IN THE CONSTITUTIONAL COURT OF

Case No.: CCT 11 and 12/95

In the matter between:

THE STATE and

BHULWANA

And in the matter between:

THE STATE and

GWADISO

AFFIDAVIT

I, the undersigned,

FRANCES RIX AMES, do hereby make oath and say that:

1. I am a former Associate Professor of Neurology.

2. All of the facts deposed to in this affidavit are, unless indicated to the contrary, within my personal knowledge and belief. 44 V Page 2

3. My professional qualifications and experience are the following:

3.1 I hold the qualifications of MB.CHB, M.D., M.Med, and DPM.

3.2 I have been registered as a neurologist since 1955 and was head*of

the Neurology Department at the Faculty of Medicine of the

University of Cape Town and at from 1976

to 1985.

3.3 I am a qualified, but not a registered, psychiatrist.

3.4 I was awarded an Associate Professorship in the 1970's by the for research work. Amongst my research publications are those set out in annexure "A" hereto.

3.5 I am presently in semi-retirement, but continue to hold consulting and teaching appointments at various hospitals in the Western Cape including the Psychiatry Department at Groote Schuur Hospital, and at the EEG and Out-Patients Clinic at .

3.6 Although my qualification, professorial appointment and research have been in the general discipline of Neurology, a specific area in which I have practised extensively and in which I have conducted research is the neurological and general medical effects which marijuana has on the human body and on the brain. Page 3

3.7 During the course of my practice and research over 37 years I have dealt with many patients who are consumers of marijuana and I have accordingly reasonably frequently had exposure to the sociological aspects of their consumption of marijuana.

3.8 By virtue of my qualifications and my experience I have given evidence as an expert in various courts in South Africa on the medical effects of marijuana.

4. The evidence which I tender to this Honourable Court is:

4.1 There is worldwide research which indicates that marijuana has

specific medicinal properties.

4.2 Many patients genuinely believe marijuana to have medicinal properties and possess and consume it in the bonafide belief that it does assist them in their ailments.

4.3 Patients whom I have treated or whom I have interviewed do, by virtue of their belief in the consumption of marijuana, purchase quantities for their own consumption and purchase such quantities as may easily exceed 115 grams. Furthermore, any patient who has chronic disease is entitled to a stock of medication, which stock may possibly exceed 115 grams of marijuana. Page 4

5. Concerning the research which indicates that marijuana has medicinal

properties:

5.1 Although I am informed that this fact is not central to the question to be decided by this Honourable Court, there is ongoing research which is conducted worldwide on the medicinal properties of cannabis sativa (dagga, marijuana).

5.2 Such research seems to indicate that marijuana can assist in the

treatment of certain specified medical conditions, including multiple

sclerosis, the nausea and vomiting accompanying chemotherapy,

AIDS, glaucoma, movement disorders, asthma and epilepsy.

5.3 That research also indicates that patients do consume the substance

in the hope, and the belief, that it will satisfactorily treat their

ailment.

5.4 I annex hereto as annexures "B" and "C" copies of the articles written by some of the researchers who have conducted research in this area. Those articles record positive results from the consumption of marijuana in the treatment of multiple sclerosis and of epilepsy. Similar research has been conducted with respect to the other medical conditions referred to above.

6. Concerning the possession and consumption of marijuana in the belief that it treats ailments: Page 5

6.1 I have on various occasions treated and interviewed patients who

have consumed marijuana in the genuine and bona fide belief that

such consumption assists them in their ailment.

6.2 Although one may tend to be cynical about whether the possession of a banned substance could be bona fide, there are patients, the details of whom are irrelevant for the present purposes, whom I have treated, and whom I am completely persuaded possessed and consumed marijuana in the genuine belief that it would assist them in their condition. In this regard, I specifically refer to the case of Francois Le Blond who is a sufferer of multiple sclerosis, and who has possessed marijuana for the purposes of assisting him in the relief of his symptoms. I refer to him specifically as his case has enjoyed some publicity in the media recently.

6.3 Concerning my own experience in the treatment of epilepsy, I was consulted about a patient who was accused in a criminal matter in the Magistrates' Court for . In that matter I was consulted on the question of evidence which was to be submitted to the effect that the particular patient had consumed the drug believing it to assist him in the treatment of epilepsy. The Court accepted as a fact that the patient's epilepsy had improved with the consumption of marijuana after having this opinion confirmed by another expert who appeared to give evidence in court. Page 6

7. Concerning the quantities which are possessed by patients for their treatment:

7.1 The administration of drugs to sufferers of various chronic diseases listed above is accepted practice. It is routine practice for hospital dispensaries to issue such patients with a full month's supply of medication. Provision is often made to repeat this for three months.

7.2 I refer to the case of Mr Le Blond. He is a patient who is wheelchair-bound and who possesses marijuana for his own use. By virtue of his disability he tended to accumulate sufficiently large quantities to preclude his having to send someone to purchase other quantities in the near future. During the course of my interviews with the patient it became clear that as a fact he did not deal in the substance but possessed the marijuana for his own consumption. The quantity which had been in his possession well exceeded 115 grams, as it represented sufficient medication for 2 years.

7.3 In general it may be said that patients who obtain illicit drugs must accumulate sufficient quantities of them so as to reduce the risk of arrest and prosecution. Thus, as the purchase of an illicit drug exposes one to the risk of prosecution, the single purchase of a large amount obviously carries less risk than the repeated purchases of the small amounts. Page 7

7.4 A further factor with a drug of the nature as cannabis is that the plant extract varies in potency. It is therefore clearly sensible for the consumer of cannabis to acquire as large a quantity of potent cannabis as possible should the opportunity arise. Such purchases of cannabis may thus easily exceed the amount of 115 grams.

8. Although this does not arise as a result of my own research, it has been reported in medical journals that individuals use cannabis for reasons other than social or medical purposes, and specifically also for religious purposes. It has been reported by one research group that members of a cult used between 2 and 4 ounces of "ganja-tobacco mixture" daily. That quantity equates with between 60 and 120 grams. Ganja is a form of cannabis sativa that is about three times more potent than marijuana. I annex hereto as annexure "DH a copy of the article written by the researchers in that case.

9. I do not hold myself out as an expert in the sociological aspects of marijuana consumption and am regrettably unable to place before this Honourable Court reliable statistics concerning the numbers of people who possess quantities in excess of 115 grams for their own consumption, as opposed to for the purpose of dealing. However, in my experience the possession of 115 grams of marijuana is not unreasonable, and is indeed acceptable in patients with chronic neurological and medical diseases. Page 8

10. The statutory presumption which relates to the possession of 115 grams or more of marijuana does therefore not reflect the factual situation relating to persons who possess and consume marijuana for medical purposes.

nfv *vvU-^| ' * FRANCES RIX AMES

I certify that:

1. The Deponent acknowledged to me that:

1.1 She knows and understands the contents of this declaration;

1.2 She has no objection to taking the prescribed oath;

1.3 She considers the oath to be binding on her conscience;

2. The Deponent thereafter uttered the words: "I swear that the contents of this declaration are true, so help me God."

3. The Deponent signed this declaration in my presence at the address set out hereunder on this the day of 1995.

COMMKSKJNER OF OATHS

[AMES] ANNEXURE "A"

1. "A clinical and metabolic study of acute intoxication with cannabis sativa and its role in the model psychoses": Journal of mental science (1958) Vol. 104 page 972.

2. Ames et al: "Effects of the oral administration of cannabis sativa (dagga) on thacma baboons (Papio ursinus)": South African Medical Journal (1979) page 1127.

3. "The effects of Cannabis sativa on the behaviour of adult female thacme baboons (Papio ursinus) in captivity": Levett, Saayman & Ames: Psychopharmacology (1977) Vol. 58 page 79.

4. "Cannabis and the brain: David Castle and Frances Ames (in press) Australian Journal of Psychiatry: March 1995.

5. (In press) An article on the neurological effects of cannabis in general: South African Medical Journal 1995.

