The historical and contemporary, medicinal uses of cannabis have been reviewed on several occasions.
Perhaps the earliest published report to contain at least some objectivity on the subject was that of O’Shaughnessy (1842), an Irish surgeon, working in India, who described the analgesic, anticonvulsant and muscle relaxant properties of the drug. This report triggered the appearance of over 100 publications on the medicinal use of cannabis in American and European medical journals over the next 60 years. One such use was to treat nausea and vomiting; but it was not until the advent of potent cancer chemotherapeutic drugs that the antiemetic properties of cannabis became more widely investigated and then employed.
One can argue that the available clinical evidence of efficacy is stronger here than for any other application and that proponents of its use are most likely to be successful in arguing that cannabis should be re-scheduled (to permit its use as a medicine) because it has a “currently accepted medical use”.
- 1 Specific Medicinal Uses of Cannabis: Use as an Antiemetic
- 2 Specific Medicinal Uses of Cannabis: Glaucoma
- 3 Specific Medicinal Uses of Cannabis: Multiple Sclerosis
- 4 Spastic Conditions
- 5 Specific Medicinal Uses of Cannabis: Anticonvulsant Activity
- 6 Anti-Asthmatic Activity
- 7 Specific Medicinal Uses of Cannabis: Effects on Anxiety and Insomnia
- 8 Depression
- 9 Appetite Loss and Anorexia
- 10 Alcoholism
- 11 Hypertension
- 12 Inflammation
- 13 Anti-Tumour Activity
- 14 Anti-infective Effect
A discussion of the efficacy of cannabis in the relief of spasticity associated with multiple sclerosis appears in Multiple Sclerosis. This should not be viewed in isolation, as it is possible that the underlying neuropharmacology and thus approach to treatment of a range of disorders, may be similar.
Two studies have noted improvement of spinal trauma symptoms secondary to cannabis use. In the former study, 5 of 10 male patients who admitted using cannabis after injury reported improvements in spasticity; but 3 had no such effect. Two patients had no initial spasticity anyway.
Despite anecdotal reports of improvement, cannabis smoking has not stood up to objective, laboratory assessment of controlling Parkinsonian tremor. Similarly, early results in Huntingdon’s disease were not confirmed in placebo controlled trials.
However, cannabis has been used successfully to treat motor tics in Tourette’s syndrome and torsion dystonia. Idiopathic dystonia (a group of disorders characterised by abnormal movements and postures produced by prolonged muscle spasms) has also responded to smoking cannabis.
CBD has been shown to have significant muscle relaxant effects and to reduce muscular spasm in humans. This derivative has been used with reported success to treat a variety of dystonias at oral doses ranging from 100 to 600 mg daily. Consroe et al. () observed dose related improvement in dystonia in each of five patients, ranging from 20–50%. Side effects were described as mild and included hypotension, dry mouth, psychomotor slowing, light-headedness and sedation. At doses of over 300 mg per day, hypokinesia and tremor were exacerbated in two patients with coexisting Parkinsonian features.
Consroe et al. () reported the use of CBD in 15, neuroleptic-free patients with Huntingdon’s disease. CBD, in doses up to 700 mg daily, and placebo were given orally, in double blind, randomised, crossover fashion for 6 weeks. No clinically significant advantages were demonstrated for CBD compared to treatment with placebo. The level of side effects did not differ between groups either; although serum levels of CBD, demonstrating adequate absorption throughout the study, were measured in this careful trial.
In conclusion, evidence that cannabis can relieve muscle spasm in a range of dystonias is largely anecdotal and larger, properly controlled trials are required. An unconfirmed observation that cannabinoids can effect the action of neuroleptic drugs beneficially, is interesting (); experiments with individual cannabinoids may hold clues as to how cannabis works in this respect.
Early reports indicated that acute inhalation increased airway patency in healthy individuals and improved specific airway conductance in asthmatics. However, there is good evidence that chronic smoking of cannabis restricts the airways and that, as with tobacco, unspecified irritants in the smoke can cause bronchospasm.
