried leaf, smoked born from mothers exposed to THC at a by a 19-year-old woman, was active. The dose of 1 mg/kg exhibited a small increment subject was hospitalized with pancrea- in the place conditioning induced by mor- titisCS220. phine. The possible implication of the HPA Panic disorder. Sixty-six panic disorder was analyzed by monitoring plasma levels of patients were included in a study. All of adrenocorticotropic hormone (ACTH) and whom met the DSM-IV diagnosis of panic corticosterone in basal and moderate-stress disorder (n = 45) or panic disorder with ago- conditions (after the end of the CPP test). raphobia ([PDA]; n = 21). Twenty-four Female offspring perinatally exposed to patients experienced their first panic attack THC (1 or 5 mg/kg) displayed high basal within 48 hours of cannabis use and then levels of corticosterone and a blunted adre- went on to develop panic disorder. All the nal response to the HPA-activating effects patients were treated with paroxetine of the CPP test. Male offspring born from (gradually increased up to 40 mg/day). The mothers exposed to THC (1 or 5 mg/kg) dis- two groups responded equally well to played the opposite pattern: normal to low paroxetine treatment as measured at the 8 basal levels of corticosterone, and a sharp weeks and 12 months follow-up visits. adrenal response to the CPP challengeCS436. There were no significant effects of age, sex, THC administration to rats at a low dose and duration of illness as covariates with (1.5 mg/kg) resulted in failing to develop response rates between the two groups. In place conditioning, and developing a place addition, panic disorder or panic disorder aversion at a high dose (15 mg/kg). Admin- 78 MEDICINAL PLANTS OF THE WORLD istration of the cannabinoid antagonist Assessment Scale administered at 1–3 days SR141716A induced a CPP at both a low of age. Adjusting for cannabis exposure had (0.5 mg/kg) and a high (5 mg/kg) doseCS451. no effect on these relationships between Plant germination effect. Methyl chloride plasma NE and the depressed and orienta- extract of the dried seed produced weak tion clustersCS449. activity on Amaranthus spinosus (25.8%) Pneumonic effect. A case–control study inhibitionCS176. Methyl chloride extract of was conducted in 7001 individuals. Odds the dried leaves produced 17.5% inhibition ratios were calculated by conditional logis- of Amaranthus spinosusCS176. tic regression with substance use and social Plasma norepinephrine concentration. factors as cofounders. Pneumonia was not Forty-six newborn infants participated in a associated with kava use. Crude odds ratios prospective study of the neonatal and long- = 1.26 (0.74–2.14, p = 0.386) increased after term effects of prenatal cocaine exposure. controlling for confounders (OR = 1.98, Based on maternal self-report, maternal 0.63–6.23, p = 0.237) but was not signifi- urine screening, and infant meconium cant. Adjusted odds ratios for pneumonia analysis, 24 infants were classified as CE and cases involving kava and alcohol users was 22 as unexposed. Between 24 and 72 hours 1.19 (0.39–3.62, p = 0.756). Crude odds postpartum, plasma samples for norepi- ratios for associations between pneumonia nephrine (NE), epinephrine, dopamine, and cannabis use (OR = 2.27, 1.18–4.37, and dihydroxyphenylalanine analysis were p = 0.014) and alcohol use (OR = 1.95, obtained. The Neonatal Behavioral Assess- 1.07–3.53, p = 0.026) were statistically ment Scale was administered at 1–3 days of significant and approached significance for age and at 2 weeks of age by examiners petrol sniffing (OR = 1.98, 0.99–3.95, masked to the drug exposure status of the p = 0.056)CS335. newborns. The CE newborns had increased Postural syncope. Twenty-nine volunteers plasma NE concentrations when compared participated in a randomized, double-blind, with the unexposed infants (geometric placebo-controlled study. Cerebral blood mean, 923 pg/mL vs 667 pg/mL). There velocity, pulse rate, blood pressure, skin per- were no significant differences in plasma fusion on forehead and plasma ∆-9-THC epinephrine, dopamine, or dihydroxyphe- levels were quantified during reclining and nylalanine concentrations. Analysis for the standing for 10 minutes before and after effect of potential confounding variables THC infusions and cannabis smoking. Both revealed that maternal cannabis use was also THC and cannabis induced postural dizzi- associated with increased plasma NE, ness, with 28% reporting severe symptoms. although birth-weight, gender, and mater- Intoxication and dizziness peaked immedi- nal use of alcohol or cigarettes were not. ately after drug. The severe dizziness group Geometric mean plasma NE was 1164 pg/ showed the most marked postural drop in mL in those infants with in utero exposure cerebral blood velocity and blood pressure to both cocaine and cannabis compared to and showed a drop in pulse rate after an ini- 812 pg/mL in those exposed to only cocaine tial increase during standing. Postural dizzi- and 667.0 pg/mL in those exposed to nei- ness was unrelated to plasma levels of THC ther. Among the CE infants, plasma NE and other indicesCS340. concentration correlated with an increased Prenatal exposure. Data collected from the score for the depressed cluster (r = 0.53) and National Household Survey on Drug Abuse, a decreased score for the orientation cluster a nationally representative sample survey of (r = –0.43) of the Neonatal Behavioral 22,303 noninstitutionalized women aged CANNABIS SATIVA 79

18–44 years, of whom 1249 were pregnant, week before and throughout pregnancy were analyzed. During the 2-year study were 90 g lighter than the offspring of other period, 6.4% of the non-pregnant women of women. No significant adjusted effects were childbearing age and 2.8% of the pregnant seen for birth length and head circum- women reported that they used illicit drugs. ferenceCS389. In two hospitals, 12,885 preg- Of the women who used drugs, the relative nant women answered questionnaires proportion of women who abstained from regarding consumption of alcohol, tobacco, illicit drugs after recognition of pregnancy cannabis, and other drugs. The prevalence increased from 28% during the first trimes- of cannabis use was 0.8%. Women using ter of pregnancy to 93% by the third trimes- cannabis, but no other illicit drugs were ter. However, because of postpregnancy each retrospectively matched with four ran- relapse, the net pregnancy-related reduction domly chosen pregnant women in the same in illicit drug use at postpartum was only period and the same age group and with 24%. Cannabis accounted for three-fourths same parity. Eighty-four cannabis users were of illicit drug use, and cocaine accounted for included. These women were socioeco- one-tenth of illicit drug use. Of those who nomically disadvantaged and had a higher used illicit drugs, over half of pregnant and prevalence of present and past use of alco- two-thirds of non-pregnant women used hol, tobacco, and other drugs. No signifi- cigarettes and alcohol. Among the cant difference in pregnancy, delivery, or sociodemographic subgroups, pregnant and puerperal outcome was found. Children of non-pregnant women who were young (18– women using cannabis were 150 g lighter, 30 years) or unmarried, and pregnant 1.2 cm shorter, and had 0.2 cm smaller head women with less than a high school educa- circumference than the control infantsCS418. tion had the highest rates of illicit drug A 27-year-old woman who smoked a joint useCS357. Over 12,000 women at 18–20 weeks (cannabis) and 20 cigarettes (tobacco) daily of gestation were enrolled in an Avon Lon- up to the time of a positive pregnancy test gitudinal Study of Pregnancy and Child- at 7 weeks and 4 days, was evaluated. On hood. Five percent of the mothers reported day 20 of pregnancy, she had a LSD smoking cannabis before and/or during minitrip. The patient had a spontaneous pregnancy; they were younger, of lower par- term delivery. The baby boy weight was ity, better educated, and more