[2-AMES] Journal of // JNeuroI (1989) 236:120-122 'tasmaierialnifty be Neurology subjecno copyright. © Springer-Verlag 1989 '

aan outeurs,eg ondcr-

Effect of cannabinoids on spasticity and ataxia in multiple sclerosis*

H.-M.Meinck, P.W.Schonle, and B.Conrad Department of Clinical Neurophysioiogy, University of Gottingen, Federal Republic of Germany

Summary. The chronic motor handicaps of a 30-year-old and 25 October. On 22 October, one "experimental" marihuana multiple sclerosis patient acutely improved while he smoked a cigarette was allowed, and various electrophysiological exper- marihuana cigarette. This effect was quantitatively assessed iments were performed as described below. I by means of clinical rating, electromyographic investigation of Clinical rating was performed daily by the same neuro- the leg flexor reflexes and electromagnetic recording of the logist and on 22 October before and after the "experimental" hand action tremor. It is concluded that cannabinoids may cigarette. Rating comprised motor functions relevant to the have powerful beneficial effects on both spasticity and ataxia electrophysiological tests described below (see Fig. 1). that warrant further evaluation. Key words: Multiple sclerosis - Spasticity - Ataxia - Can- nabinoids - Flexor reflex ....

Introduction

This study was prompted by a young man with multiple sclero- sis (MS) who used marihuana as a remedy for his various sit motor, micturition and sexual handicaps. After smoking a mod marihuana cigarette on the ward, he clinically improved. He nor agreed to the beneficial effects of marihuana being investi- ilt gated by means of quantitative clinical and electrophysiologi- mod cai assessment. mod IN m Case report eig JT

This male patient, born in 1955, had had MS since 1983. At elf the time of our experiments he was bound to a wheelchair be- Big cause of severe limb and gait ataxia and spastic tetraparesis. elf After micturition, his residual urine volume was 100-150 ml. sht He complained of impotence, with erections lasting less than tag 5min and lacking ejaculation. He tried a marihuana cigarette sus in about 1984 and noted an instantaneous improvement of his sht Ing motor and sexual functions lasting for several days. Since SOS then, he regularly took some marihuana biscuits each week, sol which enabled him to climb stairs, to walk on even ground, drs and to have erections for more than 30min, allowing him a shn f.

quite satisfactory sexual life. OCT ' 17 ' II ' 19 ' 21 22 23 ' 24 tt t Methods Fig. 1. Results of clinical rating (shaded) on the days before and after smoking the marihuana cigarette (arrow on time scale). Force (ac- From 12 October 1985 the patient abstained from ail drugs, in- cording to the MRC scale) of the iliopsoas (IP), quadriceps (QF), and tibialis anterior (TA) muscles. Muscle tone (knee and ankle joints): cluding marihuana. He was hospitalized between 17 October normal (nor), slightly (sit) and moderately (mod) increased. Ataxia at finger-nose testing (FNT): moderate (mod), severe (sev). Deep ten- • Dedicated to Professor H. H. Kornhuber on the occasion of his 60th don reflexes of the achilles (AT) and patella tendons (PT) and hip ad- birthday ductors (AD): very brisk (viv), exaggerated (exg), doniform (elf). Offprint requests to: H.-M.Meinck, Neurologische Universitiitsklinik, Ankle (AT) and patella (PT) clonus: short (sht), long (Ing), sus Im Neuenheimer Feld 400, D-6900 Heidelberg, Federal Republic of (sus). Babinski sign (BS) elicitablefrom the foof^le (sol), footdtor Germany sum (drs), shin (shn) TA

before

Kg. 2a, b. Influence of smoking two whiffs of a marihuana cigarette ankle and knee clonus. The receptive field of the Babinski on a the abnormal flexor reflex, and b on the finger and hand action sign covered the whole foot and the shin. Ataxia in the arms tremor, a EMG records from the quadriceps (Qj, posterior biceps was severe and could not be tested in the legs because of dis- (PB), gastrocnemius (G) and tibialis anterior (TA) muscles. Each tinct hip flexor paresis. recording represents eight rectified and summated reflexes. Figures to the left indicate the time before (-) and after (+) the first whiff, the About 45 min after the marihuana cigarette, muscle force second whiff being taken 18 min after the first. Vertical and horizontal was somewhat increased in the knee extensors and ankle calibrations apply for all recordings; stimulation at Oms. b Electro- flexors (but not in the hip flexors), and muscle tone was magnetic recording of the finger and hand action tremor in a pointing reduced. The leg deep tendon reflexes showed normalization, task on the morning before and in the evening after smoking the too, corresponding to a clear shortening of the periods of marihuana cigarette clonus. The receptive field of the Babinski sign was confined to the lateral fool sole margin. Ataxia in finger-nose testing was moderate. After the flexor reflex experiment, the patient was able to walk a few metres between the couch and his The flexor reflex was elicited by a painful electrical shock wheelchair with support. Some of these improvements lasted to the foot sole and recorded from the quadriceps (Q), poste- beyond 23 October and even 24 October (Fig. 1). rior biceps (PB), gastrocnemius (G) and tibialis anterior (TA) The flexor reflex showed the desynchronized and prolonged muscles. The EMG was full-wave rectified, and eight consecu- reflex pattern typical of spastic paresis (Fig. 2a; cf [13]). As tive reflexes were summated. Five control series of eight con- soon as 2min after the whiff of the marihuana cigarette, a secutive reflexes each were run at intervals of about 5 min. clear attenuation of the reflex activity was noted. Attenuation The patient was then asked to take one whiff of his "experi- was about equal in all four muscles (20% -30% of the last mental" cigarette, and further series of reflexes were run in three control recordings) and progressed until 17 min after the the manner described above (for details see [12]). whiff. A second whiff (18 min after the first one) did not Finger movements were recorded in a standardized point- induce further reflex attenuation. Single sweep recordings ing task performed before and after both the "experimental" showed that the reflex attenuation after marihuana was not cigarette and the flexor reflex experiment. Basically, the re- due to enhanced habituation: after marihuana even the first of cording device consisted of a three-coil-transmitter system the eight consecutive reflex responses was attenuated. generating non-homogeneous magnetic fields, and a miniatur- Electromagnetic recording of action tremor revealed a ized receiver coil attached to the finger tip. When the finger coarse 3 Hz hand and finger tremor with an amplitude be- moved through the magnetic fields a signal was induced in the tween 1 and 3 cm, persisting throughout nearly the whole receiver coil, allowing the computation of the two-dimen- movement. Hours after the "experimental" cigarette, action sional movement trajectory (for details see [15]). Ten trials tremor was almost completely abolished, although the move- were performed before and after marihuana smoking, each ments were made at about the same speed (Fig. 2b). consisting of a pointing movement of the right index finger over a 10-cm distance. The forearm rested on a stable support, but the finger and hand could not reach the target. Discussion

Our findings clearly show that there are indeed motor actions Results of marihuana which were (a) reproducible in a laboratory situ- ation most exhaustive to the patient, (b) quantitatively assess- Clinical rating showed a moderate deterioration of motor able by means of electrophysiological testing, and (c) in line functions between 17 October and 22 October (Fig. 1). On 22 with the results of clinical rating. Our findings further corre- October, before the "experimental" cigarette, he was incap- spond with earlier anecdotal clinical reports [4, 6,11,14]. able of walking a few steps even with support; his muscle force Little is known about the neurophysiologjcal background in the legs did not exceed MRC grade 3. Muscle tone ranged of the antispastic and antiataxic actions of marihuana seen in between slightly and moderately increased, and the leg deep our patient. However, some findings in experimental tendon reflexes were exaggerated or clonic with sustained seem relevant to our observations. Cannabjhpids in high* 122