Aerosolised preparations of THC have produced bronchodilation in both healthy individuals and asthmatics (); but in asthmatic subjects, bronchoconstriction has also been observed. For example, Abboud and Sanders administered aerosolised THC to six asthmatic patients, three of whom showed increases in specific airway conductance indicating bronchodilation; the remaining three subjects showed a decrease in conductance and the overall mean, excluding one of these patients who experienced severe bronchoconstriction which had to be reversed with salbutamol, was not significant compared to placebo. Similar experiments have found no evidence of tolerance to the bronchodilating effect of THC for up to 20 days of use. Williams et al. () showed that a combination of salbutamol and THC produced a more rapid improvement in ventilatory function in asthmatic subjects than salbutamol alone.
Problems with aerosolised THC may be at least in part due to the failure to develop a satisfactory formulation of the drug. Oral THC does produce some bronchodilation, but due to unpredictable absorption, onset is delayed and the degree of bronchodilation uncertain. Both delta-8- and delta-9-THC have bronchodilating effects whereas cannabidiol and cannabinol do not; it therefore seems that the bronchodilatory property resides in psychoactive material.
Oral nabilone has been shown to inhibit bronchospasm induced in healthy volunteers by methacholine but was, in contrast to terbutyline, ineffective in patients with chronic stable asthma. No further data on nabilone are available.
In conclusion, problems with bronchoconstriction after smoking or aerosolised administration, slow onset of action of orally administered cannabinoids and the existence of a range of effective and relatively safe alternatives, preclude the use of cannabis or its derivatives as adjuvants in the management of asthma at present. This is reflected in the low level of research activity in this area.
Indeed, asthmatics should be warned against smoking marihuana for two reasons: firstly, the irritant effects could lead to bronchospasm; secondly, components of marihuana smoke are known to inhibit the metabolism of at least one drug used in asthma — theophylline.
Mode of Action
The pharmacology of established anti-asthmatic drugs is well-characterised. If any of the cannabinoids or their derivatives are to be useful in asthma, development of a lead compound is only likely when based on a good understanding of the way in which it promotes bronchodilation and how side effects can be minimised.
The bronchodilator effect of THC does not appear to be related to beta-adrenergic stimulation or muscarinic inhibition. Orzalek et al. () showed that the bronchodilator effects of the cannabinoids are due to mechanisms which are different to those of the more familiar anti-asthmatic drugs. THC and nabilone did not appear to interfere with cholinergic or histaminergic responses; nor did they alter prostaglandin F2-alpha-induced contractile responses. The authors suggest that the effects may be centrally mediated. Laviolette and Belanger showed that when THC was smoked by healthy volunteers, significant increases in specific airway conductance and forced expiratory volume were produced which were not inhibited by bronchoconstricting prostaglandin administration. This is in contrast to in vitro experiments which suggest that many of the physiological effects of marijuana may be mediated via prostaglandins.
It is well recognised that smoking marijuana can produce a euphoric high. When psychological tests have been performed on patients receiving cannabis or THC for nausea and vomiting associated with cancer chemotherapy, mood elevations have been observed); however, results are far from consistent. Eight psychiatric patients, hospitalised for moderate or severe depression, received low doses of THC each day for a week; but no mood elevation was observed. In the absence of rigorously controlled trials of these agents, it is impossible to predict how useful the mild, mood elevating properties, noted in trials of THC when used for other purposes, would be in specifically depressed patients; further objective measurement is required.
Appetite Loss and Anorexia
Users of cannabis often experience hunger and a desire to eat sweet foods, leading to the proposal that its use may increase food intake and therefore slow weight loss in cancer patients.
Hollister described a double-blind study using cannabis or placebo cigarettes. Increased appetite and caloric consumption was demonstrated in those using the drug but the degree to which this took place was highly variable between patients.