likely to use between the 5th and the 50th percentile, alcohol, cigarettes, coffee, tea, and hard length between the 50th and the 90th per- drugs. Cannabis use during pregnancy was centile, normal umbilical arterial and unrelated to risk of perinatal death or need venous pH values, and Apgar scores of 7/9/ for special care, but the babies of women 10. There were no visible abnormalities, and who used cannabis at least once per week behavior was normalCS419. Eight hundred before and throughout pregnancy were 216 seven consecutive positive-pregnancy test g lighter than those of nonusers, had signifi- urine samples were screened for a range of cantly shorter birth lengths, and smaller drugs, including cotinine as an indicator of head circumferences. After adjustment for maternal smoking habits. A positive test for confounding factors, the association cannabinoids was found in 117 (14.5%) of between cannabis use and birth-weight the samples. Smaller numbers of samples failed to be statistically significant (p = were positive for other drugs: opiates (11), 0.056) and was clearly nonlinear. The benzodiazepines (4), cocaine (3), and one adjusted mean birth-weights for babies of each for amphetamines and methadone. women using cannabis at least once per Polydrug use was detected in nine individu- 80 MEDICINAL PLANTS OF THE WORLD als. Only two samples tested positive for sivity were assessed using a Continuous Per- ethanol. The proportion with a urine coti- formance Task. Second and third trimester nine level indicative of active smoking was of tobacco exposure and first trimester of 34.3%. The outcome of the pregnancy was cocaine use predicted increased omission traced for 288 of the subjects. Cannabis use errors. Second trimester cannabis use pre- was associated with a lower gestational age dicted more commission errors and fewer at delivery (p < 0.005), an increased risk of omission errors. There were no significant prematurity (p < 0.02), and reduction in effects of prenatal alcohol exposure. Lower birth-weight (p < 0.002). Maternal smoking Stanford-Binet Intelligence Scale compos- was associated with a reduction in infant ite scores, male gender, and an adult male birth-weight (p < 0.05). This was less pro- in the household predicted more errors of nounced than the effect of other substance commission. Lower Standford-Binet Intel- misuseCS422. A sample of low-income women ligence Scale composite scores, younger attending a prenatal clinic was assessed. The child age, maternal work/school status, and majority of the women decreased their use higher maternal hostility scores predicted of cannabis during pregnancy. The assess- more omission errorsCS429. The neurophysi- ments of child behavior problems included ological effects of prenatal cannabis expo- the Child Behavior Checklist, Teacher’s sure on response inhibition were assessed in Report Form, and the Swanson, Noland, thirty-one participants aged 18–22. Ottawa and Pelham checklist. Multiple and logistic Prenatal Prospective Study performed a regressions were employed to analyze the blocked design Go/No-Go task while neu- relations between cannabis use and behav- ral activity was imaged with functional mag- ior problems of the children at age 10, while netic resonance imaging. The Ottawa controlling for the effects of other extrane- Prenatal Prospective Study is a longitudinal ous variables. Prenatal cannabis use was sig- study that provides a unique body of infor- nificantly related to increased hyperactivity, mation collected from each participant over impulsivity, and inattention symptoms as 20 years, including prenatal drug history, measured by the Swanson, Noland, and detailed cognitive/behavioral performance Pelham, increased delinquency as mea- from infancy to young adulthood, and cur- sured by the Child Behavior Checklist, and rent and past drug usage. The functional increased delinquency and externalizing magnetic resonance imaging results showed problems as measured by the Teacher’s that with increased prenatal cannabis expo- Report Form. The pathway between prena- sure, there was a significant increase in neu- tal cannabis exposure and delinquency was ral activity in bilateral PFC and right mediated by the effects of cannabis exposure premotor cortex during response inhibition. on inattention symptomsCS413. Attention There was also an attenuation of activity in and impulsivity of prenatally substance- left cerebellum with increased prenatal exposed 6-year-olds were assessed as part of exposure to cannabis when challenging the a longitudinal study. Most of the women response inhibition neural circuitry. Prena- were light-to-moderate users of alcohol and tally exposed offspring had significantly cannabis who decreased their use after the more commission errors than non-exposed first trimester of pregnancy. Tobacco was participants, but all participants were able used by a majority of women and did not to perform the task with more than 85% change during pregnancy. The women, accuracy. The findings were observed when recruited from a prenatal clinic, were of low controlling for present cannabis use and pre- socioeconomic status. Attention and impul- natal exposure to nicotine, alcohol, and CANNABIS SATIVA 81 caffeine, and suggest that prenatal cannabis unchanged in most of the gray-matter exposure was related to changes in neural structures analyzed (cerebral cortex, BAL activity during response inhibition that last nucleus, hippocampus, thalamic and hypo- into young adulthoodCS282. The effects of pre- thalamic nuclei, basal ganglia, and sub- natal cannabis and alcohol exposure on ventricular zones) and also in a few school achievement at 10 years of age were white-matter structures (fornix and fascicu- examined. Women were interviewed about lus retroflexus). The increase in L1-mRNA their substance use at the end of each tri- levels reached statistical significance only in mester of pregnancy, at 8 and 18 months, ∆-9-THC-exposed males but not females, and at 3, 6, 10, 14, and 16 years. The women where only trends or no effects were were of lower socioeconomic status, high detected. The results supported evidence on school-educated, and light-to-moderate a sexual dimorphism, with greater effects in users of cannabis and alcohol. At the 10-year male fetuses, for the action of cannabinoids follow-up, the effects of prenatal exposure in the developing brainCS295. Fetal cannabis to cannabis or alcohol on the academic per- exposure has no consistent effect on out- formance of 606 children were assessed. come. Prenatal cocaine exposure has not Exposure to one or more cannabis joints per been shown to have any detrimental effect day during the first trimester predicted on cognition, except as mediated through deficits in Wide Range Achievement Test- cocaine effects on head size. Although fetal Revised reading and spelling scores and a cocaine exposure has been linked to numer- lower rating on the teachers’ evaluations of ous abnormalities in arousal, attention, and the children’s performance. This relation neurological and neurophysiological func- was mediated by the effects of first-trimester tion, most such effects appear to be self-lim- cannabis exposure on the children’s depres- ited and restricted to early infancy and sion and anxiety symptoms. Second-trimes- childhood. Opiate exposure elicits a well- ter cannabis use was significantly associated described withdrawal syndrome affecting with reading comprehension and under- the central nervous, autonomic, and gas- achievement. Exposure to alcohol during trointestinal systems, which is most severe the first and second trimesters of pregnancy among methadone-exposed infantsCS319. predicted poorer teachers’ ratings of overall Executive functioning in cocaine/polydrug school performance. Second-trimester binge (cannabis, alcohol, and tobacco)-exposed drinking predicted lower reading scores. infants was assessed in a single session, There was no interaction between prenatal occurring between 9.5 and 12.5 