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Home , Effects of cannabis

BRITISH JOURNAL OF PSYCHIATRY %2001), 178, 107^115

Therapeutic aspects of and {{ gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use- PHILIP ROBSON fulness as an anti-emetic. After these observations were published in 1842, medicinal use of cannabis ex- panded rapidly.It soon became available `over the counter' in pharmacies and by 1854 it had found its way into the Dispensatory.The American market became flooded with dozens of cannabis- containing home remedies. Background Review commissioned in In 1996 I was commissioned by the Depart- Queen Victoria's personal physician 1996 by the DepartmentofDepartment of ment of Health DOH) to review the wrote Reynolds, 1890), on the basis of scientific literature regarding the potential more than 30 years' experience, that DOH). therapeutic utility of cannabis and its ``Indian , when pure and administered Aims Assess therapeutic profile of derivatives.The review was based upon carefully, is one of the most valuable primary sources identified from a Medline medicines we possess''.He found it incom- cannabis and cannabinoids. literature search, reference lists supplied by parable for ``senile insomnia'', ``night MethodMethod Medline search, references the DOH and the Institute for the Study of restlessness'' and ``temper disease'' in both Dependence, and personal communi- children and adults, but not helpful in supplied by DOH and others, and cations with relevant academics and melancholia, ``very uncertain'' in alcoholic personal communications. clinicians).This paper is a greatly shortened delirium, and ``worse than useless'' in version of the review.The 4 years which mania.It was very effective in neuralgia, Results and Conclusions CannabisCannabis have elapsed have seen little in the way of period pains, migraine, ``lightning pain of and some cannabinoids are effective anti- new clinical results but considerable the ataxic patient'' and gout, but useless emetics and analgesics and reduce intra- advances in basic science in sciatica and ``hysteric pains''.He ocular pressure.There is evidence of Institute of Medicine, 1999).Government found it impressive in clonic spasms and licences have recently been granted for certain epileptiform convulsions related symptomrelief andimprovedwell-beingin several controlled trials of both synthetic to , but no good at all in selectedselectedneurologicalconditions, neurologicalconditions, AIDS and and plant-derived cannabinoids in multiple petit mal or ``chronic epilepsy'', tetanus, certain cancers.Cannabinoids may reduce sclerosis and chronic pain.In January 2000, chorea or paralysis agitans.It effectively and improve sleep. Anticonvulsant I was appointed Medical Director of GW relieved nocturnal cramps, asthma and activityrequires clarification.Other Pharmaceuticals, a company established to dysmenorrhoea. derive medicinal extracts from standardised Reynolds was writing at a time when propertiesidentified by basic cannabis plants. the zenith of cannabis as prescribed medicine awaitevaluation.Standardawait evaluation. Standard treatments for and home remedy was already past. many relevant disorders are Although Sir William Osler was still recom- unsatisfactory.Cannabisis safein overdose HISTORY OF THERAPEUTIC mending it for migraine sufferers in 1913, it was by then in steep decline because of butoftenbut often produces unwanted effects, USE variable potency of herbal preparations, typically sedation, intoxication, The first formal report of cannabis as a poor storage stability, unpredictable clumsiness, dizziness, dry mouth, lowered medicine appeared in China nearly 5000 response to oral administration, increasing blood pressure or increased . years ago when it was recommended for enthusiasm for parenteral medicines and The discovery of specific receptors and malaria, constipation, rheumatic pains and availability of potent synthetic alternatives, childbirth and, mixed with wine, as a commercial pressures and American con- naturalligands maylead to drug surgical analgesic Mechoulam, 1986). cern about recreational use.Cannabis was developments.Researchis needed to There are subsequent records of its use outlawed in 1928 by ratification of the optimise dose and route of administration, throughout Asia, the Middle East, Southern 1925 Geneva Convention on the manu- quantify therapeutic and adverse effects, Africa and South America.Accounts by facture, sale and movement of dangerous and examine interactions. Pliny, Dioscorides and Galen remained .Prescription remained possible until influential in European medicine for 16 final prohibition under the 1971 Misuse Declaration of interest FundingFunding centuries.centuries. of Drugs Act, against the advice of the It was not until the 19th century that Advisory Committee on Drug Dependence. from DOH.Between writing this paper cannabis became a mainstream medicine In the USA, medical use was effectively andandits its acceptance for publication,P.R. in Britain.W.B.O'Shaughnessy, an Irish ruled out by the Tax Act 1937. was appointed Medical Director of scientist and physician, observed its use in This ruling has been under almost constant GW Pharmaceuticals. India as an analgesic, anticonvulsant, anti- legal challenge and many special dispen- spasmodic, anti-emetic and .After sations were made between 1976 and 1992 {{See editorial, p.98, thisissue. experiments on goats and dogs, he for individuals to receive `compassionate

