2

Cannabichromene (CBC) (CBN)

Tetrahydrocannabinol (THC) What is Medicinal (CBD) ? The facts and the fiction. Mental Health and & Alcohol Nurses’ Forum September 2017.

(THCA) (THCV) Justin Sinclair Research Fellow, NICM (Western Sydney University)

Beta-myrcene Alpha-pinene [email protected] www.tmconsultancy.com.au nicm.edu.au 3 Disclosures

Justin Sinclair (Pharmacognosist)

MHerbMed (USyd) BHSc (UNE) ND DBM DNut FNHAA MICRS MSCC

• Research Fellow – NICM (Western Sydney University) • Scientific Advisory Board Member – Bioceuticals • Chief Scientist, Scientific Advisory Council – United in Compassion (Registered Charity) nicm.edu.au • Lecturer – Endeavour Cannabis Botany 4

Family: (AHP 2014) Botanical nomenclature: (AHP 2014) . (L) . (Lam) . (Janisch)

Common names: (AHP 2014) Pot, weed, cannabis, , , , reefer. Part used: Medicinally: Dried unfertilised female inflorescence, Resin glands (aka ), leaves

Industry: Figure 1: Graphic representation of Cannabis Seeds (i.e. oil, protein) and fibre (i.e. sativa (L), showing seeds, stamens, leaves, ovaries and inflorescence. Photo from Kohler Textiles, paper, building material) (1887)

nicm.edu.au 5

Cannabis Origins

BLD – Broad Leaf Drug: Cannabis indica ssp. NLD – Narrow Leaf Drug: Cannabis indica ssp. indica afghanica

BLH –FigureBroad 3: LeafGraphic Hemp: representation Cannabis of indicapresentssp. day ranges of variousNLH Cannabis– Narrow biotypes. Leaf Hemp: As seen Cannabis in Clarke & sativa Merlin ssp.2013 . chinensisnicm.edu.au sativa Cannabis Morphology 6

Acuminate apex

Serrated leaf margin

Figure 2: The short, broad leaf exhibited Figure 3: The long, narrow leaf seen in by Cannabis indica, or what is also Cannabis sativa. being described as a broad-leaf drug nicm.edu.au variety. Cannabis Morphology 7

Stamens Pollen

Figure 4: The androecium, or “male place” of Figure 5: The female inflorescence made up of the Cannabis comprised of filaments and many smaller florets and populated with anthers, collectively known as stamens. pistils/stigmas

nicm.edu.au Cannabis Morphology 8

Pistils / Stigmas Glandular trichomes

Figure 6: The covering of glandular trichomes Figure 7: Magnified glandular trichomes on on a female Cannabis plant. Cannabis plant.

nicm.edu.au Cannabis Morphology 9

Figure 8: The compressed glandular trichomes Figure 9: Hashish can be sifted or hand rubbed. of the Cannabis plant, known commonly as The hand rubbed product is known as . hashish or hash. Photo by Pierre Arnoud-Chouvy

nicm.edu.au Cannabis Morphology 10

Figure 10: The covering of glandular trichomes Figure 11: Another broad leaf drug variety on a specific strain of Cannabis known as known as “Afghani ” obtained from a “Bubba Kush”. This is crude herb that can be licensed dispensary. smoked, vaporized or used to make edible products (THC:@11-17% / CBD: nicm.edu.au < @ 0.4%) Cannabis Morphology 11

Figure 12: Cannabis plant in vegetative growth stage...note the absence of flowers or buds forming as yet.

nicm.edu.au Cannabis Morphology 12

Figure 13: Cannabis under indoor lighting in vegetative growth stage.

nicm.edu.au Cannabis Morphology 13

Figure 14: Outdoor Cannabis plants just starting the flowering stage...notice the Cola buds forming at the end of the stems.

nicm.edu.au Cannabis Morphology 14

nicm.edu.au Cannabis Morphology 15

Figure 15: The seeds of Cannabis, a Figure 16: The fibre obtained from Cannabis great nutritional source of oil and stalks, used throughout human history for protein. millennia.