months of cannabis and alcohol exposure. Each was an age. In an A-not-B task, infants searched— independent predictor of academic perfor- after performance-adjusted delays—for an manceCS283. Pregnant rats were treated daily object hidden in a new location. The CE with ∆-9-THC from the fifth day of gesta- infants did not differ from non-CE controls tion up to the day before birth (GD21). recruited from the same at-risk population. Then rats were sacrificed and their pups Comparison of heavier-CE (n = 9) with the removed for analysis of the neural adhesion combined group of lighter-CE (n = 10) and molecule L1-mRNA levels in different non-CE (n = 32) infants revealed significant brain structures. The levels of L1 transcripts differences on A-not-B performance, as well were significantly increased in the fimbria, as on global tests of mental and motor stria terminalis, stria medullaris, corpus cal- development. Covariates investigated losum, and in gray-matter structures (sep- included socioeconomic status, marital sta- tum nuclei and the habenula). It remained tus, race, maternal age, years of education, 82 MEDICINAL PLANTS OF THE WORLD weeks of gestation, and birth-weight, as well the follicular phase. The results were signifi- as severity of prenatal cannabis, alcohol, cant at p < 0.01 levelCS221. and tobacco exposure. The relationship of Propiospinal myoclonus. A 25-year-old heavier-CE status to motor development woman with clusters of myoclonus induced was mediated by length of gestation, and the by a single exposure to inhaled cannabis was relationship of heavier-CE status to mental evaluated. Investigations excluded a struc- development was confounded with mater- tural abnormality of the spine. Multichan- nal gestational use of cigarettes. The rela- nel surface electromyogram with parallel tionship of heavier-CE status to A-not-B frontal electroencephalogram recording performance remained significant after con- confirmed the diagnosis of propriospinal trolling for potentially confounded variables myoclonusCS284. and mediators, but was not statistically sig- Prostaglandin synthetase inhibition. nificant after controlling for the variance Chromatographic fraction of the aerial parts associated with global mental develop- was active on the bull seminal vesiclesCS159. mentCS341. Weight, height, and head circum- Protein synthesis inhibition. Ethanol ference were examined in children from (95%) extract of the dried resin, adminis- birth to early adolescence for whom prena- tered intraperitoneally to toads at a dose tal exposure to cannabis and cigarettes had of 10 mg/day for 14 days, was active. The been ascertained. The subjects were from a results were significant at p < 0.01 levelCS216. low-risk, predominantly middle-class sam- Psoriatic effect. Hot water extract of the ple participating in an ongoing longitudinal dried seed, taken orally by 108 human adults study. The negative association between with psoriasis at variable dosage level, was growth measures at birth and prenatal ciga- active. After 3–4 weeks of treatment, there rette exposure was overcome, sooner in was significant improvement. The extract males than females, within the first few was taken in combination with Rehmannia years, and by the age of 6 years, the children glutinosa (rhizome), Salvia miltiorrhiza (root), of heavy smokers were heavier than control Scrophularia ningpoensis (root), Isatis tinctoria subjects. Pre- and postnatal environmental (branch and leaf), Sophora subprostrata tobacco smoke did not have a negative (root), Dictamnus dasycarpus (rootbark), effect on the growth parameters; how- Polygonum bistorta (rhizome), and Forsythia ever, the choice of bottlefeeding or shorter suspensa (fruit)CS197. duration of breastfeeding by women who Psychosocial morbidity association. Can- smoked during pregnancy appeared to play nabis dependence is a prevalent comorbid an important positive role in the catch-up substance use disorder among patients early observed among the infants of smokers. in the course of a schizophrenia-spectrum Prenatal exposure to cannabis was not sig- disorder. Among 29 eligible patients, 18 nificantly related to any growth measures at participated in the study. First-episode birth, although a smaller head circumfer- patients with comorbid cannabis depen- ence observed at all ages reached statistical dence (n = 8) reported significantly greater significance among the early adolescents childhood physical and sexual abuse com- born to heavy cannabis usersCS417. pared with those without comorbid can- Prolactin inhibition. The dried leaves, nabis dependence (n = 10). The result smoked by healthy female volunteers at a indicated the preliminary evidence of an dose of 1 g/person, produced a decrease in association between childhood maltreat- plasma prolactin levels during the luteal ment and cannabis dependence among this phase of the menstrual cycle but not during especially vulnerable population. Child- CANNABIS SATIVA 83 hood physical and sexual abuse may be a risk symptoms. The brain mechanisms underly- factor for the initiation of cannabis depen- ing the association have to be elucidated; dence and other substance use disorders in they may implicate deregulation of cannab- the early course of schizophreniaCS249. inoid and dopaminergic systems. Cannabis Psychotic effect. Thirty five hundred rep- exposure may be a risk factor for psychotic resentatives 19 years of age were examined disorders by interacting with a preexisting in a cohort study. The subjects completed a vulnerability for these disordersCS277. 40-item Community Assessment of Psychic Refractory neuropathic pain. Seven Experiences, measuring subclinical positive patients (three women and four men) aged (paranoia, hallucinations, grandiosity, first- 60 ± 14 years suffering from chronic refrac- rank symptoms) and negative psychosis tory neuropathic pain, received oral THC dimensions, depression, and drug use. Use titrated to the maximum dose of 25 mg/day of cannabis was associated positively with (mean dose: 15 ± 6 mg) during an average both positive and negative dimensions of of 55.4 days (range: 13–128). Various com- psychosis, independent of each other and of ponents of pain (continuous, paroxysmal, depression. An association between can- and brush-induced allodynia) were assessed nabis and depression disappeared after using visual analog scale scores. Health- adjustment for the negative psychosis related quality of life was evaluated using dimensions. First use of cannabis younger the Brief Pain Inventory, and the Hospital than age 16 years was associated with a Anxiety and Depression scale was used to much stronger effect than first use after age measure depression and anxiety. THC did 15 years, independent of lifetime frequency not induce significant effect on the various of use. The association between cannabis pain, health-related quality of life and anxi- and psychosis was not influenced by the dis- ety and depression scores. Numerous side tress associated with the experiences, indi- effects (notably sedation and asthenia) were cating that self-medication may be an observed in five out of seven patients, unlikely explanation for the entire associa- requiring premature discontinuation of tion between cannabis and psychosisCS264. the drug in three patientsCS361. Cross-sectional epidemiological studies Reproductive effect. Cannabis use during indicated that individuals with psychosis pregnancy in developed nations is estimated use cannabis more often than other indi- to be approx 10%. Recent evidence suggests viduals in the general population. It has that the endogenous cannabinoid system, long been considered that this association now consisting of two receptors and mul- was explained by the self-medication tiple endocannabinoid ligands, may also hypothesis, postulating that cannabis is used play an important role in the maintenance to self-medicate psychotic symptoms. This and regulation of early pregnancy and hypothesis has been recently