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BIOMEDICAL BENEFITS OF CANNABINOIDS?

Title: Biomedical benefits of cannabinoids?
Subject(s): CANNABIS -- Therapeutic use; CANNABINOIDS
Source: Addiction Biology, Apr99, Vol. 4 Issue 2, p111, 16p, 1 diagram, 1 graph
Author(s): Ashton, C. H.
Abstract: Reviews the clinical trials which have been carried out with cannabinoids including tetrahydrocannabinol (THL) and synthetic cannabinoids. Advantages and adverse effects of cannabinoids in clinical use; Medicinal uses of cannabis and cannabinoids; Double-blind clinical studies of cannabis or cannabinoids involving ten patients.

ISSN: 1355-6215


BIOMEDICAL BENEFITS OF CANNABINOIDS?

Abstract

Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential uses in epilepsy, glaucoma and asthma. Scientific evidence for any of these indications, except for antiemetic effects, is extremely sparse and claims for clinical utility are largely based on anecdotal reports. Furthermore, the mechanisms of action of any of the therapeutic effects are unknown. This paper reviews the clinical trials which have been carried out with cannabinoids including Delta[sup 9]-tetrahydrocannabinol (THC) and synthetic cannabinoids such as nabilone and levonantradol, and discusses the advantages and adverse effects of cannabinoids in clinical use. The place of cannabinoids in modern medicine remains to be properly evaluated, but present evidence suggests that they could be valuable, particularly as adjuvants, for symptom control in a range of conditions for which standard drugs are not fully satisfactory.

Historical background

Cannabis has been used medicinally for thousands of years. It was known to the Sumerians, Assyrians, Chinese and Indians as far back as the second millennium BC and recommended for many ailments including malaria, constipation, rheumatic pains and female disorders.(n1-n3) The drug entered mainstream western medicine following the advocacy of O'Shaugnessy,(n4) who had observed its use in India and was impressed by its muscle relaxant, anticonvulsant, analgesic and antiemetic properties. It was widely prescribed in the 19th century but its popularity waned as more reliable drugs became available. However, cannabis could be prescribed (as a tincture) in the United Kingdom until 1971 when it was classified under Schedule 1 of the Misuse of Drugs Act as having no therapeutic benefit. The synthetic cannabinoids nabilone in the United Kingdom, and dronabinol in the United States, remained licensed for the specific indication of vomiting due to chemotherapy.

Interest in the biomedical benefits of cannabis has been renewed recently following anecdotal reports of efficacy in a wide variety of disorders from multiple sclerosis to glaucoma.(n3) These reports, backed by an extremely limited amount of scientific evidence (see Table 1), have led to recommendations that clinical research should be implemented on the therapeutic uses of cannabinoids. A Clinical Cannabinoid Group has been set up to develop guidelines for such research.(n5)

This review is based on a Medline search of all papers on the pharmacology, clinical and therapeutic effects of cannabis and cannabinoids 1980-98, supplemented by comprehensive books and compendia and standard books and papers from the older literature. Relevant books and papers were hand-searched for additional references. Further information was supplied from the Department of Health, particularly a report on therapeutic aspects of cannabinoids by Dr P. Robson(n6) and from colleagues. The search was originally conducted for reports commissioned by the Department of Health(n7)and the British Medical Association,(n5) but has been updated. The papers quoted in the present review were selected from a very large bibliography as having direct clinical relevance. The review is not claimed to be comprehensive: it is largely confined to papers in the English language and where possible to clinical rather than preclinical or animal studies. Nevertheless, it is hoped that a balanced overall picture of the area is provided.

Pharmacology

The medicinal properties of cannabis are due to its content of cannabinoids, which are unique to the plant species Cannabis sativa. Over 60 cannabinoids, chemically aryl-substituted meroterpenes,(n8) have been identified. The pharmacology of most of these is unknown but the most potent psychoactive agent is Delta[sup9]-tetrahydrocannabinol (THC). Some plant cannabinoids are shown in Fig. 1. Not all are psychoactive but some have additive, synergistic or inhibitory interactions with THC. In addition, several synthetic cannabinoids are available for medical use and research purposes (Table 2).

Cannabinoids interact with specific cannabinoid receptors in the body.
Two types have been identified: CB[sub 1] receptors in the brain and peripheral nerves(n9, n10) and CB[sub 2] receptors in macrophages in the spleen and immune cells in other tissues.(n11) Both CB[sub 1] and

CB[sub 2] receptors belong to the class of G-protein coupled receptors which act on second messenger systems affecting cyclic AMP formation and Ca[sup ++] and K[sup +] ion transport.(n12) Natural ligands for these receptors appear to be a family of anandamides (named after the Sanskrit word for bliss, ananda).(n13) Anandamides are arachidonyl acid derivatives related to prostaglandins. The normal physiological functions of the cannabinoid/anandamide system are not known but may include modulating effects on mood, memory and cognition, sensory perception and pain, sleep, appetite, temperature control and immune responses. Pharmacological, physiological and clinical implications are reviewed by Pertwee.(n14)

Medicinal uses

Medicinal uses of cannabis and cannabinoids have recently been reviewed by the British Medical Association(n5) and by several other authors.(n6, n15-n17) Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential use in epilepsy, glaucoma and asthma. However, for most of these indications (apart from antiemetic effects) the scientific evidence is extremely sparse; there have been few if any large scale controlled trials and claims for clinical utility are based largely on anecdotal reports. Clinical trials that have been undertaken are limited by small sample size, lack of statistical power, use of different cannabis or cannabinoid preparations and heterogeneous patient groups. Furthermore, the mechanisms of action of any of the medicinal effects are not understood.