dosages attenuate the monosynaptic reflex [1, 2, 17, 18] prin- 4. Clifford DB (1983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 13:669-671 ' ' cipally corresponding to the attenuation of both deep tendon 9 reflexes and clonus in our patient (Fig. 1). Poiysynaptic re- 5. Domino EF (1976) Effects of A -tetrahydrocannabinol and can- nabinbl on rat brain acetylcholine. In: Nahas GG, Paton WDM, flexes were also attenuated after tetrahydrocannabinol deriva- Idaanpaan-Heikkila JE (eds) Marihuana - chemistry biochemis- tives in experimental animals [1, 7, 20], fitting in well with the try and cellular effects. Springer, New York Berlin Heidelberg, pp narrowing of the receptive field of the Babinski sign (Fig. 1) 407-413 and with the results of our flexor reflex experiment. As can- 6. Dunn M, Davis R (1974) The perceived effects of marijuana on nabinoids have analgesic properties [16, 20], attenuation of spinal cord injured males. Paraplegia 12:175 the pathological flexor reflex in the present case could repre- 7. Gilbert PE (1981) A comparison of THC, nantradol, nabilone, sent analgesic rather than antispastic effects of the drug. How- and morphine in the chronic spinal dog. J Gin Pharmacol 21: 311-319 ever, analgesic effects are also attributed to several antispastic 9 8. Ho BT, Johnson KM (1976) Sites of neurochemical action of A - drugs [10, 21] and, on the other hand, classical analgesics such tetrahydrocannabinol: interaction with reserpine. In: Nahas GG, as opioids may improve spastic symptoms [19]. One might, Paton WDM, Idaanpaan-Heikkila JE (eds) Marihuana - chemis- therefore, indeed wonder whether both the antispastic and try, biochemistry, and cellular effects. Springer, New York Berlin analgesic actions of such drugs are in fact at least to a substan- Heidelberg, pp 367-381 tial degree based on common neuronal mechanisms such as an 9. Howes JF, Osgood PF (1976) Cannabinoids and the inhibition of increase of presynaptic inhibition or a decrease of postsynap- prostaglandin synthesis. In: Nahas GG, Paton WDM, Idaanpaan- Heikkila JE (eds) Marihuana - chemistry, biochemistry, and cel- tic excitation of multireceptive intemeurones at various levels lular effects. Springer, New York Berlin Heidelberg, pp 415-424 of the neuraxis. Whatever the mechanism, the antispastic ac- 10. Jurna J (1984) Depression of nociceptive sensory activity in the rat tions of marihuana in both clinical rating and electrophysio- spinal cord due to the intrathecal administration of drugs: effects logical testing are similar to those seen in spastic patients after of diazepam. Neurosurgery 15:917-920 either 0.3 mg tizanidine [13], 150ugclonidine, or lOmgdiaze- 11. Malec J, Harvey RF, Cayner JJ (1982) Cannabis effect on spastic- pam (unpublished observations). The important difference is ity in spinal cord injury. Arch Phys Med Rehabil 63:116-118 that marihuana apparently also has antiataxic actions (Fig. 2b; 12. Meinck H-M, Conrad B (1986) Neuropharmacological investiga- tions in the stiff-man syndrome. J Neurol 233:340-347 see also [4]) not ascribed to any antispastic drug. 13. Meinck H-M, Benecke R, Conrad B (1985) Cutaneo-muscular The biochemical basis of the motor effects of marihuana is control in health and disease: possible implications on spasticity. obscure. Available data, although somewhat controversial, In: Struppler A, Weindl A (eds) Electromyography and evoked suggest that cannabinoids release brain serotonin from its potentials, theories and applications. Advances in applied neurological sciences, vol 1. Springer, New York Berlin Heidel- storage sites and block its re-uptake [8], inhibit the synthesis berg, pp 75-83 of prostaglandins within the CNS [9] and - in large doses - 14. Petro DJ, Ellenberger C (1981) Treatment of human spasticity elevate brain acetylcholine and reduce its utilization [5]. The with A9-tetrahydrocannabinol. J Clin Pharmacol 21:413-416 relationship of these neurotransmitters to spasticity and ataxia 15. Schanle PW, Grabe K, Wenig P, Hohne J, Schrader J, Conrad B is unknown: none of the well-established antispastic drugs is (1987) Electromagnetic articulography - use of alternating thought to interfere with them; they are only scarcely, if at all, magnetic fields for tracking movements of multiple points inside found within the cerebellum [3]. and outside the vocal tract. Brain Lang 31:26-35 16. Segal M (1986) Cannabinoids and analgesia. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC Press, Boca Acknowledgement. We thank our patient for his kind cooperation Raton, Fla, pp 105-120 throughout this study. 17. Tramposch A, Sangdee C, Franz DN, Karler R, Turkanis SA (1981) Cannabinoid-induced enhancement and depression of cat monosynaptic reflexes. Neuropharmacology 20:617-621 References 18. Turkanis SA, Karler R (1983) Effects of A9-tetrahydrocannabinol on cat spinal motoneurons. Brain Res 288:283-287 1. Boyd ES, Meritt DA (1965) Effects of a tetrahydrocannabinol de- 19. Wilier JC, Bussel B (1980) Evidence for a direct spinal mechanism rivative on some motor systems in the cat. Arch Int Pharmacodyn in morphine-induced inhibition of nociceptive reflexes in humans. Ther 153:1-12 Brain Res 187:212-215 2. Capek R, Esplin B (1976) Effects of A9-tetrahydrocannabinol on 20. Yaksh TL (1981) The antinociceptive effects of intrathecaHy the homosynaptic depression in the spinal monosynaptic pathway: administered levonantradol and desacetyllevonantradol in the rat. implications for transmitter dynamics in the primary afferents. In: J Clin Pharmacol 21:334-340 Nahas GG, Paton WDM, Idaa'npaan-Heikkila JE (eds) Marihuana 21. Yaksh TL, Reddy SVR (1981) Studies in the primate on the - chemistry, biochemistry, and cellular effects. Springer, New analgetic effects associated with intrathecal actions of opiates, a- York Berlin Heidelberg, pp 385-395 adrenergic agonists and baciofen. Anesthesioiogy 54:451—467 3. Chan-Pafay V (1984) Purkinje cells of the cerebellum: localization and function of multiple neuroactive substances. Exp Brain Res Received Novemer 30, 1987 / Received in revised form October 6, [Suppl] 9:129-144 1988 / Accepted November 6, 1988 tovic/Bichmann-

. M.: Pharmpco- ^SS (1980) erimentat acute 17-314 (1978).

Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients1

JomarM. Cunha, E.A. Carlini, Aparecido E. Pereira, Oswaldo L. Ramos, Camilo Pimentel, olcdo College Rubens Gagliardi, W.L. Sanvito, N. Lander and R. Mechoulam !edo. Departaroento de Psicobiologia, Departamento de Medicina, Departamento de Neurologta, Escola Pautista de Medicina; Departamento de Neurologia, Facuidade de Medicina da Santa Casa, Sao Paulo, and Department of Natural Products, Pharmacy School, Hebrew University, Jerusalem

Key Words. Cannabidiol • Epilepsy - Healthy volunteers

Abstract. In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 healthy human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood mdumne analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, v^S^atients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200— l 300 mg daily of CBD or placebo. The drugs were administered for as long as 4 {2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

Anecdotal reports on the antiepileptic prop- (1971) mentioned medieval Arab manuscripts erties of marihuana (Cannabis sattvaj are known in which cannabis is described as a treatment since, ancient times (Li, 1974). Rosenthal for epilepsy. During the 19th century several medical reports were published on the ameliora- tive effects of cannabis extracts on several ' This work was supported by grant No. RO1 DA 00875 from [he US National Institutes of Mental forms of convulsions (O'Shaughnessy, 1842; Health (principal investigator: E.A. Carlini). Shaw, 1843; Reynolds, 1890). 176 Cunha/Carlini/Peretra/Ramos/Pimentel/Gagliardi/Sanvito/Lander/Mechoulain