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reefers'.Although this loophole has been CLINICAL APPLICATIONS targeting established vomiting.Younger closed, a 1996 California state law permits patients may respond better than older ones. cultivation or consumption of cannabis for Nausea and vomiting Meta-analysis Plasse et aletal, 1991),1991) medical purposes, if a doctor provides a Many cytotoxic drugs are powerful suggested that an optimal balance of effi- written endorsement.Similar arrangements emetics, and this is the major limiting factor cacy and unwanted effects was achieved apply in Italy and Canberra, Australia. in patients' acceptance of cancer chemo- with relatively modest doses 7 mg/m22 oror therapy see Table 1 and Appendix). less).Sedation and psychotropic symptoms Many recreational smokers receiving are commonly reported, but are usually CANNABINOID cancer chemotherapy have told their mild to moderate in intensity and resolve PHARMACOLOGY RELEVANT doctors that cannabis relieved their nausea rapidly on discontinuation.No ``persistent TO THERTHERAPEUTICS APEUTICS Grinspoon & Bakalar, 1993).Sallan et aletal's's or fatal'' adverse effects have been 1975) randomised control trial RCT) com- reported.Many American oncologists was isolated in 1895 and canna- pared oral THC and placebo in 22 cancer encourage nauseous patients to try canna- bidiol in 1934, but the most significant dis- patients who had proved resistant to con- bis and would prescribe it if it were legal covery was that of DD99- ventional anti-emetics.Comparisons using Doblin & Kleiman, 1991).Mode of action THC) in 1964.Chromatographic and patients' self-reports of nausea and remains uncertain. spectroscopic methods subsequentlyun- vomiting demonstrated that THC was covered many closely related compounds. statistically superior to placebo.THC Capsules of synthetic THC ) 10 mg/mmg/m10 22) produced in the major- Multiple sclerosis and other have been available for restricted medical ityof patients, and one-third experienced neurological conditions use in the USA since 1985., a sedation.sedation. Drug therapy of muscle spasticity is gener- synthetic THC analogue, was marketed in Subsequent RCTs listed in Table 1) ally only moderately effective and is limited 1983 and is the only cannabinoid licensed confirmed that natural and synthetic THC by adverse effects see Appendix).Spasticity for prescription in the UK, restricted to is invariably superior to placebo.Compari- is a central feature of multiple sclerosis treatment of nausea and vomiting caused sons with anti-emetics available in the MS), cerebral palsy and spinal cord injury. by cytotoxic chemotherapy unresponsive 1970s and 1980s suggest that THC is either Tremor, and incontinence also con-con- to conventional anti-emetics.Use in other equivalent in effect or better.A com- tribute to the high incidence of anxiety and indications is only possible on a `named bination of prochlorperazine and THC depression in these conditions.Cannabis patient' basis if the drug is supplied by a was superior to either drug alone, and nabi- was often used to treat pain, muscle spasm, hospital pharmacy. lone combined with prochlorperazine was cramps and ataxia in the 19th century, and In 1988, a specific protein receptor better than dexamethazone plus meto- many modern sufferers have reported

known as CB11) for THC was discovered clopramide.Although THC and nabilone benefits Grinspoon & Bakalar, 1993). in mouse nerve cells.This mediates most produced more unwanted effects than com- Most respondents to a questionnaire of the central nervous system CNS) parison drugs, patients generally preferred sent to British and American MS patients re- responses to cannabinoids, and is abundant them.them. ported problems with symptom control in basal ganglia, hippocampus and cere- Children seem to respond well to ConsroeConsroe et aletal, 1997).Those who smoked bellum, globus pallidus, substantia nigra nabilone and are tolerant of side-effects, cannabis claimed improvements in night- and cerebral cortex.An endogenous but larger studies are required. DD88-THC-THC time spasticity and muscle pain 91±98%); was identified in 1992 and labelled ananda- performed well in a pilot study night leg pain, depression, tremor, anxiety, mide mideanandaananda: `bliss' in Sanskrit).Ananda- Abrahamov et aletal, 1995) involving eight spasms on walking, paraesthesiae 80± mide has analgesic and tranquillising children aged 3±13 years with various 89%); leg weakness, trunk numbness, facial effects in animals, is involved in muscle blood cancers receiving chemotherapy, pain 71±74%); impaired balance 57%); coordination and affects the secretion and 60% of whom had experienced distressing constipation 33%); memory loss 31%). function of certain hormones.Other endo- vomiting despite treatment with metoclo- In a small single-blind comparison with genous almost certainly exist. pramide.pramide. DD88-THC was given orally 2 hours placebo Clifford, 1983), THC improved

In 1993, a second receptor CB22) was)was before cytotoxics and repeated 6-hourly. tremor and ataxia in most patients.All ex- identified in rat spleen macrophages, and No vomiting was recorded during this perienced a `high' at the top dose 15 mg), this occurs only outside the CNS.There is treatment and over the following 2 days. and two reported dysphoria.Dose-related scope for chemical manipulation of canna- Two children were ``slightly irritable'' and improvements indystonia were noted in

