Cannabis Research A-Z

Volume 178             February 2001             pp 107-115

Background: Review commissioned in 1996 by the Department of Health (DOH).

Aims: Assess therapeutic profile of cannabis and cannabinoids.

Method: Medline search, references supplied by DOH and others, and personal communications.

Results and Conclusions: Cannabis and some cannabinoids are effective antiemetics and analgesics and reduce intraocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.

Declaration of interest: Funding from DOH. Between writing this paper and its acceptance for publication, P.R. was appointed Medical Director of GW Pharmaceuticals.

In 1996 I was commissioned by the Department of Health (DOH) to review the scientific literature regarding the potential therapeutic utility of cannabis and its derivatives. The review was based upon primary sources (identified from a Medline literature search, reference lists supplied by the DOH and the Institute for the Study of Drug Dependence, and personal communications with relevant academics and clinicians). This paper is a greatly shortened version of the review. The 4 years which have elapsed have seen little in the way of new clinical results but considerable advances in cannabinoid basic science (Institute of Medicine, 1999). Government licences have recently been granted for several controlled trials of both synthetic and plant-derived cannabinoids in multiple sclerosis and chronic pain. In January 2000, I was appointed Medical Director of GW Pharmaceuticals, a company established to derive medicinal extracts from standardised cannabis plants.

It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O'Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, antispasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its usefulness as an anti-emetic.

After these observations were published in 1842, medicinal use of cannabis expanded 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.

Queen Victoria's personal physician wrote (Reynolds, 1890), on the basis of more than 30 years' experience, that "Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess". He found it incomparable for "senile insomnia", "night restlessness" and "temper disease" in both children and adults, but not helpful in melancholia, "very uncertain" in alcoholic delirium, and "worse than useless" in mania. It was very effective in neuralgia, period pains, migraine, "lightning pain of the ataxic patient" and gout, but useless in sciatica and "hysteric pains". He found it impressive in clonic spasms and certain epileptiform convulsions related to brain damage, but no good at all in petit mal or "chronic epilepsy", tetanus, chorea or paralysis agitans. It effectively relieved nocturnal cramps, asthma and dysmenorrhoea.

Reynolds was writing at a time when the zenith of cannabis as prescribed medicine and home remedy was already past. Although Sir William Osler was still recommending it for migraine sufferers in 1913, it was by then in steep decline because of variable potency of herbal preparations, poor storage stability, unpredictable response to oral administration, increasing enthusiasm for parenteral medicines and availability of potent synthetic alternatives, commercial pressures and American concern about recreational use. Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.

In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive 'compassionate reefers'. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.

Capsules of synthetic THC (dronabinol) have been available for restricted medical use in the USA since 1985. Nabilone, a synthetic THC analogue, was marketed in 1983 and is the only cannabinoid licensed for prescription in the UK, restricted to treatment of nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional anti-emetics. Use in other indications is only possible on a 'named patient' basis if the drug is supplied by a hospital pharmacy.

In 1988, a specific protein receptor (known as CB₁) for THC was discovered in mouse nerve cells. This mediates most of the central nervous system (CNS) responses to cannabinoids, and is abundant in basal ganglia, hippocampus and cerebellum, globus pallidus, substantia nigra and cerebral cortex. An endogenous ligand was identified in 1992 and labelled anandamide (ananda: 'bliss' in Sanskrit). Anandamide has analgesic and tranquillising effects in animals, is involved in muscle coordination and affects the secretion and function of certain hormones. Other endogenous agonists almost certainly exist.

In 1993, a second receptor (CB₂) was identified in rat spleen macrophages, and this occurs only outside the CNS. There is scope for chemical manipulation of cannabinoids to maximise selectivity for CB₂ and so avoid psychoactive effects. It is thought this receptor has relevance for anti-inflammatory and immunosuppressive activity.