challenged. fertilityCS316. Drugs of abuse, like alcohol, Several prospective studies carried out in opiates, cocaine, and cannabis, are used by population-based samples, showed that can- many young people for their presumed nabis exposure was associated with an aphrodisiac properties. The opioids inhibit increased risk of psychosis. A dose–response the hypothalamus–pituitary–gonads axis relationship was found between cannabis (HPG), and increase the prolactin levels, exposure and risk of psychosis, and this which interferes with the male and female association was independent from potential sexual response. Cannabis, at high doses, confounding factors, such as exposure to could inhibit the HPG axis and reduce other drugs and preexistence of psychotic fertilityCS350. Cannabis initially increases 84 MEDICINAL PLANTS OF THE WORLD libido and potency, but chronic use causes for lactation and causes a diminution in the sexual inversionCS364. Long-term use of can- volume of the mammary glands. Significant nabis has been found to cause physiological amounts of the drug have been detected in changes that can alter individual reproduc- both mothers’ milk and the blood of new- tive potential. The effects of cannabis borns. Animal studies indicate that THC depend on the dose and can include death crosses the placenta, achieving concentra- from depression of the respiratory system. tions in the fetus as high as those in the Cannabis is absorbed rapidly and eliminated mother. Animal studies also demonstrated very slowly. ∆-9-THC is highly liposoluble increasing frequency of abortions, intrauter- and fixes to the serum proteins, passing to ine death, and declines in fetal weight. The the lungs and liver for metabolization and effects were probably caused by an alteration to the kidneys and liver for excretion. As in placental function. A human study like- with estrogens, there is an enterohepatic wise showed that cannabis use during preg- circuit for reabsorption and elimination. nancy was significantly related to poor fetal Ninety percent is eliminated in the feces, development, low birth-weight, diminished 65% within 48 hours. Because of the size, and decreased cephalic circumference. enterohepatic circuit and liposolubility, Congenital malformations have been elimination requires 1 week for completion. observed in experimental animals exposed The other important biotransformation of to THC. Declines in sperm volume and the active principle is hydroxylation. The count and abnormal sperm motility have hydroxylated derivatives are responsible for been observed in chronic cannabis users. In the psychoactivity of cannabis. Cannabis vitro studies show that THC produces a affects both neuroendocrine function and marked degeneration of human spermCS365. the germ cells. Studies on experimental ani- Among sexually experienced girls, 39% (n mals have indicated that THC can cause a = 123) reported using oral contraceptive decline in the pituitary hormones, follicle pills(OCPs), 5.4% (n = 17) used Depo- stimulating hormone, luteinizing hormone, Provera® (medroxyprogesterone acetate) or and prolactin, and in the steroids progester- Norplant® (levonorgestrel), and 55.6% (n = one, estrogen, and androgens. Human stud- 175) used no hormonal method. Logistic ies have shown that chronic users have regression analysis revealed that the factors decreased levels of serum testosterone. most significantly associated with the use of Because steroidogenesis can be restimulated hormonal methods were older age (OR = with human chorionic gonadotropin, it 1.19; 95% CI, 1.07–1.33), not using a con- appears that THC does not directly affect dom at last intercourse (OR = 0.55; CI, steroid production by the corpus luteum, but 0.34–0.90), and having had a well visit that its action is mediated by the hypothala- within 1 year (OR = 2.11; CI, 1.12–3.70). mus. Because of its potent antigonadotropic OCP users were less likely than Depo- action, THC is under study as an anovula- Provera or Norplant users to have used al- tory agent. The same animal studies have cohol (p = 0.041), cigarettes (p = 0.002), or shown that ovulation returns to normal 6 cannabis (p = 0.018) in the past 30 days. months after termination of use. High rates OCP users were less likely than nonusers of of anovulation and luteal insufficiency have hormonal methods to have smoked ciga- been observed in women smoking cannabis rettes (p = 0.034) or cannabis (p = 0.052). at least three times weekly. THC accumu- The school-based clinic had a greater pro- lates in the milk. Animal studies have shown portion of subjects using long-acting that THC depresses the enzymes necessary progestins (p < 0.001)CS443. CANNABIS SATIVA 85

Respiratory effect. Smoking a “joint” of sured. Ninety-one subjects (9.7%) were cannabis resulted in exposure to signifi- cannabis-dependent and 264 (28.1%) were cantly greater amounts of combusted mate- current tobacco smokers. After controlling rial than with a tobacco cigarette. The for tobacco use, respiratory symptoms asso- histopathological effects of cannabis-smoke ciated with cannabis dependence included exposure included changes consistent with wheezing apart from colds, exercise-induced acute and chronic bronchitis. Cellular dys- shortness of breath, nocturnal wakening plasia has also been observed, suggesting with chest tightness, and early morning that, like tobacco smoke, cannabis exposure sputum production. These were increased has the potential to cause malignancy. by 61, 65, 72 (all p < 0.05), and 144% (p < Symptoms of cough and early morning spu- 0.01) respectively, compared with non- tum production are common (20–25%) tobacco smokers. The frequency of respira- even in young individuals who smoke can- tory symptoms in cannabis-dependent nabis alone. Almost all studies indicated subjects was similar to tobacco smokers of that the effects of cannabis and tobacco 1–10 cigarettes per day. The proportion of smoking are addictive and independentCS342. cannabis-dependent study members with an A small group of current male cannabis pro- FEV1/FVC ratio of less than 80% was 36% cessors with a mean age of 43 years was stud- compared with 20% for nonsmokers (p = ied. Questionnaire data, lung function, 0.04). These outcomes occurred indepen- serial FEV1 and blood were collected from dently of coexisting bronchial asthmaCS405. all workers. Seven workers (64%) com- Reversal of cannabinoid addiction. ∆-9- plained of at least one respiratory symptom THC was administered orally to mice at a (one with byssinosis). The mean percentage dose of 10 mg/kg twice daily for 6 days to predicted FEV1 was 91.5, FVC 97.7, peak make them dependent on cannabinoids. expiratory flow 92.1, and forced expiratory Other groups of mice were administered flow between 25 and 75% of FVC 79.5. orally with a ∆-9-THC and benzoflavone Serial FEV1 measurements in the two work- from Passiflora incarnata at doses of 10 or 20 ers with work-related respiratory symptoms mg/kg twice daily for 6 days. Mice receiving revealed a mean change in FEV1 on the first the ∆-9-THC and Passiflora incarnata working day of –12.9%. This contrasted extract developed significantly less depen- with +6.25% on the last working day. dence, worse locomotor activity, and less of Respective values for the two workers with- typical withdrawal effects like paw tremors out work-related symptoms were –1.4 and and headshakes, compared with mice +3.2%CS402. Nine hundred forty-three young receiving ∆-9-THC alone. Administration adults from a birth cohort of 1037 were stud- of SR-141716A, a selective cannabinoid- ied at age 21 years. Standardized respiratory receptor antagonist (10 mg/kg, orally), to symptom questionnaires were administered. all groups on the seventh day resulted in an Spirometry and methacholine challenge artificial withdrawal. Administration of tests were undertaken. Cannabis depen- 20 mg/kg of the Passiflora incarnata benzo- dence was determined using DSM-III-R cri- flavone moiety to mice showing symptoms teria. Descriptive