binoids to maximise selectivity for CB22 one also showed ``slight euphoria''. five patients given 100± and so avoid psychoactive effects.It is In a review of 12 studies involving 600 600 mg daily for6 weeks., thought this receptor has relevance for patients Penta et aletal, 1981), THC was dry mouth, sedation and light-headedness anti-inflammatory and immunosuppressive ``effective'' in 8/9 and nabilone in 3/3. occurred but were described as mild. activity.activity. The most common side-effects were somno- Parkinsonian symptoms were aggravated Pertwee 1995) has suggested that the lence 33%), dry mouth 9%), ataxia 8%), in two subjects. system might be concerned dizziness 6%), dysphoria 6%), and ortho- An RCT by Petro & Ellenberger 1981) with mood, memory and cognition, percep- static hypotension 4%).A further review compared the effects of placebo and THC tion, movement, coordination, posture and Levitt, 1986) incorporating 55 studies, of in doses of 5 or 10 mg on muscle tone, skeletal muscle tone, sleep, thermo- which 32 were RCTs, showed that low-dose reflexes and muscle power in nine MS regulation, appetite and immune response. preventive treatment gives better results than patients.Both doses of THC reduced

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Ta b l e 11Tab Human randomised controlled trials RCTs): anti-emetic effects

Study Subjects Study design Results

Sallan et aletal 1975)22 patients mainly resistant to db, pc, r, x, sd; THC significantly superior to placebo. Sedation and euphoria conventional anti-emetics THC 10 mg/m22 occurred in the majority of patients in THC phase

ChangChang et aletal 1979)15 patients on high-dose db, pc, r, x, md; THC; ``Fourteen of 15 patients had a reduction in nausea and methotrexate oral 10 mg/m22,, vomiting on THC as compared to placebo'' smoked approx. 17 mg

EinhornEinhorn et aletal 1981)100 patients on cancer db, r, x, md; nabilone Nabilone was significantly superior in reducing nausea and vo- chemotherapy 2 mg q.d.s.; prochlorperazine miting frequency, but produced more lethargy and 10 mg q.d.s. hypotension. Nabilone was preferred by 75% of patients

Orr & McKernan 1981)55 patients on cancer db, pc, r, x, md; THC THC was significantly superior to prochlorperazine PP550.005). chemotherapy 7 mg q.d.s.; prochlorperazine Side-effects were evenly distributed, except that THC 7 mg q.d.s. produced a `high' in 82% of patients

JonesJones et aletal 1982)1982)54 patients on various db, pc, r, x, md; nabilone Nabilone reduced mean number of vomiting episodes chemotherapy 2mg PP550.001) and nausea PP550.001) in comparison with placebo. 24 evaluable) Side-effects common but ````acceptable''acceptable''

Ungerleider et aletal 1982)1982)214 patients on various db,r,x,md;THC7.5^ No significant difference in anti-nausea and vomiting between chemotherapy 12.5 mg prochlorperazine the two drugs. More side-effects on THC, yet more patients preferred it

Niiranen & Mattson 24 patients on various db, r, x, sd; nabilone 2 mg vv.. Nabilone significantly superior in reducing vomiting. More 1985) chemotherapy 15 mg prochlorperazine side-effects yet majority of patients preferred it

DalzellDalzell et aletal 1986)23 children on various db, r, x, md; nabilone vv.. Significantly fewer vomiting episodes and less nausea on chemotherapy domperidone nabilone. More side-effects, but 2/3 children preferred it

NiederleNiederle et aletal 1986)1986)20 patients on cisplatindb, r, x, md; nabilone 2 mg Nabilone reduced emesis and relieved nausea significantly b.d., alizapride 150 mg t.d.s. better than alizapride but caused more adverse effects

Pomeroy et aletal 1986)38 patients on various db, r, md; nabilone 1mg vv.. Mean number of vomiting episodes in two cycles of treatment chemotherapy domperidone 20 mg was 4.53 for nabilone and 10.81 for domperidone PP550.01)0.01)

ChanChan et aletal 1987)30 children with db, r, x, md; nabilone vv.. Improvement of retching and emesis was 70% during nabilone chemotherapy-induced prochlorperazine and 30% during prochlorperazine PPˆ0.015) emesis

LaneLane et aletal 1991)62 patients on various db, r, md; dronabinol Percentage of patients with any nausea or vomiting was 51% for chemotherapy 10 mg q.d.s.; prochlorperazine dronabinol group and 83% for prochlorperazine. A combina- 10 mg q.d.s.; or both tion of the two drugs was significantly better than either alone

o, open; sb, single-blind; db, double-blind; pc, placebo-controlled; r, randomised; x, cross-over design; sd, single-dose; md, multiple-dose; q.d.s., four times daily; b.d., twice daily; THC, tetrahydrocannabinol.

spasticity spasticity PP550.005). One patient receiving period.Mild sedation was noted on active spinal motor , somatic nerves and THC 10 mg and one patient receiving medication. neuromuscular junction. placebo felt `high' but no other side-effects Cannabidiol had no beneficial effects in were recorded.In a small RCT Ungerleider 15 patients with Huntington's disease Con- Loss of appetite and weight et aletal, 1987) with 5-day treatment periods, sroesroe et aletal, 1991).Posture and balance were in cancer and AIDS THC 7.5 mg significantly improved spasti- impaired by a single dose of smoked THC Several studies have investigated effect on city in comparison with placebo.Nabilone in 10 MS patients and 10 non-MS volun- appetite and weight Table 2).The appetite- 1 mg on alternate days was compared with teers Greenberg et aletal, 1994), but there stimulating effect of cannabis was confirm- placebo in a double-blind randomised cross- was no active control to determine the ed in fasting and non-fasting volunteers in overovertrialtrial with 4-week treatment periods in effects of standard anti-spastic medication an RCT of oral THC with , a single MS patient.Nocturia, muscle spasm in this model. and placebo Hollister, 1971). and general well-being showed striking Possible sites of action of cannabinoids in A standardised THC regime over improvement during each active treatment dystonia include basal ganglia, cerebellum, 25 days in a residential laboratory was