Pertwee (1995) has suggested that the anandamide system might be concerned with mood, memory and cognition, perception, movement, coordination, posture and skeletal muscle tone, sleep, thermoregulation, appetite and immune response.

Subsequent RCTs (listed in Table 1) confirmed that natural and synthetic THC is invariably superior to placebo. Comparisons with anti-emetics available in the 1970s and 1980s suggest that THC is either equivalent in effect or better. A combination of prochlorperazine and THC was superior to either drug alone, and nabilone combined with prochlorperazine was better than dexamethazone plus metoclopramide. Although THC and nabilone produced more unwanted effects than comparison drugs, patients generally preferred them.

Children seem to respond well to nabilone and are tolerant of side-effects, but larger studies are required. [DELTA]⁸-THC performed well in a pilot study (Abrahamov et al, 1995) involving eight children aged 3-13 years with various blood cancers receiving chemotherapy, 60% of whom had experienced distressing vomiting despite treatment with metoclopramide. [DELTA]⁸-THC was given orally 2 hours before cytotoxics and repeated 6-hourly. No vomiting was recorded during this treatment and over the following 2 days. Two children were "slightly irritable" and one also showed "slight euphoria".

In a review of 12 studies involving 600 patients (Penta et al, 1981), THC was "effective" in 8/9 and nabilone in 3/3. The most common side-effects were somnolence (33%), dry mouth (9%), ataxia (8%), dizziness (6%), dysphoria (6%), and orthostatic hypotension (4%). A further review (Levitt, 1986) incorporating 55 studies, of which 32 were RCTs, showed that low-dose preventive treatment gives better results than targeting established vomiting. Younger patients may respond better than older ones.

Meta-analysis (Plasse et al, 1991) suggested that an optimal balance of efficacy and unwanted effects was achieved with relatively modest doses (7 mg/m² or less). Sedation and psychotropic symptoms are commonly reported, but are usually mild to moderate in intensity and resolve rapidly on discontinuation. No "persistent or fatal" adverse effects have been reported. Many American oncologists encourage nauseous patients to try cannabis and would prescribe it if it were legal (Doblin & Kleiman, 1991). Mode of action remains uncertain.

Most respondents to a questionnaire sent to British and American MS patients reported problems with symptom control (Consroe et al, 1997). Those who smoked cannabis claimed improvements in night-time spasticity and muscle pain (91-98%); night leg pain, depression, tremor, anxiety, spasms on walking, paraesthesiae (80-89%); leg weakness, trunk numbness, facial pain (71-74%); impaired balance (57%); constipation (33%); memory loss (31%).

In a small single-blind comparison with placebo (Clifford, 1983), THC improved tremor and ataxia in most patients. All experienced a 'high' at the top dose (15 mg), and two reported dysphoria. Dose-related improvements in dystonia were noted in five patients given cannabidiol 100-600 mg daily for 6 weeks. Hypotension, dry mouth, sedation and light-headedness occurred but were described as mild. Parkinsonian symptoms were aggravated in two subjects.

An RCT by Petro & Ellenberger (1981) compared the effects of placebo and THC in doses of 5 or 10 mg on muscle tone, reflexes and muscle power in nine MS patients. Both doses of THC reduced spasticity (P < 0.005). One patient receiving THC 10 mg and one patient receiving placebo felt 'high' but no other side-effects were recorded. In a small RCT (Ungerleider et al, 1987) with 5-day treatment periods, THC 7.5 mg significantly improved spasticity in comparison with placebo. Nabilone 1 mg on alternate days was compared with placebo in a double-blind randomised crossover trial with 4-week treatment periods in a single MS patient. Nocturia, muscle spasm and general well-being showed striking improvement during each active treatment period. Mild sedation was noted on active medication.

Cannabidiol had no beneficial effects in 15 patients with Huntington's disease (Consroe et al, 1991). Posture and balance were impaired by a single dose of smoked THC in 10 MS patients and 10 non-MS volunteers (Greenberg et al, 1994), but there was no active control to determine the effects of standard anti-spastic medication in this model.