In spite of these promising results and its anticonvuisant effects of CBD, there have been low toxicity, the use of c anna bis preparations several additional reports on the effectiveness for medical purposes progressively decreased. of CBD and its derivatives in protecting experi- This was due to the absence of standardized mental animals from convulsions induced by preparations, the unknown chemical composi- various procedures (Karler et al., 1973; Tur- tion, and the psychotropic secondary effects kanis et at., 1974; Carlini et al., 1975; Karler produced by cannabis. and Turkanis, 1976; Consroe and Wolkin, Cannabidioi (CBD) is the major neutral non- 1977). Consroe and Wolkin (1977) demon- psychoactive cannabinoid in most cannabis strated that CBD has a high protective index preparations. It was first isolated by Adams et comparable to that of phenobarbitai and a spec- at, in 1940 but its structure was elucidated trum of anticonvuisant activity in rodents similar only 13 years later (Mechoulam and Shvo, to that of phenytoin. CBD also enfiaHceithe anti- 1963). The main active component of cannabis convuisant potency of both phenytoin and phe- is A'-tetrahydrocannabinol (A'-THC) which nobarbitai (Consroe and Wolkin, 1911 ;Chesher was isolated in a pure form and its structure 'and Jackson, l914;Chesher et al., 1975). was determined by Gaoni and Mechoulam in In addition to its favorable anticonvuisant 1964. It is also named A9-THC. Numerous effects and absence of toxicity in animals, CBD other natural cannabinoids are known today seems to be devoid of psychotropic activity and {Mechoulam, 1973;Mechoulam et al, 1976). other undesirable side effects in humans. The The unraveling of the chemistry of C sativa lack of toxicity of CBD in animals was demon- brought a new interest in its pharmacology, and strated by intraperitoneal injection of 50 mg/kg quite expectedly many laboratories studied the daily for 90 days in mice, oral ingestton of anticonvuisant properties of its components 5-20 mg/kg daily for 90 days and 50 mg/kg for especially since early reports had shown that 27 days by rats and intravenous injection of some natural and synthetic cannabinoids pro- 1,000 mg/kg in rabbits. No toxicity was ob- tected rats from convulsions (Loeweand Good- served (Cunha and Carlini, to be published). In man, 1947) and were of therapeutic value in mart, oral intake of doses from 15 to 160 mg/ epileptic children (Davis and Ramsey, 1949). day (Kamioletal, 1974; HoMister, 1973; Car- More recently many reports have appeared at- lini et al., 1979), inhalation of 0.15 mg/kg tributing anticonvuisant properties to A'-THC (Dalton et al., 1976a), and intravenous injec- and other cannabinoids, in a variety of experi- tion of 30 mg (Perez-Reyes et al., 1973; mental procedures (Garriott et al, \968;Sofia Hollister, 1973) were not followed by ill ef- et at, 1911; Consroe and Man, 1973; Karter et fects. Chronic oral administration of 10 mg al., 1973, 1974; Plomikoff, 1976). As a rule, daily for 21 days did not induce any change in A'-THC was the most studied compound. Most neurological (including EEG), clinical (includ- of the results obtained confirmed the rather ing ECG), psychiatric, blood and urine exami- potent anticonvuisant property of this drug. Its nations (Mincis etaL, 1973). possible use as an antiepileptic drug in humans Another recent investigation in our labora- has, however, been hindered by its known tory {Consroe et al., 1979) showed that CBD psychotropic effects. neither interferes with several psychomotor Since Brazilian workers (Carlini etaL, 1973; and psychological functions in humans nor Izquierdo et al., 1973) first demonstrated the potentiates alcohol effects on these functions. Cannabidiol and Human Epilepsy 177

The above data led us to undertake the kg. 1 volunteer took 4 capsules of CBD daily (6 mg/ present investigation which was performed in kg) on the last 3 days of the experiment. two phases. In phase I, 3-6 mg/kg of CBD On the 3rd, 7th, 15th, 31st and,37th days after the beginning of drug ingestion, the subjects returned to (roughly corresponding to 200—400 mg/ the hospital to undergo the examinations described subject) was administered daily to healthy above. human volunteers for 30 days. In phase 2, patients suffering from secondary generalized Drug epilepsy with temporal irritative activity re- Cannabidiol, in crystalline form (m.p. 66-67°) was isolated from hashish of undetermined age. It was ceived 200—300 mg of the drug for periods of of Lebanese origin and was supplied by the Israeli up to 4.5 months. Police. The isolation procedure has been described (Qconi and Mechoulam. 1971). Part of the CBD was a gift from Makor Chemicals, P.O.B. 6570, Jerusalem.

Experiment 1 (Phase 1 of Study) Results

Material and Methods General Observations During the entire period of the experiment, Subjects 16 adult volunteers (11 men and 5 women) aged the subjects did not report any symptoms 22-35, with an average weight of 65 kg were chosen suggestive of psychotropic effect of CBD. Of from the staff of Escola Paulista de Medicina.. They the 8 volunteers receiving the placebo, 1 gave were in good health showing neither clinical nor up on the 21st day of the experiment for laboratory evidence of cardiovascular, renal, hepatic or personal reasons; a second placebo subject re- other impairments. The institutional review committee at Escota Paulista de Medicina previously approved the ported sudoresis and 'palpitations' from the 7th protocol of the experiments. to the 10th day in the veins of the feet, legs and On the first day of the experiment the patients head, stating that he had to uncover his feet to were submitted to a complete medical check-up, in- feel the palpitations less in order to sleep. cluding clinical and neurological examinations, EEG, Clinical and laboratory examinations' were nor- ECG, blood tests (hematocrit, hemoglobin, leukocyte and erythrocyte counts, bilirubin, oxaloacetic and mal and the symptoms subsided after the 1 lth pynivic transaminases and creatinine) and urine tests day without any measures on the part of the (osmolarity, pH, albumin, leukocyte and erythrocyte investigators. counts, cylinders and crystals) in the Department of Of the 8 volunteers receiving CBD, 2 re- Medicine of the Hospital Sao Paulo of Escola Paulista ported somnolence, 1 during the first week and de Medicina. On the 7th day, they returned to the hospital, signed the informed consent and were ran- the otheTlfiroughout the entire period of the domly divided in two groups of 8. Each group started experiment. A 3rd subject, with a history of urine exami- the ingestion of identical gelatine capsules containing mild insomnia, reported being able to sleep either glucose as placebo (control group) or CBD better during the fust week of medication. (experimental group). The experiment was performed Neurological and clinical examinations, EEG on a double-blind basis and the subjects were instruc- ted to ingest the assigned capsules, one in the morning and ECG tracings, and blood and urine analyses and the second in the afternoon for 30 days. Each (detailed above) were within normal limits in capsule contained an amount of CBD (or glucose) the 16 subjects before, during and after the equivalent to 1.5 mg/kg, i.e. a daily dosage of 3.0 mg/ experiment. 178 Cunha/Cariini/Pereira/Ramos/Pimentel/Gagliardi/Sanvito/Lander/Mechoularn

Comments were diagnosed as cases of secondary generalized epilepsy; EEG tracings revealed irritative activity with temporal projection. They had at least one generalized It has been suggested that A'-THC and other convulsive crisis weekly. Clinical ana laboratory ex- cannabinoids may possess therapeutic potential SminatI6ns~showe(rno"signs of renai, cardiovascular or as antidepressive drugs in patients with cancer hepatic disease. The experiment was performed in the (Regelson et at., 1975) or in the treatment of Neurology Out-Patient Clinics of the Hospital SSo glaucoma {Hepler and Frank, 1971), asthma Paulo (8 patients) and the Hospital da Santa Casa (7 patients). Each patient was followed by the same (Tashkin et al, 1972), etc. For a recent review investigator, beginning 2 weeks before first drug ad- see Mechoulam and Carlini (1978). However, ministration and then throughout the whole period of acute-administration of 20—60mg of A'-THC drug administration. In the 2 weeks before CBD or induces a marked psychic change and has pe- placebo administration, the number of focal and gen- ripheral effects such as an increase in heart rate eralized convulsive crises was recorded and considered as the baseline to evaluate treatment. On the first day (Isbeit et al, 1967; Kiplinger et at, 1971; of the experiment, the patients were submitted to the Karniol et al., 1975) which would limit its examinations described in experiment 1. They were therapeutic use. randomly divided into one group of 8 (control group) In contrast, the present experiment shows and another group of 7 (CBD group) and returned to that 3 mg/kg/day of CBD administered for 30 the hospital for 2 more days. After 1 week each group received placebo or CBD capsules in a double-blind days (1 volunteer received 6 mg/kg/day during procedure in addition to the antieptleptic drugs they the last 3 days of experiment) did not induce were already receiving (see table I). 1 placebo patient any psychic or other side effects and was well (Z.S.M.) was transferred to the CBD group after I tolerated by the 8 subjects. Thus CBD does not month. Half of each group of patients was treated in appear to have any toxic effect in humans when each hospital. The patients were instructed to take 2 or 3 capsules daily (containing 100 mg of CBD or administered at the above dosage over a long glucose) and to return to the hospital every week for period. This confirms our previous data ob- clinical and/or laboratory examinations. tained in animal (Cunha and Carlini, to be Clinical evaluation of drug treatment was made published). weekly using a scale with score 0-3, which took into In our opinion these findings justified the consideration absence of convulsive crises or absence trial of the drug in epileptic patients. of generalization and self-reported subjective improve- ment (see table II). According to this criterion all patients were scored 3 during the predrug phase (baseline).