Patients receiving THC for nausea and vomiting associated with cancer chemotherapy have often shown improved appetite after receiving THC, but the effect is unpredictable. In a small study comparing THC with diazepam in patients with anorexia nervosa, THC did not improve caloric intake and three of the eleven patients who took the drug developed paranoia. The Food and Drug Administration approved the use of synthetic THC (dronabinol) for anorexia associated with weight loss in patients with AIDS, based on clinical studies in which the effect of THC was sustained for up to 5 months: a placebo-controlled trial involving 139 patients with AIDS in the US and Puerto Rico was carried out for an initial period of 6 weeks. The patients in the active arm of the trial received 2.5 mg THC twice daily before meals. THC produced a significant increase in appetite compared to the placebo but no corresponding increase in weight gain. Side effects associated with THC included palpitations, tachycardia, confusion, dizziness, euphoria and ataxia. THC did not interact with drugs commonly used to treat AIDS patients, such as zidovudine, but the side effects mentioned above were accentuated when drugs with similar side effect profiles were used, eg: increased drowsiness with benzodiazepines.
Plasse et al. () described a study in ten AIDS patients in which doses of THC (as dronabinol) which were sufficiently tolerable for chronic administration up to 5 months, were effective in stabilising or improving weight and enhancing appetite. The dose used was a maximum of 2.5 mg, three times a day, but patients were allowed to adjust the dose downward to avoid side effects. The same group subsequently conducted a multicenter, randomised, double-blind, placebo-controlled trial in 88 evaluable patients with AIDS-related anorexia and weight loss. Patients received 2.5 mg THC twice daily or placebo. Significant improvements above baseline and compared to placebo were observed after 6 weeks, in appetite and reduced nausea; mood was also improved but did not reach statistical significance (p=0.06). Subjects taking the placebo had a mean loss of 0.4kg, while the weight of the patients taking THC remained stable. Side effects were mostly mild and there was no statistical difference between the number of discontinuations in either group. THC was adjudged to be safe and effective for anorexia and associated weight loss in patients with AIDS, making a significant contribution to quality of life.
Summarising, use of cannabis or its derivatives as specific appetite stimulants does not look promising, because of the wide variability in response. Based on the evidence discussed above, synthetic THC (dronabinol) has been approved in the US as an appetite stimulant in AIDS patients; but because of its putative abuse potential, the drug remains a schedule 2 controlled substance.
Mode of Action
The way in which appetite stimulation occurs in debilitated AIDS or cancer patients is probably multifactorial. Relief of pain, nausea, anxiety and depression may all play a part. Regelson et al. () have suggested a specific effect on the mechanisms producing cachexia in cancer patients.
The acute and chronic toxicity profile of cannabis is described in «Cannabis Use and Abuse by Man: An Historical Perspective»0 of this volume. Liver damage is not a prominent feature and it has been suggested that alcoholics might be encouraged to shift their dependence from alcohol to cannabis on grounds of increased safety, in a parallel with the substitution of methadone for heroin in addiction with the latter. There are no reports of individual cannabinoids being investigated in this respect.
In spite of early reports of success in weaning alcoholics from their primary addiction, subsequent findings are far from encouraging. Rosenberg et al. () reported a trial in which 56 alcoholics were given disulfiram or cannabis, alone or in combination, in an attempt to wean them from alcohol. Cannabis proved ineffective at reducing alcohol consumption.
Cannabis and alcohol are commonly used and abused together and surveys have shown that it is the most prevalent drug combination among adolescents and young adults; however, substitution of one addictive substance with another whose toxicity has not been fully characterised, whose use is still illegal in many countries and whose effectiveness in reducing alcohol consumption is in question, would appear to be unjustified.
Hypotension and tachycardia are well-recognised effects of cannabis and cannabinoid use in man. The antihypertensive effects of the cannabinoids appear to be independent of their psychotropic effects; for example CBD, a non-psychotropic derivative, is active. There is no clinical trial evidence that cannabis or any of its derivatives would be satisfactory alternatives to established agents in the long-term control of elevated blood pressure. While these agents have a hypotensive effect, the pharmacology of this process remains unclear and is complex, possibly involving stimulation of vasodilatory prostaglandins.
Interestingly, CBD appears to have a bradycardic effect in animal models where THC produces tachycardia (); therefore if cannabinoid analogues are to be developed as antihypertensive agents, it may be more useful to explore derivatives based on the structure of the former rather than the latter.
Mode of Action
While it has been suggested that atropine-like material in raw cannabis is responsible for the hypotension and tachycardie effect, this is difficult to reconcile with the fact that supposedly pure cannabinoids have similar activity. Certainly the effects do seem to be mediated through the autonomie nervous system. Beta-adreno-receptor blockers, such as propranolol, and muscarinic antagonists, like atropine have been shown to antagonise the vascular effects of THC in man.