nicm.edu.au Cannabis Phytochemistry 16

Tetrahydrocannabinol (THC) Structure

Figure 17: A large Cannabis Cannabidiol (CBD) Structure inflorescence nearing maturity and harvest. nicm.edu.au Cannabis Phytochemistry 17

(Andre, Hausman & Guerriero 2016) nicm.edu.au Cannabis Phytochemistry 18

(Giacoppo et al. 2014; AHP 2014)

(Giacoppo et al. 2014; AHP 2014) nicm.edu.au Cannabis Phytochemistry 19

Cannabigerolic acid (CBGA) Δ9-Tetrahydrocannabinolic acid (THCA) Cannabidiolic acid (CBDA)

Cannabichromic acid (CBCA) Cannabielsoinic acid

Psychoactive

Non Psychoactive non-enzymatic decarboxylation (heat)

THCA THC

(Giacoppo et al. 2014; AHP 2014) nicm.edu.au Cannabis Phytochemistry 20

Tetrahydrocannabinol (THC) Structure Cannabidiol (CBD) Structure

Pharmacological actions attributed to THC * Pharmacological actions attributed to CBD

Analgesic (Rahn & Hohmann, 2009) Anticonvulsant (Jones et al. 2010)

Antiemetic (Haney et al. 2007; Hollister 1971; Machado et al. 2008) Antagonizes effects of THC (Pertwee 2008)

Anti-inflammatory (Hampson et al. 1998) Analgesic (Davis & Hartoum, 1983)

Antipruritic (Neff et al. 2002) Anti-inflammatory (Booz, 2011)

Bronchodilator (Williams et al. 1976) Antiemetic / Antinausea (Rock et al. 2010)

Muscle relaxant (Kavia et al. 2010) Anxiolytic (Russo et al. 2005; Campos & Guimares, 2008)

Antioxidant, Neuroprotective (Hampson et al. 1998) Antioxidant (Hampson et al. 1998)

 symptoms of Alzheimer’s (Eubanks et al. 2006) Neuroprotective (Hampson et al. 1998)

(Russo 2011; AHP 2014) * Denotes psychoactivity nicm.edu.au Cannabis Phytochemistry 21

Cannabichromene Tetrahydocannabivarin Delta-8-Tetrahydrocannabinol * Weak analgesic (Turner et al. 1980) THC antagonist (Pertwee et al. 2007) Appetite stimulant (Avraham et al. 2004) Anti-inflammatory (Davis & Hatoum, 1983) Anticonvulsant (Hill et al. 2010) Less psychoactive then Delta-9-THC Antimicrobial (Turner & ElSohly, 1981) Improved glucose tolerance (Wargent et al. Binds to CB1 receptors in the brain like 2010) Delta-9 Antiemetic and analgesic

Cannabigerol Cannabinol Analgesic (Cascio et al. 2010) Antipsoriatic (Wilkinson & Williamson 2007) Anti-inflammatory Sedative (Musty et al. 1976) Anticonvulsant (Hill et al. 2010) Antifungal (ElSohly et al. 1982) Antimicrobial against MRSA (Appendino et al. 2008) Antipsoriatic (Wilkinson & Williamson 2007) (Russo 2011; AHP 2014) nicm.edu.au 22

nicm.edu.au (Russo 2011; AHP 2014) Terpene Phytochemistry 23

Limonene CBD Anxiolytic (Carvahlo-Freitas & Costa, 2002) Immunostimulant if inhaled (Komori et al. 1995) Antioxidant Apoptosis of breast cancer (Viguishin et al. CBD 1998)

Beta-Myrcene THC Anti-inflammatory (Lorenzetti et al. 1991) Analgesic (Rao et al. 1990) Sedative & hypnotic (do Vale et al. 2002) Muscle relaxant (do Vale et al. 2002)

CBD

Alpha-pinene Anti-inflammatory (Gil et al. 1989)

Bronchodilatory (Falk et al. 1980) THC

(Russo 2011; AHP 2014) nicm.edu.au 24

nicm.edu.au (Russo 2011; AHP 2014) Cannabis Phytochemistry 25

Coumarins Flavonoids

Flavones Polysaccharides

Flavonols Alcohols

Glycosides Steroids Phenols

(AHP 2014) nicm.edu.au Cannabis Dosage Forms 26

Dosage Form Pros Cons Smoking Quick onset of effect; Cheap; Smoke can irritate the lungs; easy to adjust dosing Pulmonary disease  effect

Vaporising Quick onset of effect; better for Vaporising units can be lung health than smoking expensive.