Experiment 2 (Phase 2 of Study)

Material and Methods Results

Subjects General Observations 15 epileptic patients, 11 women and 4 men, aged During the course of the experiment none of 14-49 (average 24 years), with a documented history the 8 patients receiving CBD showed evidence of frequent convulsions for at least 1 year, were of behavioral alterations which could be sug- selected. These patients were not reacting satisfacto- rily to the prescribed antiepileptic drugs they were gestive of a psychotropic effect. The minimum receiving (table I) in spite of special care to assure that and maximum times of drug administration the patients were taking them properly. The patients were 8 and 18 weeks for most patients (control r/Mechoulam Cannabidiol and Human Epilepsy 179

' generalized Tabl« ». Epileptic patients, the prescribed medicines they were taking before and during the experiment, and activity with the frequency of convulsive crises at the 2 weeks before the beginning of CBD administration (baseline) •4a ic generalized iboratory ex- Group Initials Prescribed medicine FCC at week GCC at week iiovascular or formed in the 2 1 2 1 Hospital S3o a b >anta Casa (7 Placebo J.O.R. Comital L + Tridione >10 >10 2 1 by the same J.S. Comital L 2 5 3 1 0 d first drug ad- M.G.S. Gardenal + Hidantal 0 2 3 2 e f tole period of J.S.V. Primidona + Rivotril + Gardenal 3 4 1 3 :fore CBD or M.L.M. Gardenal + Rivotril + Zarontim* >10 >10 I I 0 ocal and gen- R.C. Hidantai + Fenobarbital 5 4 4 2 id GAfidered M.D.M.S. Comital L I 1 1 1 i tiSRst day 1 Z.S.M. Hidantai + Fenobarbital >IO >10 1 2 m it ted to the . They were CBD Z.S.M.1 Hidantai + Fenobarbital >ia >i0 1 2 ontrol group) h F.R.F. Rivotril + Tegretol >10 >10 1 2 d returned to e O.E.B.N. Gardenal + Mysoline + Rivotril 0 I 1 1 ;k each group A.A.S. Hidantai + Gardenal 7 3 2 3 double-blind A.S.R. Hidantai + Fenobarbital 4 3 - 1 :ic drugs they 2 N.P. Primidona 3 5 acebo patient ' 1 1 Gardenal + Mysoline >10 >]LO troup after 1 N.D. 3 4 Fenobarbital 0 1 vaj treated in M.C.P. 2 I ted to take 2 FCC = Number of focal convulsive crises; GCC = number of generalized convulsive crises. a Phenytoin + ; of CBD or mephobarbital + phenobarbital; b trimethadione; c phenobarbital; d phenytoin; e primidone; f clonazepan; very week for 8 ethosuximide; h carbamazepine. 1 After 4 weeks on placebo crossed over to CBD. nt was made itch took into ;es or absence ctive improve- and CBD groups). 2 of the placebo patients did Table II. Criteria used to evaluate clinical efficacy ot" cannabidiol in epileptic patients ; criterion all not return after the end of the 4th week and 1 CBD patient after the 6th week. 1 placebo Score Clinical significance patient (Z.S.M.) whose condition remained un- altered during 4 weeks, wanted to give up the complete improvement experiment, but remained in it after crossing partial improvement over to the CBD group. small improvement without improvement 4 patients under CBD and 1 receiving pla- cebo complained of somnolence during the 0 = Total absence of convulsive crises and self- experiment. Another CrJD patient (M.C.P.) reported subjective improvement. nent none of complained of painful gastric sensations after 1 = Absence of generalization of crises and self- ved evidence drug ingestion at the 6th week. These symp- reported subjective improvement. ould be sug- toms disappeared after prescription of an ant- 2 = Only self-reported subjective improvement. he minimum 3 = No reduction in crises and no self-reported acid and did not return throughout the experi- lministration improvement. ment. ents (control ISO Cunha/Cailini/Pcreira/Ramos/Pjmeniei/Gagiiardi/Sanvito/Z^nder/Mecfioulam

TabU'lll. EEG analysis of epileptic patients under CBD or placebo treatment (plus other drugs; see table I)

Group Patient Analysis of EHG performed at days

30 60 120

Placebo J.O.R. Ab B J.S. Ar* - M.G.S. AT - J.S.V. Al** C B M.L.M. Ab B B R.C. AJ B n.p. M.D.M.S. AT B B Z.S.M. AT B

CBD Z.S.M. AT B F,R.F. Al" C C O.E.B.N. AT" C C A.A.S. Al c A.S.R. AT B n.p. N.P. Al B n.p. N.D. Al 13 M.C.P. AT itp

A ~ Irritative activity with temporal projection: b = bilateral, r = right hemisphere, 1 = left hemisphere: B EEC unaltered in relation to the first one (0 day); C = EEG improved in relation to the first one (0 day). • Highly active with frequent generalizations; •* extremely active; n.p. = EEG not pert&rmed.

Neurological Examination and EEG crises throughout the experiment. 2 placebo Before drug treatment I CBD patient (N.D.) patients also had improved EEG patterns showed paresthetic walking towards the right, (J.O.R., and J.S.V.) on one occasion, with a with spastic hypomotility of the right arm and return to their previous condition on subse- leg, mainly of the right hand. He also presented quent examination. a decrease in psychomotor functions. 2 other patients in the CBD group (AA.S. andZ.S.M.) Clinical and Laboratory Examinations showed in examinations prior to the experi- Clinical examination proved normal for all ment some mental underdevelopment. Neuro- patients and the pulse, cardiac and respiratory logical examinations of all other patients were rates remained constant during the course of within normal limits. the experiment. ECG tracings, blood and urine Table III shows the results of the EEG analy- analysis (detailed in experiment I - material sis in a condensed form. Of the patients receiv- and methods) were within normal limits. Also, ing CBD, 3 showed improvement in EEG pat- in all patients neither CBD nor placebo altered tem witrPsigns of decrease in frequency of creatinine, bilirubin or transaminase values.