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associated with significant increases in calorie BealBeal et aletal 1995) conducted an RCT over anecdotal reports Grinspoon & Bakalar, intake and frequency of eating occasions in 42 days of treatment with dronabinol 5 mg 1993) of benefits in bone and pain, comparison with placebo. daily in 139 AIDS patients who had lost at migraine, cancer pain, menstrual cramps Open studies in cancer patients also least 2.3 kg. Six receiving dronabinol and and labour. showed appetite improvements and slowing three receiving placebo withdrew because Five small RCTs Table 3) show that of weight loss.Regelson et aletal's 1976) RCT of ``perceived drug toxicity''.Dronabinol THC is significantly superior to placebo explored the effect on appetite and mood) boosted appetite in comparison to placebo and produces dose-related analgesia peak- of oral THC in 54 cancer patients over a PP550.015) and nausea was reduced ing at around 5 hours, comparable to but 2-week period.There were nine with- PPˆ0.05). Improvement in mood was a out-lasting that of codeine.Side-effects drawalsdrawalsduedue to side-effects six in THC strong trend PPˆ0.06) and there was a were also dose-related, and consisted of period ± dizziness, disassociation, confused tendency toward weight gain PPˆ0.1).0.1). slurred speech, sedation and mental cloud- thinking, panic, ``feelings of disturbance''; Dronabinol produced more adverse effects ing, blurred vision, dizziness and ataxia. three in the placebo period ± anxiety, fits, than placebo PP550.001), but 75% of these was also superior to placebo dizziness, lethargy, weakness).Patients were mild or moderate.Most frequent were and notably long-acting, but almost half the receiving THC in the first period gained euphoria 9), dizziness 5), thinking abnorm-abnorm- patients reported sedation.Cannabinoids weight weightPP550.05), and those receiving alities 5) and sedation 4). may have considerable potential in neuro- placebo first showed reduced weight loss Further investigation is amply justified. pathic pain Institute of Medicine, 1999). on transfer to THC PP550.05). Depression, Careful monitoring of possible effects upon tranquillity and ``forthrightness'' scores all the immune system is needed, although a improved on THC.In a quarter of the prospective multi-centre study Kaslow etet Raised intra-ocular pressure patients, somnolence, dizziness and dis- alal, 1989), which followed nearly 5000 Glaucoma due to obstructed outflow of association were severe enough to negate HIV-positive men for 18 months, showed aqueous humour or anatomical eye defects these effects. no link between use of psychoactive sub- is the most common cause of blindness in Many people with AIDS have claimed stances and mean T-cell counts or progres- the Western world.Some RCTs investi- that smoking marijuana inhibits nausea, sion to AIDS. gating this area are given in Table 4. improves appetite, reduces anxiety, relieves There have been many anecdotal aches and pains, improves sleep and in- reports that street marijuana can relieve hibits oral candidiasis.A small pilot study PainPain glaucoma symptoms and individuals have supported the hypothesis that dronabinol Cannabinoids are effective analgesics in successfully argued in the USA for legal might reduce weight loss or even promote animal models with non-opiate mechan- access to the drug Grinspoon & Bakalar, weight gain Plasse et aletal, 1991).,1991). isms predominating.There are many 1993).A pilot study of smoked marijuana

TaTable b l e 2 Human randomised controlled trials RCTs): appetite and weight

StudySubjects Study design Results

Hollister 1971)i. 12 fasting volunteers i. db, pc, r, x, sd; THC 0.5mg/kg;0.5 mg/kg; There was large variation between subjects, but ``those results ii. 12 non-fasting volunteers 1ml/kg 95% ethanol; 0.2mg/kg0.2 mg/kg confirm the notion that marijuana has a stimulating effect upon dexamphetamine appetite and food consumption'' ii.db,pc,r,x,sd;THC0.35mg/kg ethanol as in i

Regelson et aletal 1976)54 patients with cancerdb, pc, r, x, md; oral THC ``THC stimulates appetite and helps retard the chronic weight 0.1mg/kg t.d.s. loss associated with cancer''.``Limiting side-effects which restrict use in 25% patients are somnolence, dizziness, and disassociation''

Gross et aletal 1983)1983)11 11patients patients with db, pc, r, x, md;md;THC THC 7.5^107.5^10mg mg ``THC is not efficacious, in short-term administration, in the anorexia nervosa daily; diazepam active placebo) treatment of primary anorexia nervosa and is associated with 3^15mg/day significant psychic disturbances in some PAN patients''