analyses and comparisons of withdrawal owing to administration of between cannabis-dependent, tobacco- SR-141716A produced a marked attenua- smoking, and nonsmoking groups were tion of withdrawal effectsCS375. undertaken. Adjusted odds ratios for respi- Schizophrenic effect. The nerve growth ratory symptoms, lung function, and airway factor (NGF) serum levels of 109 consecu- hyperresponsiveness (PC20) were mea- tive drug-naïve schizophrenic patients were 86 MEDICINAL PLANTS OF THE WORLD measured and compared with those of tion. During eight test sessions, 55 male vol- healthy controls. The results were corre- unteers made repeated ratings of subjective lated with the long-term intake of cannabis “high,” sedation, and stimulation, as well as and other drugs. Mean (± standard devia- rating their perceptions of motivation and tion) NGF serum levels of 61 control performance on cognitive tests. The long, persons (33.1 ± 31 pg/mL) and 76 schizo- relative to the short, breath-holding dura- phrenics who did not consume illegal drugs tion increased “high” ratings after smoking (26.3 ± 19.5 pg/mL) did not differ signifi- cannabis, but not placebo. Cannabis smok- cantly. Schizophrenic patients with regular ing increased sedation and a perception of cannabis intake (> 0.5 g per day on average worsened test performance, and decreased for at least 2 years) had significantly raised motivation with respect to test perfor- NGF serum levels of 412.9 ± 288.4 pg/mL mance. Paradoxical subjective effects were (n = 21) compared with controls and schizo- observed in those subjects reporting some phrenic patients not consuming cannabis stimulation, as well as sedation after smok- (p < 0.001). In schizophrenic patients who ing cannabis, particularly with the long abused not only cannabis, but also addi- breath-holding duration. Breath-holding tional substances, NGF concentrations were duration did not produce any subjective as high as 2336.2 ± 1711.4 pg/mL (n = 12). effects that were independent of the drug On average, heavy cannabis consumers suf- treatment (i.e., occurred equally after smok- fered their first episode of schizophrenia 3.5 ing of cannabis and placebo)CS438. years (n = 21) earlier than schizophrenic Sexual headache. Sexual headaches usu- patients who abstained from cannabis. ally develop during orgasm. The case of a These results indicate that cannabis is a pos- young man and heavy cannabis smoker who sible risk factor for the development of suffered posterior cerebral artery infarction schizophrenia. This might be reflected in during his first episode of coital headache the raised NGF-serum concentrations when was reportedCS386. both schizophrenia and long-term cannabis Sexual receptivity. The effects of THC on abuse prevailCS304. sexual behavior in female rats and its influ- Schizotypy correlation. Two hundred ence on steroid hormone receptors and neu- eleven healthy adults who used cannabis rotransmitters in the facilitation of sexual showed higher scores on schizotypy, border- receptivity was examined. Results revealed line, and psychoticism scales than never- that the facilitatory effect of THC was users. Multivariate analysis, covarying lie inhibited by antagonists to both progester- scale scores, age, and educational level indi- one and dopamine D(1) receptors. To test cated that high schizotypal traits best further the idea that progesterone receptors discriminated subjects who had used (PR) and/or dopamine receptors (D[1]R) in cannabis from never-users, whether or not the hypothalamus were required for THC- they reported having used other recre- facilitated sexual behavior in rodents, ational drugs. The results indicated that antisense, and sense oligonucleotides to cannabis use was related to a personality PR and D(1)R were administered intra- dimension of psychosis-proneness in healthy cerebroventricularly into the third cerebral peopleCS457. ventricle of ovariectomized, estradiol ben- Sedative and stimulant effects. A double- zoate-primed rats. Progesterone- and THC- blind, placebo-controlled study assessed facilitated sexual behavior was inhibited in subjective effects of smoking cannabis with animals treated with antisense oligonucle- either a long or short breath-holding dura- otides to PR or to D(1)R. Antagonists to CANNABIS SATIVA 87 cannabinoid receptor-1 subtype (CB1), but toneally to rats at a dose of 0.89 mg/kg, was not to cannabinoid receptor-2 subtype active vs corneo-palpebral reflexCS022. (CB2) inhibited progesterone- and dopam- Smooth muscle stimulant activity. Hot ine-facilitated sexual receptivity in female water extract of the dried leaf was active on ratsCS408. Adult female and male rats that had the rabbit and guinea pig intestineCS177. been perinatally exposed to hashish extracts Water extract of the dried aerial parts at a were investigated. Adult males perinatally concentration of 1:1 was equivocal on the exposed to hashish extracts exhibited guinea pig ileumCS243. marked changes in the behavioral patterns Spasticity treatment. Standardized plant executed in the sociosexual approach extract was administered orally to 57 MS behavior test; these changes did not exist in patients with poorly controlled spasticity, at females. Control males first visited the a dose of 2.5 mg of THC and 0.9 mg of CBD. incentive male and took longer to visit the Patients in group A started with a drug incentive female, whereas hashish-exposed escalation phase from 15 to a maximum of males followed the opposite pattern. Hash- 30 mg of THC by 5 mg per day if well toler- ish-exposed males spent more time in the ated, being on active medication for 14 days vicinity of the incentive female, whereas before starting placebo. Patients in group B they decreased their frequency of visits to, started with placebo for 7 days, crossed to and the time spent in, the male incentive the active period (14 days), and closed with area. This behavior was observed during the a three-day placebo period (active drug-dose first third of the test, but became normal- escalation and placebo sham escalation as ized and even inverted during the last two- in group A). Measures used included daily thirds. In the social interaction test, the self-report of spasm frequency and symp- normal reduction in the time spent in active toms, Ashworth Scale, Rivermead Mobility social interaction following the exposure to Index, 10-meter timed walk, nine-hole peg a neophobic situation (high light levels) in test, paced auditory serial addition test, and controls did not occur in hashish-exposed the digit span test. There were no statisti- males, although these exhibited a response cally significant differences associated with in the dark-light emergence test similar to active treatment compared with placebo, that of their corresponding controls. No but trends in favor of active treatment were changes were seen in spontaneous locomo- seen for spasm frequency, mobility, and get- tor activity in both tests. These behavioral ting to sleep. In the 37 patients (per-proto- alterations observed in hashish-exposed col set) who received at least 90% of their males were paralleled by a significant prescribed dose, improvements in spasm decrease in L-3,4-dihydroxyphenylacetic frequency (p = 0.013) and mobility after acid contents in the limbic forebrain; this excluding a patient who fell and stopped suggests a decreased activity of mesolimbic walking were seen (p = 0.01). Minor adverse dopaminergic neurons. No effects were seen events were slightly more frequent and in femalesCS459. severe during active treatment, and toxicity Smooth muscle relaxant activity. Ethanol symptoms, which were generally mild, were (95%) and water extracts of the dried aerial more pronounced in the active phaseCS270. parts, at a concentration of 1:1, produced Six hundred thirty participants with stable weak activity on the rabbit duodenum. The MS and muscle spasticity were treated with ethanol extract was equivocal on the guinea oral cannabis extract (n = 211), ∆-9-THC pig