Possible sites of action of cannabinoids in dystonia include basal ganglia, cerebellum, spinal motor neurons, somatic nerves and neuromuscular junction.

Many people with AIDS have claimed that smoking marijuana inhibits nausea, improves appetite, reduces anxiety, relieves aches and pains, improves sleep and inhibits oral candidiasis. A small pilot study supported the hypothesis that dronabinol might reduce weight loss or even promote weight gain (Plasse et al, 1991).

Beal et al (1995) conducted an RCT over 42 days of treatment with dronabinol 5 mg daily in 139 AIDS patients who had lost at least 2.3 kg. Six receiving dronabinol and three receiving placebo withdrew because of "perceived drug toxicity". Dronabinol boosted appetite in comparison to placebo (P<0.015) and nausea was reduced (P=0.05). Improvement in mood was a strong trend (P=0.06) and there was a tendency toward weight gain (P=0.1). Dronabinol produced more adverse effects than placebo (P<0.001), but 75% of these were mild or moderate. Most frequent were euphoria (9), dizziness (5), thinking abnormalities (5) and sedation (4).

Further investigation is amply justified. Careful monitoring of possible effects upon the immune system is needed, although a prospective multi-centre study (Kaslow et al, 1989), which followed nearly 5000 HIV-positive men for 18 months, showed no link between use of psychoactive substances and mean T-cell counts or progression to AIDS.

Five small RCTs (Table 3) show that THC is significantly superior to placebo and produces dose-related analgesia peaking at around 5 hours, comparable to but out-lasting that of codeine. Side-effects were also dose-related, and consisted of slurred speech, sedation and mental clouding, blurred vision, dizziness and ataxia. Levonantradol was also superior to placebo and notably long-acting, but almost half the patients reported sedation. Cannabinoids may have considerable potential in neuropathic pain (Institute of Medicine, 1999).

Randomised controlled trials in volunteers confirmed that oral, injected or smoked cannabinoids produce dose-related reductions of IOP (Hepler et al, 1976; Perez-Reyes et al, 1976). Conjunctival engorgement and tear reduction were often noted. THC, [DELTA]⁸-THC and 11-hydroxy-THC are more effective than cannabinol, while cannabidiol was without effect. Tolerance may develop on multiple dosing.

An RCT in patients showed IOP reductions of similar magnitude following smoked THC along with "alterations in mental status" and tachycardia (Merritt et al, 1980). THC eyedrops produced dose-related IOP reduction with minimal side-effects though parallel reductions in the untreated eye (also seen in animal models) suggested a systemic rather than local mode of action.

Table 5.

Preliminary data suggest that cannabidiol (160 mg) may be an effective hypnotic, and that THC (0.1 mg/kg) may have antidepressant properties in cancer patients and others (Grinspoon & Bakalar, 1993).

The effect of cannabinoids on seizure activity in laboratory animals is complicated. Cannabidiol is a powerful anti-convulsant free of tolerance, but its profile varies between species. THC can produce seizures in big doses or when genetically seizure-sensitive animals are used, yet it is also robustly anticonvulsant in certain seizure models. A lack of stereospecificity suggests that the mechanism may not be related to a single receptor interaction. Serotonin, [gamma]-aminobutyric acid, acetylcholine or prostaglandin systems may be involved.

There are many anecdotal reports of beneficial effects in humans with epilepsy (Grinspoon & Bakalar, 1993) but research data are virtually non-existent. Two single-case reports (Keeler & Reifler, 1967; Consroe et al, 1975) give confounding information. A young man suffered seizures on his regular medication and began smoking several cannabis cigarettes nightly alongside this. No further seizures occurred while this combination was maintained. In contrast, a man with grand mal epilepsy stopped taking anticonvulsants and suffered no fits for 6 months. He then smoked cannabis on seven occasions over a 3-week period and suffered three fits during this time, although not coincident with actual intoxication.