Animal studies have shown the situation to be complex. THC can reduce myocardial contractility without decreasing heart rate although the mechanism remains obscure. Burstein and Ossman showed that aspirin inhibited the hypertensive effect of THC, suggesting the prostaglandins are involved. However this does not appear to be the case with tachycardia. A dimethylheptyl side-chain derivative of THC has been shown to be a potent hypotensive agent with less psychoactivity in man; however the vascular and psychological activities have by no means been divorced.
Extracts of cannabis were administered during the 19th century for fever before the introduction of aspirin and cannabinoids have been shown to possess antipyretic and analgesic properties. While there are no studies of cannabis or the cannabinoids in acute or chronic inflammatory conditions in man, a study of their actions in animals may provide an impression of the potential usefulness of the cannabinoids in this area. Assessments using models other than those involving pain production and heat have often produced contradictory results. Koserky et al. () could not demonstrate any anti-inflammatory action for THC in carrageenan-induced oedema in the rat paw model. However, Sofia et al. () showed that, in the same model, oral THC was 20 times more potent than aspirin and twice as potent as hydrocortisone. The selective inhibitory action of various cannabinoids at various stages of the inflammatory process has been demonstrated in animals. Formukong et al. () reviewed the in vitro and in vivo anti-inflammatory activity of a range of cannabinoids, including THC and CBD; both compounds were active, but CBD was the most effective compound in terms of inhibiting the erythema produced by applying tetradecanoylphorbol acetate (TPA) to the skin of mice and inhibition of rabbit blood platelet aggregation. CBD was also more potent then THC in inhibiting soyabean lipo-oxygenase; but THC was more effective than CBD in inhibiting cyclooxygenase in microsomal preparations. The authors concluded that the effects of the cannabinoids are complex, probably involving several membrane-associated enzymes.
The beneficial effects of cannabis in several disease processes have been attributed, at least in part, to its ability to suppress the production or subsequent action of prostaglandins and other inflammatory mediators. Recent evidence suggests that additional compounds in cannabis, which are structurally and biologically distinct from the cannabinoids, have a significant inhibitory effect on prostaglandin release in vitro (). In the absence of trials in man, it is impossible to tell if cannabis or its derivatives have any potential as anti-inflammatory drugs. It is clear that several may find a role in relief of pain, as indicated in «Cannabis and Cannabinoids in Pain Relief» and perhaps evidence of anti-inflammatory efficacy will result from trials in this area. It has been pointed out earlier that chronic cannabis smoking may affect lung function, not least because the compounds in the smoke may suppress the immune response. This may be encouraging from the viewpoint of inflammatory lung disease, but worrying if the patient has a lung infection or is already immunocompromised.
There have been no studies of cannabis or its derivatives in man and studies in animal models have yielded inconclusive results. THC was half as potent as standard anti-cancer chemotherapy in reducing tumour growth in mice innoculated with a murine lung cancer strain; cannabidiol was ineffective. Inhibition of tumour growth and improved animal survival following treatment with THC may be in part due to the ability of cannabinoids to inhibit macromolecular synthesis. In another study, cannabinol accelerated tumour growth in tissue culture.
The importance of these findings is unclear; however, it could be surmised that when cannabis is used to alleviate nausea and vomiting associated with cancer chemotherapy, certain of its components could promote tumour growth. It would be reassuring to know that this is not the case and this potential problem should be investigated.
Traditional uses of cannabis include inhalation for a range of systemic disorders which may or may not have an underlying infectious pathology and local application of lotions or ointments for skin disorders. While in vitro studies have shown cannabis to have some antibacterial and antifungal activity and cannabidiol to possess activity against Gram positive bacteria, there are no reports of efficacy in vivo and no comparisons with standard antibiotics. It therefore seems unlikely that cannabis derivatives will be developed for their antibiotic effects.
Blevins and Dumic were able to show that in vitro, THC was capable of decreasing Herpes simplex virus replication and/or infectivity in human cell cultures; further developments of this research have not been published.