ileumCS243. Petroleum ether extract of the (n = 206), or placebo (n = 213) for 15 weeks. dried entire plant, administered intraperi- Six hundred eleven of 630 patients were 88 MEDICINAL PLANTS OF THE WORLD followed up for the primary end point. No Spontaneous pneumomediastinum. Spon- treatment effect of cannabinoids on the taneous pneumomediastinum is defined as primary outcome (p = 0.40) was noted. The pneumomediastinum in the absence of an estimated difference in mean reduction in underlying lung disease. It is the second total Ashworth score for participants taking most common cause of chest pain in young, cannabis extract compared with placebo healthy individuals (<30 years) necessi- was 0.32 (95% CI, –1.04 to 1.67), and for tating hospital visits. Inhalational drug use those taking ∆-9-THC vs placebo it was (cocaine and cannabis) has been associ- 0.94 (–0.44 to 2.31). There was an evidence ated with a significant number of cases, of a treatment effect on patient-reported although cases with no apparent etiological spasticity and pain (p = 0.003), with or incriminating factors are well-recognized. improvement in spasticity reported in 61% A case of an 18-year-old high school student (n = 121, 95% CI, 54.6–68.2), 60% (n = with spontaneous pneumomediastinum was 108, 52.5–66.8), and 46% (n = 91, 39–52.9) evaluatedCS421. of participants on cannabis extract, ∆-9- Sudden cardiac death. An 18-year-old THC, and placebo, respectivelyCS322. male suffered sudden cardiac death follow- Spatial working memory effect. Func- ing the use of cocaine, cannabis, and tional magnetic resonance imaging was used ethanolCS439. to examine brain activity in 12 long-term Sudden infant death syndrome. In a heavy cannabis users, 6–36 hours after last nationwide case–control study of 369 cases use, and in 10 control subjects while they and 1558 controls, two-thirds of SIDS performed a spatial working memory task. deaths occurred at night (between 10 PM Regional brain activation was analyzed and and 7:30 AM). The odds ratio (95% CI) for compared using statistical parametric map- prone sleep position was 3.86 (2.67–5.59) ping techniques. Compared with controls, for deaths occurring at night, and 7.25 cannabis users exhibited increased activa- (4.52–11.63) for deaths occurring during tion of brain regions typically used for spa- the day; the difference was significant. The tial working memory tasks (such as PFC and odds ratio for maternal smoking and SIDS anterior cingulate). Users also recruited deaths occurring at night was 2.28 (1.52– additional regions not typically used for 3.42), and for the day, 1.27 (0.79–2.03). If spatial working memory (such as regions in the mother was single, the odds ratio was the basal ganglia). The findings remained 2.69 (1.29–3.99) for a nighttime death, and essentially unchanged when reanalyzed 1.25 (0.76–2.04) for a daytime death. Both using the subjects ages as a covariate. Brain interactions were significant. The interac- activation showed little or no significant tions between time of death and bed shar- correlation with subjects years of education, ing, not sleeping in a cot or bassinet, verbal IQ, lifetime episodes of cannabis use, ethnicity, late timing of prenatal care, binge or urinary cannabinoid levels at the time of drinking, cannabis use, and illness in the scanningCS281. baby were also significant. All were more Spermicidal effect. Petroleum ether strongly associated with SIDS occurring at extract of the dried aerial parts at a concen- nightCS366. In a nationwide case–control tration of 0.74 mmol was active on the study, 393 cases and 1592 controls were ana- human spermatozoaCS186. lyzed. Adjusting for ethnicity and maternal Spontaneous activity reduction. Petro- tobacco use, the SIDS odds ratio for weekly leum ether extract of the dried entire plant, maternal cannabis use since the infant’s administered intraperitoneally to guinea birth was 2.23 (95% CI = 1.39, 3.57) com- pigs at a dose of 100 mg/kg, was activeCS022. pared with nonusers, and the multivariate CANNABIS SATIVA 89 odds ratio was 1.55 (95% CI = 0.87, environmental vulnerabilities predisposing 2.75)CS403. to both outcomes. In contrast, associations Suicidal effect. Standardized interview as- between cannabis dependence and suicidal sessments were conducted with 2311 youths behaviors cannot be entirely explained by aged 8–15 years who used drugs before age common predisposing genetic and/or shared 16. Approximately 15 years after recruit- environmental predispositionCS260. ment, 1695 persons (mean age = 21 years) Synergic cytotoxicity. THC, in A549 lung were reassessed. One hundred fifty-five of tumor cells culture at concentrations of less them made suicide attempts (SA) and 218 than 5 µg/mL, produced no cytotoxic effect. had onset of depression-related suicide ide- At higher levels it induced cell necrosis, ation (SI). The relative risk, from survival with a lethal concentration (LC)50 of 16–18 analysis and logistic regression models, to µg/mL. Butylated hydroxyanisole ([BHA], a study early use of tobacco, alcohol, can- food additive)alone at concentrations of nabis, and inhalants, with covariate adjust- 10–200 µM, produced limited cell toxicity ments for age, sex, race/ethnicity, and other and significantly enhanced the necrotic pertinent covariates were examined. Early- death resulting from concurrent exposure to onset of cannabis use and inhalant use for THC. In the presence of BHA at 200 µM, µ females, but not for males, signaled a mod- the LC50 for THC decreased to 10–12 g/ est excess risk of SA (cannabis-associated mL. Similar results were obtained with RR = 1.9; p = 0.04; inhalant-associated RR smoke extracts prepared from cannabis ciga- = 2.2; p = 0.05). Early-onset of cannabis use rettes, but not with extracts from tobacco or by females (but not for males) signaled placebo cannabis cigarettes (containing no excess risk for SI (RR = 2.9; p = 0.006). THC). Experiments were repeated in the Early-onset alcohol and tobacco use were presence of either diphenyleneiodonium or not associated with later risk of SA or SICS252. dicumarol as inhibitors of the redox cycling Two hundred seventy-seven same-sex twin pathway. Neither of the compounds pro- pairs (median age: 30 years) discordant for tected cells from the effects of combined cannabis dependence and 311 pairs discor- THC and BHA, but rather enhanced dant for early-onset cannabis use (before age necrotic cell death. Measurements of cellu- 17 years) were examined. Individuals who lar ATP revealed that both THC and BHA were cannabis-dependent had odds of SI reduced ATP levels in A549 cells, consis- and SA that were 2.5–2.9 times higher tent with toxic effects on mitochondrial than those of their noncannabis-dependent electron transport. The combination was co-twin. Cannabis dependence was associ- synergistic in this respect, reducing ATP ated with elevated risks of major depressive levels to less than 15% of the control. disorder (MDD) in dizygotic, but not in Exposure to cannabis smoke in conjunction monozygotic twins. Twins who initiated with BHA may promote deleterious health cannabis use before age 17 years of age had effects in the lungCS373. elevated rates of subsequent SA (OR, 3.5, Teratogenic activity. Resin, administered 95% CI, 1.4–8.6) but not of MDD or SI. orally to pregnant rabbits at a dose of 1 mL/ Early MDD and SI were significantly associ- kg, was activeCS167. Alcohol extract of the ated with subsequent risks of cannabis dried leaves, administered intragastrically to dependence in discordant dizygotic pairs, pregnant rats at a dose of 125 mg/kg from but not in discordant monozygotic pairs. days 7 to 16 of gestation, was active. The The results indicated that the comorbidity fetuses showed several gross abnormali- between cannabis dependence and MDD ties, visceral anomalies, and skeletal mal- likely arises through shared genetic and formationsCS233. Water extract of the dried 90 MEDICINAL PLANTS OF THE WORLD leaf, administered intragastrically to preg- sible