Only one RCT (Cunha et al, 1980) exists. Fifteen poorly controlled patients with secondary generalised epilepsy continued with their regular therapy but were also given either cannabidiol or placebo daily for up to 4.5 months while undergoing regular clinical and electroencephalogram evaluation. Half the patients on cannabidiol remained "almost free" of fits throughout the experiment, and all but one of the others showed "partial improvement". All but one of the placebo patients remained entirely unchanged. Somnolence occurred in four patients receiving cannabidiol.

Many individuals with MS have claimed a benefit from cannabis and small controlled trials support this, although effect upon posture and balance requires clarification. THC is an effective analgesic at the expense of sedation with larger doses and may have special merit in neuropathic pain. No conclusions are possible as yet about anticonvulsant potential. Some cannabinoids reduce IOP, though side-effects of products currently available limit application and effects of tolerance are uncertain. The mechanism for bronchodilation probably differs from that of [beta]₂-stimulants, so synergistic combinations may be possible.

Cannabis and THC are effective appetitc stimulants. Alongside anti-emetic, analgesic, anxiolytic, hypnotic and antipyretic properties this suggests a unique role in alleviating symptoms in selected patients with cancer or AIDS. This is a compelling area for future research, although possible effects upon immune function require careful monitoring.

Optimal doses and routes of delivery have not been established. Absorption by the oral route is unreliable. Smoking the drug is generally not a viable option since advantages such as rapid onset, accurate titration of effects and reliability in patients who are vomiting have to be set against the likelihood of lung irritation or damage, and it would in any case be unacceptable to most patients. However, pending availability of more satisfactory preparations, I believe that the existing profile of efficacy and toxicity justifies the provision of a legal supply of standardised herbal material ('compassionate reefers') to patients with terminal conditions who currently obtain relief with street cannabis. Sublingual sprays or tablets, nebulisers and aerosols look promising for the future, and THC is effective by the rectal route. Many potentially active cannabinoids have yet to be investigated and the recent identification of a peripheral receptor may lead to new drugs devoid of central nervous system effects.

Cannabis arouses passion in those who support or condemn it, and few people approach the clinical literature with dispassionate objectivity. Poorly controlled research produces ambiguous results which are then interpreted according to the prejudices of the reader. Anecdotes seem to be more readily accepted when they point to adverse rather than positive effects (Hall et al, 1994). Yet the known adverse effects of oral cannabinoids are rarely intolerable or life-threatening, in contrast to those associated with some standard therapies. A British Medical Association survey indicated that many UK doctors believe that cannabis should once again be available on prescription (Meek, 1994).

Under the auspices of the Royal Pharmaceutical Society, large-scale multi-centre trials are under way to explore further the efficacy of cannabinoids in relieving spasticity and postoperative pain. A pharmaceutical company has obtained a licence to cultivate medicinal cannabis on a large scale in the UK. By selecting a specific genotype then carefully controlling all other relevant variables such as soil conditions, temperature and humidity, it is possible to obtain levels of purity in plant extracts equal or superior to those of 'pure' synthetic cannabinoids. Most of the 60 or so naturally occurring cannabinoids are present in tiny amounts, and synthetic cannabinoids such as nabilone themselves contain up to 5% impurities, some of which are of unknown identity. Whether obtained by synthetic means or by plant extraction, it is essential that cannabinoids for prescription and research in the future should demonstrate excellent purity, stability and bioavailability.

The medicinal properties of cannabis are still mainly delineated by the anecdotal reports of those who believe their symptoms are relieved by its use, and these accounts are often dismissed as wishful thinking or even mischievous. Since the conventional treatments for many of these disorders are both toxic and relatively ineffectual, a more constructive response would be to expose such claims to careful scientific examination and, in the meantime, search for a way to avoid criminalising those who seek only to assuage their own suffering.

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