Therapeutic Aspects of Cannabis and Cannabinoids
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BRITISH JOURNAL OF PSYCHIATRY %2001), 178, 107^115 Therapeutic aspects of cannabis and cannabinoids{{ 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 United States 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 Health 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 hemp, 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 Drug 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 cannabinoid 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 brain damage, 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 anxiety 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 research 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 heart rate. 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 drugs.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 Marijuana 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 hypnotic.After sations were made between 1976 and 1992 {{See editorial, p.98, thisissue. toxicity experiments on goats and dogs, he for individuals to receive `compassionate 107 Downloaded from https://www.cambridge.org/core. 23 Sep 2021 at 19:55:12, subject to the Cambridge Core terms of use. ROBSON 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 Cannabinol 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-tetrahydrocannabinol 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 dronabinol) 10 mg/mmg/m10 22) produced euphoria 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.Nabilone, 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, ataxia 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