«Cannabis Use and Abuse by Man: An Historical Perspective» of this site provides a fascinating, historical account of the use of cannabis across many cultures and centuries. Suffice it to say here that any natural substance with over 5000 years of medical history will have attached to it a heritage of hearsay and legend through which one must sift to identify areas of true therapeutic potential for us in the late twentieth century and beyond. A summary of conditions for which cannabis has been used, ranging through various shades of rationality, appears in Table Medicinal and quasi-medicinal uses for cannabis and its derivatives:
|Indications for which only anecdote or reports of traditional use exist:|
|aphrodisiac||muscular spasm in rabies / tetanus||Huntingdon’s chorea||jaundice||toothache|
|menstrual cramps||rheumatism||movement disorders||gut spasm||pyrexia|
|inflammed tonsils||migraine||headache||increasing uterine
contractions in childbirth
|urinary retention/ bladder spasm|
|parasite infection||fatigue||allergy||fever||herpetic pain|
|Indications for which there are at least some trial data:|
|depression||anxiety||insomnia||infected wounds||muscle spasm|
|asthma||muscle spasticity||pain of various aetiologies||sedation||alcoholism|
|epilepsy||phantom limb pain||Parkinsonian tremor||Tourette’s syndrome/ torsion dystonia|
|Indications for which there is general acceptance of efficacy, at least in some patients, at some stage of their disease:|
|glaucoma||chemotherapy induced nausea and vomiting||relief of pain and muscle spasm in multiple sclerosis||lost appetite and anorexia particularly in AIDS patients|
Many areas of use are shrouded, maybe totally obscured, in anecdotal reports, merging with folklore and tradition, which come nowhere near providing the minimum of scientific evidence required to show that cannabis has any real beneficial effect at all. In other areas, a body of knowledge is expanding rapidly to reveal indications in which the use of cannabis or its derivatives is justified, or at least, where research effort into new synthetic analogues of the cannabinoids holds most promise.
As mentioned in «The Chemistry of Cannabis», cannabis contains over thirty cannabinoids, some of which may be harmful; others may have beneficial effects. The cannabinoid content of raw cannabis can vary considerably, both in quantity and proportion, depending on cultivation conditions of the plant and the methods used to extract them. It is little wonder then that one of the major problems one encounters when trying to compare clinical trials involving crude extracts of cannabis lies in determining the standard of the preparation used.
After the isolation of delta-9-tetrahydrocannabinol (THC) in 1964, efforts to assess its therapeutic potential proceeded apace in a diverse range of conditions, including: hypertension, asthma, endogenous depression, glaucoma, bacterial infection, epilepsy, emesis, pain and anxiety. Additional compounds were also synthesised in attempts to create useful therapeutic agents based on the chemistry of THC and other cannabinoids. The availability of these purified compounds allowed firstly, an objective assessment of their pharmacology in animals and in some cases, subsequently in man; secondly, it was possible to achieve some standardisation of dosing in clinical investigations. One further advantage was the recognition that a single agent, although derived from cannabis, might not appear so attractive to potential abusers as the parent material, simplifying the path to obtaining an investigator’s licence.
The legislative environment in which these experiments were carried out, in academia, government laboratories and the pharmaceutical industry, was not a friendly one (see «Analytical and Legislative Aspects of Cannabis»). In the US, the Marihuana Tax Act of 1937 prompted the removal of cannabis from the US Pharmacopoeia in 1941. Cannabis had already been removed from the British Pharmacopoeia in 1932.
To this day in the US, in spite of stiff lobbying, cannabis remains a Schedule 1 substance under the Controlled Substance Act, as a drug which has a high abuse potential, lacks an “accepted” medical use and is unsafe for use under medical supervision. Similarly in the UK, the listing of cannabis under Schedule 1 of the Misuse of Drugs Act 1971, makes it illegal to prescribe cannabis for therapeutic purposes or to research the plant without a special licence from the Home Office.