FoltinFoltin et aletal 1986)9 volunteers sb, pc, r, x, md; marijuana ``Smoked marijuana can produce significant increases in food 1.84% THC) intake with small groups of subjects in a residential laboratory setting''setting''

BealBeal et aletal 1995)1995)139 patients with db, pc, r, md; dronabinol 2.5 mg b.d.In comparison with placebo, dronabinol improved appetite AIDS-related anorexia PPˆ0.015), mood PPˆ0.06) and decreased nausea PPˆ0.05). and weight loss There was a trend toward weight stabilisation PPˆ0.1)

o, open; sb, single-blind; db, double-blind; pc, placebo-controlled; r, randomised; x, cross-over design; sd, single-dose; md, multiple-dose; t.d.s.,d.s.,threetimesdaily;b.d.,twicedaily; three times daily; b.d., twice daily; PAN, primary anorexia nervosa; THC, tetrahydrocannabinol.

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and oral THC 15 mg) in 11 glaucoma patients in comparison to placebo The effect of cannabinoids on seizure patients found an average intra-ocular pres- PP550.001), which were mirrored by other activity in laboratory animals is compli- sure IOP) reduction of 30% in seven sub- measures Fabre & McLendon, 1981). cated.Cannabidiol is a powerful anti- jects and no response in four Hepler etet Seven days into the study, nabilone convulsant free of tolerance, but its profile alal, 1976).,1976). patients' anxiety scores were halved, and varies between species.THC can produce Randomised controlled trials in volun- this persisted unchanged throughout treat- seizures in big doses or when genetically teers confirmed that oral, injected or ment.Side-effects included dry mouth, dry seizure-sensitive animals are used, yet it is smoked cannabinoids produce dose-related eyes and drowsiness.The authors con- also robustly anticonvulsant in certain reductions of IOP Hepler et aletal, 1976;,1976; cluded that nabilone is a ``very effective seizure models.A lack of stereospecificity Perez-Reyes et aletal, 1976).Conjunctival anxiolytic deserving of further study''.In suggests that the mechanism may not be engorgement and tear reduction were oftenoften a cross-over comparison of nabilone 1± related to a single receptor interaction. noted.THC, DD88-THC and 11-hydroxy- THCTHC 2.5 mg twice daily) and placebo in 11 Serotonin,Serotonin, gg-aminobutyric acid, acetylcho- are more effective than cannabinol, while anxious patients Ilaria et aletal, 1981), signifi- line or prostaglandin systems may be cannabidiol was without effect.Tolerance cant improvements in anxiety scores involved.involved. may develop on multiple dosing. PP550.05) were again noted. The only clini- There are many anecdotal reports of An RCT in patients showed IOP cally significant adverse effect was postural beneficial effects in humans with epilepsy reductions of similar magnitude following hypotension with related dizziness, light- Grinspoon & Bakalar, 1993) but research smoked THC along with ``alterations in headedness or weakness.This was dose- data are virtually non-existent.Two single- mental status'' and tachycardia Merritt etet related, experienced by most patients, and case reports Keeler & Reifler, 1967; alal, 1980).THC eyedrops produced dose- tended to tolerate out over time. ConsroeConsroe et aletal, 1975) give confounding in- related IOP reduction with minimal side- Preliminary data suggest that canna- formation.A young man suffered seizures effects though parallel reductions in the bidiol 160 mg) may be an effective on his regular medication and began untreated eye also seen in animal models) hypnotic, and that THC 0.1 mg/kg) may smoking several cannabis cigarettes nightly suggested a systemic rather than local have antidepressant properties in cancer alongside this.No further seizures occurred mode of action. patients and others Grinspoon & Bakalar, while this combination was maintained.In 1993).1993). contrast, a man with grand mal epilepsy stopped taking anticonvulsants and Insomnia, anxiety and depression suffered no fits for 6 months.He then Randomised controlled trials investigating Epilepsy smoked cannabis on seven occasions over insomnia, anxiety and depression are given Epilepsy afflicts 1% of the world's popu- a 3-week period and suffered three fits in Table 5.5.inTable lation.Conventional anticonvulsants pro- during this time, although not coincident Nabilone 1 mg three times daily) pro- vide unsatisfactory control for up to 30% with actual intoxication. duced ``dramatic improvements'' on the of patients, and all can produce disabling Only one RCT Cunha et aletal, 1980),1980) Hamilton Anxiety Scale in 20 anxious or even life-threatening adverse effects. exists.Fifteen poorly controlled patients

Ta b l e 33Tab Human randomised controlled trials RCTs): pain

Study Subjects Study design Results

NoyesNoyes et aletal 19751975aa))10 patients with cancer db,pc,r,x,sd;THC5,10,15db, pc, r, x, sd; THC 5, 10, 15 ``Pain relief significantly superior to placebo was demonstrated pain &20mg&20mg at high dose levels 15, 20 mg)''

NoyesNoyes et aletal 19751975bb))36 patients with cancer db, pc, r, x, md; THC 20 mg, Codeine and THC were equally effective, but higher dose of pain codeine 120 mg THC sedated most patients and some found its psychoactive effects uncomfortable