• :.•( -• nder/Mechoulam '• Cannabidiol and Human Epilepsy 181

gs;see table 1) Table IV. Weekly clinical evaluation of epileptic patients under CBD or placebo treatments (plus other drugs, see table!) ;

Patient Drug Clinical evaluation during treatments (as compared to Median3 120 baseline values) of week1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

J.O.R. placebo 133333333333 3 J.S. placebo 2 3 3 3 M.G.S. placebo 3 3 3 3 I.S.V. placebo 023323233333 3 M.L.M. placebo 13 3 3 3 2 3 2 3 R.C. placebo 112333333333333333 3 M.D.M.S. placebo 010001001000000010 0 Z.S.M. placebo 3 3 3 3 3

Z.S.M. CBD 200 112 3 3 2 2 F.R.F. CBD 200 03OO11O11OO31011 1 O.E.B.N. CBD 200 0 000001001000000 0 A.A.S. CBD 200 0 0 0 0 0 0 0 A.S.R. CBD 200 001001110110110000 ' 0 N.P. CBD 200 2222222211222221 ' 2 N.D. CBD 200 3 3 3 3 3 3 hemisphere; B 300 3 3 3 (0 day). M.C.P. CBD 200 0 3 0 2 2 2 I. 300 I 0 1 0 0 0 0

1 See tables I and II. 3 Calculated from total weekly results. ent. 2 placebo EEG patterns

:casiflkL with a W subse- Clinical Evaluation of Treatment state. At the end of the placeh^reatment, 7 Clinical evaluation was performed weekly, patients had a median of 3 (i.e. no improve- scoring O-3 points to each patient compared to ment) whereas patient M.D.M.S. showed com- linations its own baseline (see table II and 'methods' for plete improvement (median 0). 2 placebo pa- normal for all details). At the end of the treatment, the tients (J.S. and M.G.S.) with no improvement and respiratory median of weekly score for each patient was received the capsules for the 4 th week of ; the course of calculated. The results are presented in ta- treatment but did not return. 3 other placebo ilood and urine ble IV. During the first week of treatment there patients (J.O.R.; J.S.V.; M.L.M.) remained un- t I - material was general improvement in almost ail patients der treatment for the period stated in table IV, lal limits. Also, (placebo and CBD groups), but from the second after which it was decided to withdraw them placebo altered week, all placebo patients with one exception from the experiment and to change the antiepi- tase values. (M.D.M.S.) returned to their previous clinical leptic drugs they were receiving (see table I) in 182 Cunha/Cartini/Pereira/RamosyPimentel/GagJiardi/Sanvtto/Lander/Mechoulain an attempt to improve their condition. Patient As already stated in the introduction, many R.C. remained in the placebo group for 18 ancient reports mention the antiepileptic prop- weeks and received all known antiepileptic erties of cannabis. More recently Consroe et drugs without success. Patient Z.S.M. was on ai (1975) described an epileptic patient receiv- placebo for 4 weeks without improvement and ing phenobarbital and phenytoin without good was subsequently transferred to 200 mg of CBD results, who benefitted by smoking marihuana. daily for 6 weeks (without her knowledge) with These accounts indicate that marihuana con- a small improvement (median 2). tains chemical entities which may possess anti- Of the 8 patients receiving CBD, 4 showed epileptic properties. considerable improvement in their clinical con- According to the present data, CBD may dition (median 0). However, in 1 case (M.C.P.) turn out to be a useful drug for the treatment this was achieved by increasing the dosage to of some cases of epilepsy. There is hardly any 300 mg daily. Patient A.A.S., who showed toxicity as shown in our phase I study; there much improvement from the first week, unfor- were no changes in EEG, ECG, blood and urine tunately moved to another city after complet- analyses and neurological and clinical examina- ing 6 weeks of treatment with CBD. The 5th tions were normal in 8 healthy volunteers re- patient (F.R.F.) improved only partially (me- ceiving 3 mg/kg of CBD daily for 30 days. A dian 1) although he attained score 0 in clinical similar absence of toxicity was also noted in evaluation (no convulsive crisis and subjective our phase 2 study in which 8 epileptic patients improvement) in 7 out of the 16 weeks of received 200 or 300 mg for up to 4% months. treatment. 2 of the 3 remaining patients Furthermore, none of thp i6 subjects receiving showed small improvement (score 2) whereas CBD showed any psycHic A'-THC-type effects. the last patient (N.D.) did not improve at all in The present data obtained aHeirTong-terrn ad- spite of increasing CBD to 300 mg daily for the ministration also confirm previous reports last 2 weeks of treatment. showing the absence of toxicity in acute studies {Hollister, l973;Carlinietai, 1979). Somnolence reported by 3 healthy volun- Discussion teers and 4 epileptic patients (43% of the subjects receiving the drug) was the only CBD Treatment of epilepsy is based mainly on side effect noted. A certain hypnotic effect is anticonvulsant drugs. However, even when pro- frequently observed with drugs which possess perly administered in well-diagnosed cases, antiepileptic properties. We have in fact recent- these drugs succeed in helping only about 70- ly demonstrated that CBD does induce better 75% of the epileptic patients, whereas about sleep in human volunteers (Carlini et ai. 30% of the patients do not benefit at all (Robb, 1979). On the other hand, CBD induced a 1975). Furthermore, all clinically effective anti- remarkable improvement (median 0) in 4 of 8 epileptic drugs induce undesirable side effects epileptic patients who remained almosTTree of at normal dosage (osteomalacia, megaloblastic convulsive crises during the entire period of the anemia; gingival hyperplasia) or due to overdose experiment. In a 5th patient (median 1), the (nystagmus, motor incoordination, coma and crises were absent in 7 of the 16 weeks of death) or to idiosyncratic reactions (Kutt and treatment. All of these patients (as well as their Louis, 1972). relatives) reported subjective improvement. A dcr/MechouIam Cannabidiol and Human Epilepsy 183

luction, many similar subjective effect was also reported by 2 (1976) showed that A'-THC in cats induced pileptic prop- more patients and only in 1 patient CBD failed EEG changes resembling those observed in con- y Consroe et to induce any form of clinical benefit. This is in vulsions, and Perez-Reyes and Wingfleld (1974) patient receiv- striking contrast to the results obtained with described a similar effect of CBD in man. In without good the 8 patients receiving placebo of whom 7 neither case, however, were behavioral convul- ig marihuana, showed no improvement in their clinical con- sions observed. It is interesting in this context irihuana con- dition. that phenytoin may increase activity of focal ' possess anti- However, EEG results were not as consistent spikes {Millichap, 1969). To the best of our as the clinicsrevaluation. As seen in table III, knowledge there is only one report attributing a :a, CBD may clinical improvement was not always followed worsening of an epileptic convulsive crisis the treatment by positive changes in the tracings. As the (grand mal) following use of marihuana smok- is h^dly any International League against Epilepsy (Commis- ing (Keeler and Reifler, 1967), and we do not sn^P; there sion on Antiepileptic Drugs) does not consider know of any cases described for CBD. Further- ood and urine EEG mandatory in this type of research (Penry, more, in none of our 8 epileptic patients did we tical examina- 1973), EEG data were not included in the observe deterioration of clinical symptomatol- voiunteers re- overall clinical evaluation of CBD effects. It ogy or of EEG, but rather the opposite effect •r 30 days. A should also be emphasized that the abnormal was true. also noted in EEGs were present from the beginning of the The mechanism by which CBD benefitted eptic patients experiment even though all patients were re- our epileptic patients is not, known. All 8 1 4V2 months. ceiving known antiepileptic drugs. Further- patients were also receiving known antiepileptic jects receiving more, phenytoin and barbiturates fail to con- drugs which were by themselves, however,, in- --type effects, trol the EEG abnormalities of epileptics in spite effective. One possibility is that CBD poten- long-term ad- of being able to abolish their behavioral convul- tiated their action since enhancement by CBD 'ious reports sions; phenytoin may even increase the promi- of anticonvulsant activity of phenobarbital and acute studies nence of focal spikes (Morrei et al., l959;Milli- phenytoin in animals has been demonstrated 9). chap, 1969). (Consroe and Wolkin, 1977; Chesher and Jack- ealthy volun- Wall et al (1976) have reported pharmaco- son, 1974; Chesher et aL, 1975). In man, 3 (43% of the kinetic studies in man with H-CBD injected however, 50-500 Mg/kg CBD given in cigarette :he only CBD intravenously into 5 healthy volunteers. They form is not able to alter plasma concentrations loti^Hfect is observed that 8% of the total initial dose of secobaibital {Dalton et ai, 1976b). The A-hicn possess (20 mg of CBD) was present in plasma 30min possibility that CBD acts per se should also be in fact recent- after injection, to fall to 3% after 60 min. 3 taken into consideration, as shown by several induce better days later, 33% was excreted in the feces and reports describing its direct anticonvulsant ef- irlini et al., 16% in the urine, with 50% remaining in tissues fects in animals. ~ """ D induced a and organs. Therefore, CBD seems to have a In conclusion, we have found that CBD had i 0) in 4 of 8 relatively long half-life, which favors its use as a a beneficial effect in patients suffering from ilmost free of drug in epileptics. secondary generalized epilepsy with temporal period of the However, in spite of the large number of focus, who did not benefit from known anti- ledian 1), the reports showing beneficial effects of cannabis epiieptic drugs. Further research with more 16 weeks of and its preparations in many forms of experi- patients and other forms of epilepsy is needed is well as their mental convulsions and in human epilepsy, a to establish the scope of the antiepileptic ef- arovement. A few reports claim the contrary. Feeney et ai fects of CBD in humans. 184 Cu nh a/Carlini/Pereira/Ramos/Pimentel/Gagiiardi/Sanvito/ Lander/Mechoulam