The term “accepted” is an interesting one when applied to cannabis. For specific indications such as the control of cancer chemotherapy-induced nausea and vomiting, a growing number of patients and their doctors, reported relief after smoking cannabis when other therapies had proven ineffective. Clinicians could refer to limited clinical trial evidence which did provide some proof in this area. This lead, albeit temporarily, to a number of patients receiving cannabis legally, for therapeutic purposes, in the US. From 1978, legislation allowing patients to use cannabis (as marihuana), for therapeutic purposes, under their doctor’s supervision, was enacted in 36 states. Ten states went as far as to establish, with the necessary government approval, formal research programs with cannabis. These have since foundered because of the bureaucracy still associated with handling the drug.
The growing demand did however persuade the Food and Drug Administration (PDA) to investigate Compassionate Investigational New Drug (CIND) status for cannabis, for physicians whose patients needed cannabis where no other drug was effective. Uptake of this CIND was small initially; however, it increased dramatically in 1989, in parallel with an upturn in the number of patients diagnosed as having AIDS where the drug was used for pain relief and as an appetite stimulant.
In 1991, the US Public Health Service suspended the CIND programme on the grounds that it was contrary to the administration’s opposition to the use of illegal drugs, and it withered on the vine, to the extent that no new CINDs were granted in 1992. A few patients remained who were receiving cannabis legally; for all others, use was illegal.
As «Analytical and Legislative Aspects of Cannabis» in this book indicates, the legal status of cannabis and its derivatives is in a state of flux in many countries. In Australia, where the cultivation and possession of cannabis is permitted, the authorities have judged the evidence, such as it is, and have concluded that the benefits outweigh the risks. In others, such as the UK and Holland, legislators remain unconvinced, citing the available evidence as being deficient in scope, size and other methodology. However, two cannabis derivatives — nabilone and dronabinol (‘synthetic’ THC) — are available on prescription for extremely limited indications.
It is logical, but not necessarily likely, that advocates of the use of cannabis and its derivatives should indeed focus their pleas for legalisation for prescription use in a limited number of identifiable, serious conditions for which there is convincing evidence of efficacy, allied to acceptable risk, if they are to be successful.
Most recently, legislation (proposition 215) was passed to allow doctors in California to recommend cannabis verbally but not by written prescription, for treating conditions such as cancer, AIDS, anorexia, chronic pain, spasticity and glaucoma. Similar laws have been passed in Arizona, Florida, Idaho, Ohio and Washington. These new state laws conflict with federal law however, as it is still a crime to sell or possess cannabis and therefore in theory, the drug cannot be purchased legally. The law can be invoked as a legitimate defence by someone who is arrested for possession and can persuade the authorities that it was being used for a medical condition on their Doctor’s recommendation. There is considerable inter-state variation; for example, the Arizona law requires the prescriber to write a scientific opinion, which must be corroborated by a second physician, on why a particular patient needs cannabis, before the patient can obtain the drug.
The remainder of this chapter discusses the available evidence on a disease state basis. An analysis of the efficacy of the crude drug (cannabis) is followed by a discussion of trials with THC or other cannabinoid derivatives and where possible, a brief summary of theories on the mode of action is given.
Pain features as a component of many of the illnesses discussed and a separate chapter by Dr Bill Notcutt and Mario Price, describes the clinical evidence available which supports this use.
The post concludes with a discussion of where the real therapeutic and developmental potential lies for the derivatives of cannabis.
Side Effects Associated With The Therapeutic Use Of Cannabinoids
The unwanted effects associated with the therapeutic use of cannabis and its derivatives have been evaluated in numerous clinical trials in a variety of disorders. Table Acute side effects of cannabis and its derivatives observed in clinical trials provides a summary of the findings and provides a broad analysis by route of administration and severity.