Edibles Long lasting effect; option for Longer onset of action; can be those that do not smoke stronger effect.

Juicing Rich in THCA; non- Not a great deal of evidence to psychoactive support this form.

Tinctures / Oils Easy to control dosage; Slower than smoking in onset. palatable; Good for children

Capsules Long lasting effect; option for Longer onset of action; those that do not smoke Excipient ingestion.

Suppositories Absorbed quickly; Long lasting Difficult to administer; Needs effect refrigeration

Topically Can be used for local skin Not a great deal of evidence to nicm.edu.au conditions; Not psychoactive support this form. Cannabis specific drug interactions 27

Cannabis phytochemical Interaction

Cannabidiol (CBD) Can potently inhibit CYP3A4, CYP3A5 and CYP2D6 enzymes

Tetrahydrocannabinol In-vitro inhibition of CYP2C9 has been (THC) observed (Cannabis smoke)

Cannabidiol (CBD) In-vitro inhibition of CYP2C9 has been observed (Cannabis smoke)

Cannabinol (CBN) In-vitro inhibition of CYP2C9 has been observed (Cannabis smoke)

nicm.edu.au How did we get here? 28

nicm.edu.au How did we get here? 29

nicm.edu.au How did we get here? 30

nicm.edu.au Cannabis lowers your IQ? 31

. Cannabis may cause short term memory impairment whilst under the influence. . This is considered reversible upon cessation...not permanent. . Certain Cannabis phytochemicals such as Cannabidiol (CBD) actually exhibit neuroprotective activity. . Animal studies are now showing the possibility of specific Cannabis phytochemistry assisting in:

. Foetal hypoxia (Alvarez et al. 2008) . Multiple sclerosis . Hypoxic brain injury (Ischaemic Figure 18: The female inflorescence (bud) of stroke) “Super Silver Haze”, one of hundreds of different Cannabis strains. . Alzheimer’s Disease (Ramirez et al. 2005)

nicm.edu.au Cannabis lowers your IQ? 32

nicm.edu.au All Cannabis gets you “high”? 33 . The psychoactivity of cannabis is largely dependent on the phytochemistry exhibited in the specific strain of the plant. . There exist numerous strains of Cannabis that have been selectively bred to be low in THC, but higher in other phytochemicals such as CBD. . Individual dosing (titration) and appropriate selection is key to reducing psychoactive effects.

Figure 19: Harlequin, is rich in CBD and has much lower levels of THC (the main psychoactive ) than most recreationally used varieties. Phytochemical profile produced with permission from Steep Hill (Halent) Laboratories (USA). nicm.edu.au Cannabis is a drug of dependence? 34

(Anthony, Warner & Kessler 1994). nicm.edu.au Cannabis is a drug of dependence? 35

. Cannabis dependency does exist but is also dependent on the individual. . Factors such as individual polymorphic expression, individual variability, the strain of Cannabis being utilised and the dosage taken are also important contributing factors.

(Anthony, Warner & Kessler 1994). nicm.edu.au Cannabis is a drug of dependence? 36

We are both legal

nicm.edu.au Cannabis is a gateway drug? 37

. A Gateway drug is defined as “one that apparently can lead to the use of harder, more addictive or dangerous ”. . Examples of hard drugs may include: . Heroine . Methamphetamine . Cocaine

(Reiman 2009) nicm.edu.au Cannabis is a gateway drug? 38 Table 1: Percent of sample reporting using cannabis as a substitute. Type of substitution # of Participants % of Participants EtOH substitute n = 134 40% Illicit drug substitute n= 87 26% Prescription drug substitute n= 219 65.8%