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Pharmacol. 8: 213-246 humanos. Revta Asoc. med. Brasil 19: 185-190 (1974). (1973). Wall, M.E.; Brine, D.R., and Perez-Reyes, M.: Metabo- Morrel, F.; Bradley, W., and Ptashne, M.: Effects of lism of cannabinoids in man; in Braude and Szara, drugs on discharge characteristics of chronic epilep- The pharmacology of marihuana (Raven Press, togenic lesions. Neurology 9: 492-498 (1959). New York 1976). O'Shaughnessy, W.B.: On the preparations of the Indian hemp or gunjah. Trans, med. Phys. Soc. Bombay 5:421-461 (1842). Penry, J.K.: Principles for clinical testing of antiepilep- tic drugs. Epilepsia 14: 451-458 (1973). Received: June 10, 1979 Perez-Reyes, M.; Timmons, M.C.; Davis, K.H., and Accepted: January 3,1980 Wall, MX.: A comparison of the pharmacological activity in man of intravenously administered A-9- Jomar M. Cunha, Departamento de Psicobiologia, tetrahydrocannabinoi, cannabinol and cannabidioL Escola Paultsta de Medicina, Rua Botucatu 862, Experiential; 1368-1369(1973). 04023 S3o Paulo (Brasii) Cognition and Long-Term Use of Ganja (Caiuiabis) cluded remote {years and months), re- cent (weeks, days, hours, minutes), and Abstract. Neuropsychoiogicai variables and urine cannabinoid metabolites were immediate events (within seconds). evaluated in ten subjects born, raised, and educated in the United States and having An enzyme immunoassay method histories of heavy or prolonged use ofcannabis. No impairment of cognitive function (Emit-d.a.u.) (2/) was used to analyze was found. Cannabinoid metabolites in excess of 50 nanograms per milliiiter were urine samples. The assay is a semiquan- present in the ten urine samples. The tetrahydrocannabinol content of cannabis titative immunochemical test designed to exceeded 8.0 percent. detect a level of at least 50 ng of 11-nor- A9-tetrahydrocannabinol carboxylic acid Several studies have attempted to Subjects in this study agreed to pro- per milliiiter of urine with greater than characterize the mental or cognitive vide approximately 15 ml of fresh urine 95 percent confidence. Each of the ten functioning of persons with histories of for enzyme immunoassay of cannabinoid urine samples contained concentrations heavy and prolonged use of ganja (can- metabolite content. Specimens were pre- of cannabinoids at 50 ng/ml (one subject) nabis). Generally, investigators have served with approximately 4 mg of sodi- or well above this level (nine subjects). concluded that heavy and prolonged use um azide per 15 ml of urine that was None of the neuropsychoiogicai test has not led to impairment of mental and collected. Urine samples for each of the data indicated impairment of cognitive cognitive functions consistent with brain ten individuals studied were obtained functioning. Language areas of function, or cerebral dysfunction (1—4). immediately before each subject began a nonlanguage areas of function, memory, Although several studies have shown series of selected neuropsychoiogicai complex multimodal learning, and gener- decrements in neuropsychoiogicai per- tests designed to assess a broad range of al level of intellectual functioning were formance among those with brief or spo- cognitive functions. all completely unimpaired, compared fedic patterns of cannabis use here in the A modified version of the Michigan with standardized-normative informa- "nited States (5-9), comparable studies Neuropsychoiogicai Test Sequence was tion available for each test (Table 1). of prolonged heavy use in this country used (11-13). Each subject was adminis- The mean IQ scores (Table 1) are all in have not been performed. Thus, the only tered exactly the same group of tests in the superior to very superior range of available literature is based on studies exactly the same order. General intellec- intellectual functioning, ranging from the conducted in foreign countries (Jamaica, tual functioning was assessed on the upper 6.7 percent to the upper 2.2 per- Greece, Egypt, and Costa Rica). basis of a prorated version of the cent of the population (14). Scores ob- We had the opportunity to observe a Wechsler Adult Intelligence Scale (Table tained on all of the other psychometric group of long-term heavy users of ganja 1) (14). Additional neuropsychoiogicai tests were also well within the normal in both a Southern state and a Caribbean tests included the following: Benton Vi- range for age (11-20). There was nothing island. The ganja was used by this group sual Retention Test (administration C) found in any of the ten subjects' proto- for religious purposes and symbolized (15), Rey Auditory-Verbal Learning Test cols that might suggest impaired mental the sacrament of communion—"the (16), Symbol-Digit Modalities Test (17), functioning due to brain or cerebral dys- Green Herb of the Bible." It was used, Hooper Visual Organization Test (18), function resulting from heavy and pro- as we observed, even during the exten- Raven's Progressive Matrices Test (19), longed use of ganja. sive neuropsychoiogicai evaluations that and Traitmaking Test (forms A and B) While several previous studies have we completed, in a continuous and ritu- (20). The following cognitive functions reported transient cognitive impairment alistic manner throughout virtually all were assessed: language areas of func- resulting from the acute effects of canna- waking hours. Very large cigarettes (or tion, nonlanguage areas of function, bis, primarily with respect to attention- "spliffs") and pipes, containing ganja memory, complex multimodal learning, concentration and visuomotor (hand- .mixed with tobacco, were regularly and general intellectual functioning. Au- eye) coordination (8, 9, 22, 23), none of Shared by members of the group (10). ditory and visual memory functions in- the studies involving prolonged and We examined ten subjects (seven males and three females) ranging in age from 25 to 36 years. The mean number of Table 1. Summary of neuropsychoiogicai data (means ± standard deviations). years of education was 13.5 (all were Number Scaled born, raised, and educated in the United Test correct score States), and all were Caucasian. None had any history of disease that could be Wechsler Adult Intelligence Scale Information 26.2 3.12 16.5 ± 2.55 related to central nervous system dys- Arithmetic 15.2 2.10 14.3 ± 1.95 function. By their own report, they used Similarities 20.8 2.30 14.2 i 1.97 between 2 and 4 ounces of the ganja- Digit symbol 69.6 8.73 13.8 ± 2.49 tobacco mixture per day, with a reported Block design 42.7 5.95 13.8 ± 2.39 mean duration of use of 7.4 years (the Picture arrangement 29.1 5.30 13.0 ± 2.98 Verbal IQ* 129.0 10.87 time since joining this particular church). Performance IQ* 124.2 13.07 All subjects actively engaged in daily Full-scale IQ* 128.4 10.36 work, largely agricultural and business, Other instruments and led active and spiritually oriented Benton 8.8 ± 1.02 lives (10). It was not possible to collect Rey 14.9 ± 0.32 ' control data in this environment, as all Symbol-digit 60.4 ± 10.25 church members continuously smoked Hooper 28.7 ^ 1.06 ganja. Thus, comparisons were made Raven 35.2 ± 0.79 Trailmaking (in seconds) with the published standards and norma- Form A 28.8 ± 6.88t tive data for the psychometric instru- FormB 53.5 ± 15.28t ments used. •Prorated. tNo errors.