Jain et aletal 1981) 56 patients with db, pc, r, sd; levonantradol All doses significantly superior to placebo at least PP550.05), butbut0.05), postoperative pain 1.5, 2, 2.5 or 3 mg i.m. no dose^response effect; 57% patients reported at least one side-effect, but ``general acceptability was good''

MaurerMaurer et aletal 1990)1990)1 patient with spinal db, pc, r, x, md; THC 5 mg, ``Delta-9-THC and codeine both had an analgesic effect in cord injury codeine 50 mg comparison with placebo. Only THC showed a significant effect on spasticity''

HoldcroftHoldcroft et aletal 1997)1997)1patientwithGI 1 patient with GI db, pc, x, md; THC 50 mg Morphine requirement significantly reduced PP550.01) during tract pain familial daily active treatment Mediterranean fever)

o, open; sb, single-blind; db, double-blind; pc, placebo-controlled; r, randomised; x, cross-over design; sd, single-dose; md, multiple-dose; i.m., intramuscularly; GI, gastrointestinal; THC, tetrahydrocannabinol.

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TaTable b l e 4 Human randomised controlled trials RCTs): raised intra-ocular pressure IOP)

StudySubjects Study designResults

Hepler et aletal 1976)i. 429 normal volunteers i. db, pc, r, sd; smoked THC 1, 2 & i. ``dose-related and statistically significant effect in ii. 48 hospitalised subjects 4%;4%;oralTHC15,30&40mg oral THC 15, 30 & 40 mg reducing acutely the intraocular pressure''; iii. 11 patients with glaucoma ii. sb, pc, md; smoked THC 1 & 2% ``pressure drop was in the range of 30% for 2% THC'' iii. o; smoked THCTHC1, 1, 2 4% oral ii. ``consistent drop in IOP around 30% for 2% THC'' THC 15 mgmgTHC and ``no indications of cumulative effects upon IOP'' iii. 7 patients showed a similar response to the above, 4 patients had no demonstrable drug effect

Perez-Reyes et aletal 1976)12 normal volunteers sb, pc, r, x, sd; i.v. infusion of ````DD88-THC, DD99-THC, and 11-hydroxy-THC produced various cannabinoids significant reductions in IOP, whereas cannabinol, 8-bb-OH-THC and cannabidiol were less effective''

Merritt et aletal 1980)18 patients with glaucomadb,pc,sd;smoked db, pc, sd; smoked Significant reductions in IOP, but hypotension, tachy- marijuana ^ THCˆ2%2% cardia, palpitations and psychotropic effects ``mitigate against routine use in the general glaucoma population''

Merritt et aletal 1981)8 patients with ``hypertensive db, pc, sd; THC eye drops; Dose-related reductions in IOP; 1% drops produced glaucoma''glaucoma'' 0.01%, 0.05%, 1% mild hypotension, no psychic effects at any dose. Effect in both eyes suggests systemic mechanism of action

Jones et aletal 1981)13 normal volunteers db, pc, x, md; 10^30 mg THC 4-hourlySignificant reductions in IOP tend to tolerate out after 10 days regular dosing. Abrupt withdrawal of THC produces rebound increase in pressure above baseline

o, open; sb, single-blind; db, double-blind; pc, placebo-controlled; r, randomised; x, cross-over design; sd, single-dose; md, multiple-dose; i.v., intravenous; THC, tetrahydrocannabinol.

TaTable b l e 5 Human randomised controled trials RCTs): insomnia, anxiety, depression

StudySubjects Study design Results

Regelson et aletal 1976) 54 patients with cancerdb,pc,r,x,md;oralTHC db, pc, r, x, md; oral THC ``THC in cancer patients at acceptable dosage 0.1mg/kg t.d.s. 0.1mg/kg tt.i.d..i.d. orally) had the effect of a tranquilli- ser and mild mood elevator, clearly without unto- ward effect on personality or emotional stability''

Carlini & Cunha 1981) 15 insomniac volunteersdb, pc, r, x, sd; cannabidiol Large placebo effect on sleep induction similar to 40, 80, 160160mg; mg; nitrazepam that of active drugs. Cannabidiol significantly 5mg increased duration of sleep, and all three doses reduced dream recall

Fabre & McLendon 1981) 20 anxious patients db,pc,r,md;nabilonedb, pc, r, md; nabilone A ``dramatic improvement in anxiety in the nabilone 2^8 mg/daymg/day2^8 groupgroupwhencomparedwithplacebo when compared with placebo PP550.001)'' was reported. More dropouts from the placebo group group PP550.03). Dry mouth and eyes and drowsiness were the most common adverse effects

Ilaria et aletal 1981)1981) 11 patients with anxietydb, pc, r, x, md; nabilone Nabilone was superior to placebo PP550.05) in 1^2.5 mg b.d. relieving anxiety scores on Hamilton Anxiety Scale and Global Improvement Scale

o, open; sb, single-blind; db, double-blind; pc, placebo-controlled; r, randomised; x, cross-over design; sd, single-dose; md, multiple-dose; t.d.s.,d.s.,threetimesdaily;b.d.,twicedaily; three times daily; b.d., twice daily; THC, tetrahydrocannabinol.