Table Acute side effects of cannabis and its derivatives observed in clinical trials
|Effects observed after inhaling cannabinoids in smoke (including marijuana):|
|cough||postural hypotension||bronchocon-striction||reddening of the eyes|
|Effects after ingesting cannabinoids at ‘therapeutic’ doses by the oral route (common, >10% of subjects):|
|postural hypotension||dizziness||dry mouth||blurred vision||hangover|
|confusion||disorientation||space-time distortion||tremor||muscle weakness|
|Effects after ingesting cannabinoids at ‘therapeutic’ doses by the oral route (rare, <10% of subjects):|
|hallucinations (visual and auditory)||asthenia||paraesthesia (facial and extremities)||amnesia||syncope|
|slurred speech||faecal incontinence||tachycardia||mania||nightmares|
|lethargy||headache||psychosis||mood elevation||urinary retention|
|Effects after Parenteral administration of cannabinoids (intramuscular or intravenous). In addition to those mentioned above for the enteral route.|
|Pain at injection
|abdominal pain||leg cramps||facial neuralgia||rash|
The vast majority of these effects fit the description of a Type A adverse drug reaction, i.e., the severity is related to dose and the reaction resolves upon stopping treatment. Indeed, as with any drug, early phase clinical trials have focused on achieving an acceptable balance between therapeutic dosing and side effects. One argument against the broader acceptance of the cannabinoids as therapeutic agents has been the inability to achieve a satisfactory trade-off, particularly with respect to CNS effects and in particular, the ability to stimulate disphoria, hallucinations and depersonalisation in susceptible individuals.
The safety of cannabis has been described as remarkable. There is no known case of lethal overdose and in animal models, the ratio of lethal to ‘effective’ dose has been estimated to be 20,000–40,000 to 1 (compared to 4–10 to 1 for alcohol).
See text for side effects noted when cannabinoids were administered by the ophthalmic route.
The results of laboratory tests on the blood of patients treated with cannabinoids have been performed rarely. Available results indicate that changes are inconsistent and rarely serious.
Drug Interactions With Cannabinoids
Most clinical trials have administered cannabinoids alone to treat a particular disorder rather than in combination with other drugs. There appear have been no adverse interactions of any consequence between a wide range of cancer chemotherapies, when cannabinoids have been given to counteract the nausea and vomiting associated with the latter or indeed during specific studies in man. The beneficial effects of administering THC with another antiemetic, prochlorperazine, have been referred to above. Considering the central nervous system depressant action of these agents, it would be wise to be cautious when administering them with other, CNS depressants, such as benzodiazepines, barbiturates, antidepressants and alcohol. The interaction between marijuana smoking and the enhanced metabolism of theophylline has been well-documented. The ability of cannabinoids to produce significant hypotension, particularly postural hypotension, should be remembered if the patient is receiving antihypertensive medication.
The potential for more spectacular drug interactions to occur seems greatest when cannabinoids are consumed for pleasure, often in high doses and frequently as a cocktail with other psychoactive substances, over the counter medicines and alcohol. One would anticipate a much lower threat during the more controlled, measured use of these agents to treat a disease under medical supervision.
Polls and voter referenda have repeatedly indicated that the vast majority of Americans think cannabis should be medically available and recent surveys in the UK have also reflected this attitude.
In reviewing the potential for medicinal application of cannabis and its derivatives, one is hard-pressed to conclude that any of these related compounds would withstand rigorous, clinical trial and turn out to be effective alternatives to contemporary, established therapy. Two things are clear: cannabis is not the Dr Jekyll which some devotees would have us believe; neither is it without redemption and the Mr Hyde others assume. Evaluation of clinical trial data, where it exists, is made problematic by differences in material used (e.g.: cannabis or THC), the route of administration (inhaled smoke, oral or parenteral), dosage regimen and the study populations.
Therapeutic research with cannabis in the fields of depression, anxiety and insomnia has ceased. There is objective evidence that in several disorders, such as nausea and vomiting associated with cancer chemotherapy, glaucoma, pain relief and relief of muscle spasm, adjunctive use will provide benefit in some patients at certain stages of their disease. In some cases, e.g.: cancer, multiple sclerosis, AIDS, the nature of the illness is such that to deny access to this potentially valuable drug without first obtaining the necessary proof of efficacy from conventional clinical trials, seems unreasonably pedantic. There is considerable evidence that selected patients would and should obtain relief from the symptoms of their disease using cannabis or derivatives thereof, when no other substance will suffice. Reasons for this may be that conventional therapy is contraindicated in terms of route, dose, side effect profile or hypersensitivity or that the cannabinoid in question has a mechanism of action which makes it uniquely effective.