explanation for the clinically observed nant rats at doses of 125, 200, 400, and 800 relation between the cannabinoid system mg/kg, produced various types of malforma- and TSCS292. A single-dose, cross-over study tions in the fetusesCS228. Petroleum ether ex- in 12 patients, and a 6-week, randomized tract of the aerial parts, administered orally trial in 24 patients, demonstrated that ∆9- to rats and rabbits, was inactiveCS087. THC, the most psychoactive ingredient of Tourette syndrome. Tourette syndrome cannabis, reduced tics in TS patients. No se- (TS) is a complex inherited disorder of rious adverse effects occurred and no impair- unknown etiology, characterized by mul- ment on neuropsychological performance tiple motor and vocal tics. Involvement of was observedCS329. In the randomized, the central cannabinoid (CB1) system was double-blind, placebo-controlled study, 24 suggested because of therapeutic effects of patients with TS, according to DSM-III-R cannabis consumption and ∆-9-THC-treat- criteria, were treated over a 6-week period ment in TS patients. The central cannab- with up to 10 mg/day of THC. Tics were inoid receptor (CNR1) gene encoding the rated at six visits (visit 1, baseline; visits 2–4, CNR1 was considered as a candidate gene during treatment period; visits 5–6, after for TS and systematically screened by withdrawal of medication) using the Tour- single-strand conformation polymorphism ette Syndrome Clinical Global Impressions analysis and sequencing. Compared with the scale (TS-CGI), the Shapiro Tourette-Syn- published CNR1 sequence, three single-base drome Severity Scale (STSSS), the Yale substitutions were identified: 1326T→A, Global Tic Severity Scale (YGTSS), the 1359G→A, 1419 + 1G→C. The change at self-rated Tourette Syndrome Symptom List position 1359 is a common polymor-phism (TSSL), and a videotape-based rating scale. (1359 G/A) without allelic association with Seven patients dropped out of the study or TS. 1326T→A was present in only one TS had to be excluded, but only one because of patient and is a silent mutation, which does side effects. Using the TS-CGI, STSSS, not change codon 442 (valine). 1419 + YGTSS, and video rating scale, there was a 1G→C affects the first nucleotide immedi- significant difference (p < 0.05) or a trend ately following the coding sequence. It was toward a significant difference (p < 0.1) first detected in three of 40 TS patients and between THC and placebo groups at visits none of 81 healthy controls. This statisti- 2, 3, and/or 4. Using the TSSL at 10 treat- cally significant association with TS (p = ment days (between days 16 and 41) there 0.034) could not be confirmed in two subse- was a significant difference (p < 0.05) quent cohorts of 56 TS patients (one het- between both groups. Analysis of variance erozygous for 1419 + 1G→C) and 55 controls, also demonstrated a significant difference and 64 patients and 66 controls (one het- (p = 0.037). No serious adverse effects erozygous for 1419 + 1G→C), respectively. occurredCS345. In the randomized, double- Transcript analysis of lymphocyte RNA blind, placebo-controlled study, the effect of from five 1419 + 1G→C carriers revealed a treatment with up to 10 mg ∆-9-THC over no systematic influence on the expression a 6-week period on neuropsychological per- level of the mutated allele. In addition, seg- formance in 24 patients suffering from TS regation analysis of 1419 + 1G→C in af- was investigated. During medication and fected families gave evidence that 1419 + immediately, as well as 5–6 weeks after, 1G→C does not play a causal role in the eti- withdrawal of ∆-9-THC treatment, no det- ology of TS. It was concluded that genetic rimental effect was seen on learning curve, variations of the CNR1 gene are not a plau- interference, recall and recognition of word CANNABIS SATIVA 91 lists, immediate visual memory span, and Her temperature, blood pressure, pulse, divided attention. A trend towards a signi- hemoglobin, leukocytes, serum electrolytes, ficant immediate verbal memory span and serum urea were normal. Respiratory improvement during and after treatment rate was 12 beats per minute. Blood sugar was foundCS356. A randomized double-blind elevated. Recovery was complete within 24 placebo-controlled crossover single-dose hours with no treatmentCS047. Four patients trial of ∆-9-THC (5, 7.5, or 10 mg) in 12 suffered gastrointestinal disorders and psy- adult TS patients was performed. Tic sever- chological effects after eating salad prepared ity was assessed using the TSSL and exam- with hemp seed oil. The concentration of iner ratings (STSSS, YGTSS, TS-CGS). THC in the oil far exceeded the recom- Using the TSSL, patients also rated the mended tolerance doseCS450. From January severity of associated behavioral disor- 1998 to January 2002, 213 incidences were ders. Clinical changes were correlated to recorded of dogs that developed clinical maxi-mum plasma levels of THC and its signs following oral exposure to cannabis, metabolites 11-OH-THC and 11-nor-∆-9- with 99% having neurological signs and tetrahydrocannabinol-9-carboxylic acid. 30% exhibiting gastrointestinal signs. The Using the TSSL, there was a significant cannabis ingested ranged from 0.5 to 90 g. improvement of tics (p = 0.015) and obses- The lowest dose at which signs occurred was sive-compulsive behavior (p = 0.041) after 84.7 mg/kg and the highest reported dose treatment with ∆-9-THC compared with was 26.8 g/kg. Onset of signs ranged from 5 placebo. Examiner ratings demonstrated a minutes to 96 hours, with most signs occur- significant difference for the subscore “com- ring within 1–3 hours after ingestion. The plex motor tics” (p = 0.015) and a trend signs lasted from 30 minutes to 96 hours. towards a significant improvement for the Management consisted of decontamination, subscores “motor tics” (p = 0.065), “simple sedation (with diazepam as drug of choice), motor tics” (p = 0.093), and “vocal tics” fluid therapy, thermoregulation, and general (p = 0.093). No serious adverse reactions supportive care. All followed animals made occurred. Five patients experienced mild, full recoveriesCS309. The suspension prepared transient side effects. There was a signifi- from the benzene washing solution of can- cant correlation between tic improvement nabis seeds, administered intravenously to and maximum 11-OH-THC plasma con- mice at a dose of 3 mg/kg, produced hypoth- centrationCS384. ermia, catalepsy, pentobarbital-induced Toxic effect. Petroleum ether extract of the sleep prolongation, and suppression of loco- dried leaf, administered by gastric intuba- motor activity. These pharmacological tion to pregnant rats at a dose of 150 mg/kg, activities of benzene washing solution of produced a reduction of food and water con- cannabis seeds were significantly higher sumption and maternal weight gain. The than those of ∆-9-THC (3 mg/kg, iv)CS435. weight of pups at birth was reduced by Toxicity assessment. Ethanol (50%) approx 10% of the litter size, and pup mor- extract of the entire plant, administered tality at birth was not affected signifi- intraperitoneally to mice, produced a maxi- cantlyCS178. Water extract of the aerial parts, mum tolerated dose of 500 mg/kgCS007. administered intravenously to male adults, Transient global amnesia. A 6-year-old was activeCS042. The resin, ingested by a 4- boy became intoxicated after ingesting year-old girl, showed signs of stupor alter- cookies laced with cannabis. He was pre- nating with brief intervals of excitation and sented with retentive memory deficit of sud- foolish laughing with atactic movements. den onset that was later diagnosed as 92 MEDICINAL PLANTS OF THE WORLD transient global amnesia. Transient global accidents and interpersonal violence, amnesia owing to cannabis intoxication is respectively, were positive for cannabis an extremely rare eventCS266. compared with 43 and 27% for alcohol, Transient ischemic attack. A 22-year-old respectively. There was no significant man with a 5-year history