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with secondary generalised epilepsy con- in modern anti-emetic regimes remains to Cannabis arouses passion in those who tinued with their regular therapy but were be determined.Currently, only nabilone is support or condemn it, and few people also given either cannabidiol or placebo licensed in the UK and available for pre- approach the clinical literature with dis- daily for up to 4.5 months while under- scription and research.THC as dron- passionate objectivity.Poorly controlled going regular clinical and electro- abinol) has recently been rescheduled to research produces ambiguous results which encephalogram evaluation.Half the permit prescription but remains unlicensed are then interpreted according to the patients on cannabidiol remained ``almost and must be specially imported on a prejudices of the reader.Anecdotes seem free'' of fits throughout the experiment, named-patient basis.Delta-8-THC looks to be more readily accepted when they and all but one of the others showed ``par- worthy of further investigation, particularly point to adverse rather than positive effects tial improvement''.All but one of the in children, and is much simpler to synthe- HallHall et aletal, 1994).Yet the known adverse placebo patients remained entirely un- sise than THC. effects of oral cannabinoids are rarely intol- changed.Somnolence occurred in four Many individuals with MS have claimed erable or life-threatening, in contrast to patients receiving cannabidiol. a benefit from cannabis and small controlled those associated with some standard thera- trials support this, although effect upon pos- pies.A British Medical Association survey ture and balance requires clarification.THC indicated that many UK doctors believe Asthma is an effective analgesic at the expense of that cannabis should once again be avail- Small-scale controlled studies in volunteers sedation with larger doses and may have able on prescription Meek, 1994). with asthma show that oral, smoked and special merit in neuropathic pain.No conclu- aerosolised THC has comparable broncho- sions are possible as yet about anticonvulsant dilatory activity to salbutamol, although potential.Some cannabinoidscannabinoids reduce reduce IOP, IOP, The way forward onset is quicker with the latter.Dose-relatedlatter.Dose- related though side-effectsside-effects of products currently A Select Committee of the House of Lords tachycardia occurred in some individuals, available limit application and effects of tol- recently examined the scientific information and subjective intoxication with higher erance are uncertain.The mechanism for concerning and took doses.A THC aerosol was free of systemic bronchodilationprobably differs from that verbal and written evidence from a wide unwanted effects, but was irritant to the of bb22--,stimulants, so synergistic combinations range of witnesses.Their conclusion lungs Tashkin et aletal, 1977).Nabilone does may be possible. House of Lords, 1998) published in not produce bronchodilation.Since THC- Cannabis and THC are effective November 1998, was that, although canna- induced bronchodilation is not mediated appetite stimulants.Alongside anti-emetic, bis should remain a controlled drug, the through the sympathetic nervous system, analgesic, anxiolytic, hypnotic and anti- law should be changed to allow doctors to synergistic combinations with bb22-adreno--adreno- pyretic properties this suggests a unique prescribe ``an appropriate preparation of ceptor stimulants might be possible. role in alleviating symptoms in selected cannabis if they saw fit''.The government patients with cancer or AIDS.This is a rejected this recommendation on the day Other possible therapeutic compelling area for future research, of publication. applications although possible effects upon immune Under the auspices of the Royal function require careful monitoring. Pharmaceutical Society, large-scale multi- Basic research indicates that THC and Optimal doses and routes of delivery centre trials are under way to explore analogues inhibit withdrawal have not been established.Absorption by further the efficacy of cannabinoids in Chesher & Jackson, 1985).Anecdotal the oral route is unreliable.Smoking the relieving spasticity and postoperative pain. reports from patients also point to benefi- drug is generally not a viable option since A pharmaceutical company has obtained a cial effects beyond those which could be advantages such as rapid onset, accurate licence to cultivate medicinal cannabis on accounted for by or hypnotic titration of effects and reliability in patients a large scale in the UK.By selecting a activity.Cannabinoids inhibit primary who are vomiting have to be set against the specific genotype then carefully controlling tumour growth and increase survival in likelihood of lung irritation or damage, and all other relevant variables such as soil con- animal tumour models Harris et aletal, 1976),1976) it would in any case be unacceptable to ditions, temperature and humidity, it is by an unknown mechanism.They also most patients.However, pending avail- possible to obtain levels of purity in plant show antipyretic and anti-inflammatory ability of more satisfactory preparations, I extracts equal or superior to those of `pure' activity Formukong et aletal, 1989).,1989). believe that the existing profile of efficacy .Most of the 60 or Mechoulam 1986) has drawn attention to and toxicity justifies the provision of a so naturally occurring cannabinoids are the lack of modern research directed at legal supply of standardised herbal material present in tiny amounts, and synthetic possible antihelmintic, antimigraine and `compassionate reefers') to patients with cannabinoids such as nabilone themselves oxytocic applications. terminal conditions who currently obtain contain up to 5% impurities, some of relief with street cannabis.Sublingual which are of unknown identity.Whether sprays or tablets, nebulisers and aerosols obtained by synthetic means or by plant DISCUSSION look promising for the future, and THC is extraction, it is essential that cannabinoids effective by the rectal route.Manyroute. Many poten- poten- for prescription and research in the future Therapeutic profile on existing tially active cannabinoidshave yet to be should demonstrate excellent purity, stability evidenceevidence investigated and the recent identification and bioavailability. Tetrahydrocannabinol and nabilone are of a peripheral receptor may lead to The medicinal properties of cannabis effective anti-emeticsanti-emetics but there are no com- new drugs devoid of central nervous are still mainly delineated by the anecdotal

parisons with 5-HT33 antagonists, so a role system effects. reports of those who believe their symptoms