250

200

150

100

50

0 Alcohol (EtOH) Illicit drug substitute Prescription drug substitute Number of study participants substitute

nicm.edu.au (Reiman 2009) Cannabis is a gateway drug? 39

Reasons for using cannabis as a substitute

Less adverse side effects (n=197) Less withdrawal potential (n=103) Ability to obtain Cannabis (n=54) Greater social acceptance (n=36) Better symptom management (n=174)

(Reiman 2009)

nicm.edu.au Cannabis is a gateway drug? 40

nicm.edu.au Cannabis is a gateway drug? 41

nicm.edu.au Cannabis versus opioid medication 42

nicm.edu.au Cannabis is a gateway drug? 43

nicm.edu.au Cannabis can cause psychosis? 44 Psychosis is an inability PubMed . to distinguish what is Abstract Full text links real and can include Curr Psychiatry Rep. 2016 Feb;18(2):12. doi: 10.1007/s11920-015-0657-y. delusions and Cannabis and Psychosis: a Critical Overview of the Relationship. Ksir C1, Hart CL2,3,4,5. hallucinations. Author information . Psychosis can be a Abstract brief episode or longer Interest in the relationship between cannabis use and psychosis has increased dramatically in recent years, in part because of concerns related to the growing availability of cannabis and term as seen in potential risks to health and human functioning. There now exists a plethora of scientific articles addressing this issue, but few provide a clear verdict about the causal nature of the cannabis- psychiatric conditions psychosis association. Here, we review recent research reports on cannabis and psychosis, giving particular attention to how each report provides evidence relating to two hypotheses: (1) cannabis such as . as a contributing cause and (2) shared vulnerability. Two primary kinds of data are brought to bear on this issue: studies done with schizophrenic patients and studies of first-episode psychosis. . The exact cause of Evidence reviewed here suggests that cannabis does not in itself cause a psychosis disorder. psychosis is unknown Rather, the evidence leads us to conclude that both early use and heavy use of cannabis are more likely in individuals with a vulnerability to psychosis. The role of early and heavy cannabis use as a but likely involves a prodromal sign merits further examination, along with a variety of other problem behaviors (e.g., early or heavy use of cigarettes or alcohol and poor school performance). Future research studies complex interplay of that focus exclusively on the cannabis-psychosis association will therefore be of little value in our quest to better understand psychosis and how and why it occurs. physical, genetic, psychological and KEYWORDS: Cognition; Marijuana; Mental illness; Psychotic disorder; Schizophrenia; THC environmental factors. PMID: 26781550 [PubMed - in process]

(Ksir & Hart 2016) nicm.edu.au LinkOut - more resources

PubMed Commons PubMed Commons home

0 comments How to join PubMed Commons Cannabis can cause psychosis? 45

. In this UK study, it was estimated that to prevent one case of psychosis approximately 2000 young men would need to stop using Cannabis.

nicm.edu.au Cannabis can cause psychosis? 46

100%

75% 1%

50%

25%

1950 1960 1970 1980 1990 2000 2010 Now

Years of Cannabis use (International) nicm.edu.au Cannabis use is harmful? 47

. Statistics regarding Cannabis causing harm are skewed as they often involve multiple other drugs such as alcohol. . Data specifically relating to Cannabis overdose or toxicity is difficult to find. . Cannabis related harm is more likely, such as operating motor vehicles or predisposing to mental illness or accident.

Figure 20: An example of an old Pharmacopoeia Fluid extract of Cannabis. nicm.edu.au Cannabis use is harmful? 48

nicm.edu.au Cannabis use is harmful? 49

LD50 mg/kg in rats (oral)

8000 7060 7000 6000 5000 4000 3000 1944 LD50 mg/kg in rats (oral) 2000 1270 980 1000 636 21.8 192 0

nicm.edu.au Cannabis use is harmful? 50

nicm.edu.au How much Cannabis to cause death? 51

nicm.edu.au Cannabis hyperemesis syndrome 52

nicm.edu.au To conclude. 53

“Truth is always the first casualty of war”

- Aeschylus (523-456BCE) Figure 21: Aeschylus (523-456 BCE)

nicm.edu.au Reference list 54

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