of drug and alco- difference in hospital stay or injury severity hol abuse was presented with a left hemi- score between substance users and non- paresis preceded by three transient ischemic usersCS416. attacks. Two of the attacks occurred while Trigeminovascular system effect. Arachi- smoking cannabis. Substance abuse was the donylethanolamide is believed to be the only identifiable risk factor for the cere- endogenous ligand of the cannabinoid CB1 brovascular diseaseCS454. and CB2 receptors. Known behavioral Trauma injuries. An association between effects of AEA are antinociception, cata- combat-related posttraumatic stress disorder lepsy, hypothermia, and depression of motor (C-PTSD) and other mental disorders was activity, similar ∆-9-THC, the psychoactive studied in co-twin (male monozygotic twin constituent of cannabis. A role of the CB1 pairs in the Vietnam Era Twin Registry). receptor in the trigeminovascular system, Logistic regression analyses demonstrated using intravital to study the effects of AEA that combat exposure, adjusted for C- against various vasodilator agents was PTSD, was significantly associated with examined. AEA inhibited dural blood ves- increased risk for alcohol and cannabis sel dilation brought about by electrical dependence and that C-PTSD mediated the stimulation by 50%, calcitonin gene-related association between combat exposure and peptide (CGRP) by 30%, capsaicin by 45%, both major depression and tobacco depen- and NO by 40%. CGRP(8–37) attenuated denceCS325. Sera from 111 patients with NO-induced dilation by 50%. The AEA trauma injuries who presented during a 3- inhibition was reversed by the CB1 recep- month period were screened for blood alco- tor antagonist AM251. AEA also reduced hol. Urine specimens were analyzed for the blood pressure changes caused by CGRP metabolites of cannabis and cocaine. Sixty- injection, this effect was not reversed by two percent of patients were positive for at AM251CS314. least one substance and 20% for two or Tumor-promoting effect. A 28-year-old more. Positivity rates were as follows: can- man who abused alcohol, nicotine, and can- nabis, 46%; alcohol, 32% (with 71% of nabis for several years was investigated. He these having blood alcohol levels >80 mg/ suffered simultaneously from a squamous dL); and cocaine (6%). Substance usage was cell carcinoma of the hypopharynx with most prevalent in the third decade of life. bilateral cervical metastases, an adenocar- The patients who yielded a positive result cinoma of the transverse colon and a were significantly younger than those nega- primary hepatocellular carcinoma. There tives. There was no significant difference in were occurrences of three separate malig- age or substance usage between the victims nant tumors with different histologies in the of interpersonal violence or road traffic aerodigestive tract, which could be related accidents. In the group designated “other to a chronic abuse of cannabisCS460. accidents,” patients were significantly older Turning behavior. Cannabinoid agonists: and had a lower incidence of substance WIN (1–100 ng/mouse), CP-55,940 (0.1– usage than the other two groups. Cannabis 50 ng/mouse), and AEA (0.5–50 ng/mouse), was the most prevalent substance in all administered unilaterally into the mouse groups. Fifty and 55% of victims of road striatum, dose-dependently induced turning CANNABIS SATIVA 93 behavior. SR 141716A [N-(piperidin-1-yl) cannabis use for both maternal self- and -5-(4-chlorophenyl)-1-(2,4-dichlorophe- paternal proxy report, although the associa- nyl)-4-methyl-1H- pyrazole-3-carboxamide tion was significant only for maternal self- hydrochloride], the selective antagonist of reportCS301. CB1 receptor, antagonized the three can- Visuospatial memory effect. Twenty-five nabinoid receptor agonists-induced turning college students who were heavy cannabis with similar effective dose50 (0.13–0.15 mg/ smokers (who had smoked a median of 29 of kg, intraperitoneally). Spiroperidol (a D2 the last 30 days) were compared with 30 receptor blocker), (+)-SCH 23390 (a D1 light smokers (1 day in the last 30 days). receptor blocker), or prior 6-hydroxy- The subjects were tested after a supervised dopamine lesions of the striatum blocked period of abstinence from cannabis and WIN- and CP-55,940-induced turning, thus other drugs lasting at least 19 hours. Differ- suggesting the involvement of DA transmis- ences between the overall groups of heavy sion in cannabinoid-induced turningCS464. and light smokers did not reach statistical Tyrosinase inhibition. Methanol (80%) significance on the four subtests of attention extract of the dried aerial parts, at a con- administered. On examining data for the centration of 100 µg/mL, produced weak two sexes separately, marked and significant activityCS075. differences were found between heavy- and Uterine stimulant effect. Ethanol (50%) light-smoking women on the subtest exam- extract of the entire plant was inactive on ining visuospatial memory. On this test, the rat uterusCS007. Ethanol (95%) and water subjects were required to examine a 6 × 6 extracts of the dried aerial parts, at a con- “checkerboard” of squares in which certain centration of 1:1, produced strong activity squares were shaded. The shaded squares on the non-pregnant rat uterusCS243. Water were then erased and the subject was extract of the flowering tops produced required to indicate with the mouse which strong activity on the rat uterusCS008. squares had formerly been shaded. Increas- Ventricular septal defect. A Birth Defect ing numbers of shaded squares were pre- Case–Control Study was used to identify sented at each trial. The heavy-smoking 122 isolated simple ventricular septal defect women remembered significantly fewer (VSD) cases and 3029 control infants. squares on this test, and they made signifi- Exposure data on alcohol, cigarette, and il- cantly more errors than the light-smoking licit drug use were obtained through stan- women. These differences persisted despite dardized interviews with mothers and different methods of analysis and consider- fathers. Associations between lifestyle fac- ation for possible confounding variablesCS453. tors and VSD were calculated using mater- Weight loss. The dried leaves, adminis- nal self-reports; associations were also tered by gastric intubation to male rats at a calculated using paternal proxy reports of dose of 75 mg/kg, was activeCS215. the mother’s exposures. Maternal self-report Wilson’s disease. A patient with general- of heavy alcohol consumption and paternal ized dystonia owing to Wilson’s disease ob- proxy report of the mother’s moderate alco- tained marked improvement in response to hol consumption were associated with iso- smoking cannabisCS263. lated simple VSD. A twofold increase in risk Winiwarter-Buerger disease. Two young of isolated simple VSD was identified for men aged 18 and 20 years with juvenile maternal self- and paternal proxy-reported endarteritis were evaluated. Both developed cannabis use. Risk of isolated simple VSD acute distal ischemia of the lower or upper increased with regular (Ն3 days per week) limbs with arteriographic evidence sugges- 94 MEDICINAL PLANTS OF THE WORLD tive of Winiwarter-Buerger disease. Both CS009 Segelman, A. B., F. H. Pettler and N. smoked regularly but not excessively, and R. Farnsworth. Cannabis sativa (mari- both used cannabis regularly. In one case, huana). A correction of reported thin- layer chromatography data. Pharm the therapeutic response to withdrawal of Wkly 1970; 105: 1360–1362. cannabis was good. In the second, use of CS010 Saha, J. C., E. C. Savini and S. cannabis continued and arterial disease per- Kasinathan. Ecbolic properties of sisted. The main clinical and radiographical Indian medicinal plants. Part 1. Indian features in this condition are the same as in J Med Res 1961; 49: 130-151. CS011 Berhault, J. Flore Illustree du Senegal Winiwarter-Buerger diseaseCS430. II. Govt. 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