SCIENCE, VOL. 213, 24 JULY 1981 0036-8075/81/0724-0465S00.5G/0 Copyright © 1981 AAAS Intelligence Scale (Psychologicai Corporatidn,' rh'avef^fibwn"ariy'"sys- New York, 1955). ^ V. Rubin iDdX.Cotr^i&i^Ganld'hi'Jamaica "' in imfehtal,;.abilities 7 • 15. A. Benton, Revised Visual Retention Test: Clin- (MOuioa, The Hague,"1975).^ ->,•,.•-:••. ical and Experimental Applications (Psychologi- or cer- M. C. Braude and S, Szar&slZds., Phwmacolo- cal Corporation, New York, ed. 4, 1974). gy of Marihuana (Raven, New York, .1976). :, 16. M. Lezak, Neuropsychological Assessment R. L. Doriibutb and A. Kokkevi, in (2), p. 421. {Oxford Univ. Press, New York, 1976). y^^ included loxicologic. verifica- C. Stefanis, J.BouIongoutfs, A. tiakos, in (2), 17. A. Smith, Symbol Digit Modalities Test Manual M^PlPfj.tirteary,cannabindid metabolites, pp. 659-665. , .-.•.,- ; - - (Western Psychological Services, Los Angeles, I. M. FranJc'P. J. Lessft. fcVD. Tyrrell, P. M. 1973). . the. inhalation -of cannabis. by Hahn, S. Szara, in (2), pp. 673-679. • 18. E. Hooper, The Hooper Visual Organization S. Y. Hill and D. W. Goodwin, in (7), p. 139. Test (Western Psychological Services, Los An- "studied, and, analyzed sam- S. Cohen and R. Stillmanj'Eda.', The Therapeu- geles, 1973). tic Potential of Marijuana (PlenUm.New York, 19. J. C. Raven, Guide to Using the Coloured 1976). . , -. •• .^ : .. Progressive Matrices (Lewis, London, 1965). v ,_ OTi.,— ,, — tobacco (by gas L. L. Miller, in <7), pp. 27I-2&: 20. R. M. Reitan, Percept. Motor Skills 8, 271 ^itfib^Hltpgraphy) yielded a A9-THC con- R. T. Jones and N. Benowitcz,in.(2J, p. 627. (1958). J M. C. Dreher, personal communication (March 21. Cannabinoid Urine Assay: Emit Cannabinoid (half,canflabis,.half 1980}.;>-: • • V,-:t,'--•-..•. :• Assay (Syva, Palo Alto. 1980). THC contenf.of the A. Smith, in Drugs, Developinent and Cerebral 22. R. A. Harshman, H. Crawford, E. Hecht, in (7), Function. W. L. Smith, Ed. (Thomas, Spring- pp. 205-254. [exceeds 8.0 percent. :;" field, SI.,'1972),pp. 27-68<>rc".-- -;,' 23. Human effects," in Marihuana Research Find- 12. and C. W. Burkhind, paper presented at Ings (National Institute of Drug Abuse Mono- no transient decrements the annual meeting of the American Psychologi- graph No. 14, Government Printing Office, jStive: functioning that'.often: ac- cal Association; 1967.-• '•;•, .>•:.-, . Washington, D.C., 1977), p, 128. _', Science 1S3, 1280 (1966). Jcofflpany intermittent or sporadic use of D. Wechsler, Manual for the Wecftsler Adub 23 September 1980; revised 9 January 1981 ;;*-^"^sv>Thej*leveIopment of tolerance of the constituents of [s.may explain this phenomenon, figh.the; obtained IQ; scores were le ccmld speculate;that perhaps s'hadiproduced a priori declines Discharge Patterns of Hindlimb Motoneurons L . k._ .. teB subjects| j^ wejj During Normal Cat Locomotion p^corjEs :on ipther. neurtipsychological isjfltejr.jltivras possible, for us; to ob- ., Abstracts-Long-term- recording from, single lumbar motoneurons of intact cats £(£arjy; school academic achievement revealed activation patterns fundamentally different from those seen in decerebrate -data on two of our subjects. These preparations. In intact cats, motoneuron bursts showed marked rate modulation [.included,equivalent IQ conversion without initial doublets. Each unit's frequencygram generally resembled the enve- •es^yirtually.. identical to those we lope of the gross electromyogram simultaneously recorded from the corresponding for, those subjects. We realize muscle. Average and peak discharge rates increased for faster gaits. These findings j conversion or equivalent IQ suggest that, in cat locomotion, rate modulation is a more important contributor to ^^9Pres'?dc"y^ fr°m early - school force regulation than was previously thought. ueyenlentftest data are:not,;to be ju&ted on a one-for-one basis with cur- A prime objective in the field of motor neural control of locomotion (4-6,10-12). C^rent scores. However, we do believe that control is to fully understand the rela- We have developed long-term record- ranges provide a reasonable tions between neuronal discharge pat- ing methods in conscious, freely walk- iJJi5egreKifaf:equivalency. These achieve- terns and movements. Comprehensive ing, intact cats (13,14) in order to moni- ^meflt testi scores were obtained some. 15 studies of the electrical and mechanical tor the electrical activity of individual ^tAtO.-2P^.years earlier, long before. either properties of hindlimb muscles and their hindlimb motoneurons and to determine ^'Subjectj^began the use of cannabis, by motoneurons, the final output cells of the unitary axonaj conduction velocity and

ieir: report to; us. ,; •••--•• motor system, arose from the introduc- muscle of destination. Records obtained stress the commitment of tion of intracelluiar techniques (1) in from more than 100 motoneurons re- fe|j§ ?fc; teri^ubj^subject* s to their religious sect anesthetized cat preparations (2-8). In vealed striking differences from the char- way'of life. They told us and others contrast, until now, technical difficulties acteristic decerebrate cat patterns. .P()0)"thatmembers of the church do not have made it impossible to investigate Twelve cats trained to walk at several ^use/substances (drugs, alcohol, or psy- normal motoneuron firing patterns dur- speeds on a motorized treadmill had >;chdactiye herbs) other than ganja, and ing locomotion. The only single-unit rec- electrodes and transducers implanted .. Iwe observed them to maintain a regular ords obtained previously have come under deep pentobarbital anesthesia; ^;diet consisting primarily of vegetables, from unidentified motor axons in cut they were allowed to recover for several V^fruit; and small amounts of meat. All ten ventral root filaments of decerebrate cats days before recording sessions began. i^f£u;bjecU:Cas well as other members of the induced to "walk" by being stimulated As many as a dozen fine, flexible, insu-,^ ^Tchurch) ^appear to be healthy and highly in the mesencephalic locomotor region lated wire electrodes (Fig. 1, A and B) ^^ftinetionfll individuals adhering to a strict of the brainstem (9-//). ... were inserted in the fifth lumbar ventral \< Motoneurons in walking decerebrate root (L5 VR) through a small laminoto- ^ JEFFREY SCHAEFFER cats typically GIG in uniform bursts con- my, an approach recently shown suc- f^pepdrtmtnt of Psychiatry and sisting of an initial doublet. [a pair of cessful for recording from afferent fibers 'Sciences, University of spikes occurring within a-brief inter- (15-19). Root electrodes were of a modi- School of Medicine,..: . val, usually 3 to 10 msec (10, 11)] fol- fied "hatpin" design (14,20): a recording ks 90024, and ! • .••••: lowed by a train of spikes that stabilize at surface was exposed by obliquely cutting, Associates Incorporated, a nearly constant "preferred discharge a stiff, short indium or platinum-indium.^ rAngeles 90048 ' •"•• rate" (9) characteristic for each cell, insulated wire (easily inserted intoisoft^f :£'u.;.:?'V-- .,•:•• THERESB ANDRYSIAK which does not vary with treadmill tissue), which was welded to a compliant^ :}&%&** J. THOMAS UNGERLEIDER speed, strength of stimulation, or dura- gold lead (thereby allowing the electrode^ partment of Psychiatry and •• -•••• tion of step cycle. Discovery of these to "float"). Extracellular: recording^ Sciences, University of motoneuron firing patterns had an im- from ventral root axons^coureing out:of£ forhiS School of Medicine portant influence on current.^leVs of the the sninal canal were thus made.inji 003fr«075/81/0724-0466$00.5(VO < SCIENCE;.