The potential for cannabis and its constituents to be used as medicines is still, largely unrealised. Modern investigation of cannabis spans less than a few decades and this seems hardly sufficient time to settle the issue. Pharmacologically, crude cannabis, as opposed to THC or other specific cannabinoids is a dirty drug and has little future as a therapeutic agent for any illness. It contains many substances with multiple, sometimes antagonising, effects and unknown modes of action. It should be remembered that some of the studies mentioned in this review are no more than initial explorations of serendipitous hunches (e.g., asthma and glaucoma) and they should not be interpreted as proven therapeutic uses of cannabis. They are reflective of Phase One or early Phase Two developmental trials which address issues such as dose ranging to achieve an effect without disturbing side effects. The results of Phase 3 — type, double blind, placebocontrolled studies against accepted therapies in the disease concerned, must be generated before any firm (evidence based) conclusions can be drawn. Further information is also required on the pharmacokinetics of the cannabinoids when administered by different routes and in the presence of comorbid pathology, for example kidney disease and their potential for disturbing other biochemical and physiological processes.
As a therapeutic agent, THC itself has problems because of its central activity and disadvantages of poor water solubility, long half-life and molecular instability. It will be clear from Section 2 that several THC analogues are at an advanced stage of investigation with regard to their therapeutic potential. Much research has been directed at divorcing CNS activity, which is largely non-beneficial, from the peripheral, beneficial, effects. For example, derivatives of THC having a C-5 hydroxy moiety in the cannabinoid structure have no central activity while having potent activity against a range of enzymes such as lipooxygenase or cyclooxygenase, in the periphery. Such compounds may prove useful in asthma and other inflammatory disorders and may make useful analgesics. Analogues of CBD, which is not active centrally also hold promise in this area.
The recent discovery and cloning of THC receptors from rat brain may prove helpful in designing cannabinoid derivatives which interact with these to elicit specific, therapeutic responses. Cannabinoids are able to modulate a range of systems — dopaminergic, GABAergic, serotonergic and cholinergic; but now that a specific receptor has been defined, the search is on for receptor sub-types, the existence of which is suggested by this diversity of pharmacological activity. Most recently, a peripheral cannabinoid receptor has been identified, with distinct structural differences from brain THC receptors. If endogenous substances which act at this site can be identified, it should be possible to define structural features which could help in synthetic cannabinoid design.
If single cannabinoid analogues find their way into routine medical practice, it must be after rigorous proof of relative safety and efficacy and then will probably be in a modest role, providing symptomatic rather than curative relief, as adjuncts to conventional therapy or used as a last resort where such treatment has failed; unless new and specific indications emerge. Although cannabinoids do fill a gap in helping a small minority of refractory patients, for the majority, effective therapies with fewer side effects already exist.
The current legislative climate is slowing both private and publicly funded research aimed at providing useful, synthetic cannabinoid derivatives and has in the past caused it to cease altogether. Pharmaceutical companies fear that even if a useful compound were discovered, it would inherit the unsavoury background of cannabis with the possibility of having prohibitive prescribing restrictions enforced upon it, which would at the very least pose marketing problems. This situation might be eased if regulating bodies were to review individual cannabinoid derivatives on the basis of their pharmacological profiles and not legislate solely on the political profile of the class.
The possibility that cannabis may be used as a medicine raises moral, ethical, and political issues in addition to scientific ones. Advocates of cannabis may seek respectability for general use by having it approved as a medicine; however, it is difficult to fathom how this approval would make non-medicinal use acceptable as the methods of use are so different. Therapeutic use would be low-dose and closely controlled by prescription-only status; in addition, the availability of the oral route avoids the problems associated with smoking. Whereas recreational use would be associated largely with the latter in an uncontrolled (in terms of dose, setting and combination with other drugs of abuse) and hedonistic way.
One only has to browse the Internet to see that cannabis still arouses considerable international interest. At least 23 international symposia covering a wide range of scientific aspects have been organised in the last 27 years and interest shows no sign of abating. Our increasing understanding of this fascinating phytopharmaceutical may yield a few therapeutic surprises yet.
Selections from the book: “Cannabis. The Genus Cannabis”. Edited by David T.Brown. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 1998.