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are relieved by its use, and these accounts paraesthesiae, drowsiness, depression, rashes and, balanceinpatientswithmultiplesclerosisandnormal are often dismissed as wishful thinking or rarely, bone marrow suppression. volunteers.volunteers. Clinical Pharmacology and Therapeutics,, 5555,, 324^328. even mischievous.Since the conventional treatments for many of these disorders are REFERENCES Grinspoon, L. & Bakalar, J. B.%19 %1993) 93) Marihuana,TheMarihuana, The Forbidden Medicine. New Haven:Yale University Press. both toxic and relativelyineffectual, a more constructive response would be to expose Abrahamov, A. Abrahamov, A. & Mechoulam, R. Gross, H., Ebert, M. H., Faden,V. B., et aletal %19 83) AA %19 95)95)%19 An efficient new cannabinoid anti-emetic in double-blind trial of delta 9-tetrahydrocannabinol in such claims to careful scientific examination pediatric oncology. Life Sciences,, 5656,2097^2102. primary anorexia nervosa. Journal of Clinical and, in the meantime, search for a way to Psychopharmacology,, 33,,165^171. 165^171. Beal, J. E., Olson, R., Laubenstein, L., et aletal %19 95) avoid criminalisingthose who seek only to Dronabinol as a treatment for anorexia associated with Hall,W.,Hall, W., Solowij, N. & Lemon, J. %eds)%19 %1994) 94) TheThe assuage their own suffering. weight loss in patients with AIDS. Journal of Pain & Health and Psychological Consequences of Cannabis Use,, Symptom Management,, 1010, 89^97.,89^97. National Drug Strategy Monograph Series No. 25. Canberra: Australian Government Publishing Service. ACKNOWLEDGEMENT Carlini, E. A. & Cunha, J. M.%19 %1981) 81) Hypnotic and antiepileptic effects of cannabidiol. Journal of Clinical Harris, L. S., Munson, A. E. & Carchman, R. A. Pharmacology,, 21 suppl. 8^9), 417S^427S. %19 76) Antitumor properties of cannabinoids. InThe This review was originally commissioned and funded Pharmacology of Marihuana,Vol. 2 eds M.C. Braude Chan, H. 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effects in a single case double-blind trial. EuropeanEuropean Archives of Psychiatry and Clinical Neuroscience,, 240240,1^4. CLINICAL IMPLICATIONS Mechoulam, R.%19 %1986) 8 6) The pharmacohistory of .In Cannabinoids asTherapeutic Agents ed. R. Mechoulam), pp.1^19.Boca Raton, FL: CRC && Cannabis and its derivatives show promise of beneficial effects in a number of Press. medical conditions for which standard treatment is less than satisfactory,and further

Meek, C.%19 %1994) 94) Doctors want cannabis prescriptions controlled research is fully justified. allowed. BMA News Review,,15February,p.15. 15 February, p.15. && Cannabis is very safe in overdose, but often produces unwanted effects which are Merritt, J. C., Crawford,W.Crawford,W.J., J., Alexander, P. C., et aletal %19 8 0) Effect of marihuana on intraocular and blood better tolerated by patients with some conditions e.g. multiple sclerosis, chronic pressure in glaucoma. Ophthalmology,, 8787, 222^228.,222^228. pain, AIDS, cancer) than others e.g. glaucoma).

, Olsen, J. L., Armstrong, J. R., et aletal %19 81) TopicalTopical __ && Optimal formulations, doses and routes of delivery have not yet been established. delta 9-tetrahydrocannabinol in hypertensive glaucomas. Journal of Pharmacy and Pharmacology,, 3333,,40^41. 40^41. LIMITATIONS Niederle, N., ShuShutte,« tte, J. & Schmidt,C.G.Schmidt, C. G. %19 %1986) 8 6) Crossover comparison of the antiemetic efficacy of && Because of imposed time constraints, the review is not fully comprehensive, nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin although all accessed sources were incorporated. therapy. Klinische Wochenschrift,, 6464, 362^365. && Much of the evidence is anecdotal, and many of the research studies cited have Niiranen, A. & Mattson, K.%19 %1985) 8 5) Across-over comparison of nabilone and prochlorperazine for emesis serious methodological shortcomings. induced by cancer chemotherapy. American Journal of Clinical Oncology,, 88,,336^340. 336^340. && Few researchers or reviewers) approach the subject of cannabinoid therapeutics in a spirit of dispassionate objectivity. Noyes, R. Jr, Brunk, S. F., Baram, D. A., et aletal %19 75 aa)) Analgesic effect of delta-9-tetrahydrocannabinol. JournalJournal of Clinical Pharmacology,, 1515,139^143.

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