Cannabinoids as anti-emetics

Nausea and vomiting caused by antineoplastic chemotherapy "is at best

miserable and at worst so disabling and demoralising as to lead to refusal of treatment".(n18) With some agents (including mustine, dacarbazine, cisplatin, cyclophosphamide, doxorubicin and high dose methotrexate) these symptoms are so common that anti-emetic drugs are routinely given before and after treatment, often with the addition of dexamethasone and lorazepam. Standard anti-emetic treatment has been with dopamine receptor antagonists such as phenothiazines, metoclopramide and domperidone. These drugs are moderately although not completely effective and may produce dystonic reactions and other adverse effects. Selective serotonin 5-HT[sub 3] receptor antagonists have been introduced relatively recently but are expensive, may have to be administered intravenously, and can cause constipation, headache, hypersensitivity reactions, altered liver function and dysrthythmias.(n19)

The anti-emetic efficacy of the synthetic cannabinoids nabilone and THC (as the synthetic dronabinol) was investigated extensively, mostly in the 1980s, in patients receiving a variety of cytotoxic drugs (see references(n5,n17,n20-n23) for reviews). The evidence from a large number of controlled trials is that oral nabilone (2mg 6-12-hourly) and THC (5-15mg/m[sup 2]t.d.s. or q.d.s.) can be effective and are superior to placebo.(n24-n27) Most studies indicate that they are more effective than dopamine receptor antagonists;(n18, n28-n38) some report equal effectiveness,(n24, n39-n41) while a few have found THC to be less effective than standard drugs or placebo,(n42) especially for patients on doxorubicin or cyclophosphamide(n43) or cisplatin.(n44)

Another synthetic cannabinoid which has been tested as an anti-emetic is levonantradol.(n45, n46) This agent appeared to have similar efficacy to phenothiazines but produced an unacceptably high incidence of somnolence and dysphoria. However, Delta[sup 8]-THC looks promising. This cannabinoid, which is easier and cheaper to synthesize than Delta[sup 9]-THC, was found to be completely effective in preventing vomiting due to antineoplastic therapy in eight children.(n47) It produced minimal adverse effects and was superior to metoclopramide. Further trials are proceeding. Combinations of THC or nabilone with prochlorperazine were found to improve anti-emetic effectiveness while reducing adverse effects.(n42, n48, 49) Finally, a few investigators(n27, n50, n51) and a number of anecdotal reports(n3) have found smoked cannabis to be more effective than oral THC, possibly because of better absorption.

Adverse effects are frequent with both nabilone and THC although they are not usually severe or dangerous. The most common unwanted effect is sedation which occurs in over 50% of patients. Other common effects are dry mouth, ataxia, confusion, difficulties in concentration and dysphoria. An incidence of "intolerable" dysphoria of about 10% is reported for nabilone, possibly slightly lower for THC and higher for levonantradol.(n22) A few patients report euphoria or depersonalization and hallucinations and psychotic reactions occur rarely. Systemic effects include postural hypotension and tachycardia. Although such reactions may cause discontinuation in a minority, patients often prefer cannabinoids to standard anti-emetic drugs.(n29)

Although cannabinoids have proven effectiveness as anti-emetics for vomiting cause by cytotoxic agents in patients (including children) with a variety of cancers, there remain areas which need further investigation. First, there have been no comparisons between cannabinoids and the specific 5-HT[sub 3] antagonists (ondansetron, granisetron, tropisetron). Secondly, optimal dosages, schedules of administration and effectiveness against different cytotoxic agents have not been established. Thirdly, the use of drug combinations has not been explored. It is possible that the addition of cannabinoids as adjuvants to other anti-emetics could add to efficacy while allowing the use of lower doses and minimizing adverse effects. Careful preparation and explanation may also help to limit dysphoric reactions; patients receiving cytotoxic therapy are ill, often elderly, and unprepared for the psychological effects of cannabinoids. Fourthly, trials with other cannabinoids, such as Delta[sup 8]STHC are indicated. Finally, cannabinoids could be investigated in other types of nausea and vomiting such as that due to opioids in pain conditions and patients with AIDS.

Cannabinoids in spastic disorders

Many of the most distressing symptoms associated with spastic disorders such as multiple sclerosis, spinal cord injury and cerebral palsy are not well controlled with existing drugs. Such symptoms include recurrent painful muscle spasms, various combinations of weakness, tremor, dystonia and ataxia, acute and chronic pain syndromes and impaired bladder and bowel control. Muscle relaxants, analgesics and cholinergic or anticholinergic agents often give only partial relief or unacceptable side effects. Furthermore, many patients do not receive specialized treatment or adequate trials of various drug combinations. Anecdotally,(n49-n58) cannabis relieves many of these intractable symptoms and it is perhaps not surprising that the commonest neurological causes of taking illicit cannabis are multiple sclerosis and spinal cord injury.(n59, n60)

Despite its reputation among patients, there are only five published reports of double or single blind placebo controlled studies of cannabis or cannabinoids in multiple sclerosis, involving a total of only 41 patients world-wide. Petro & Ellenberger(n61) gave single oral doses of 5 or 10 mg THC to nine patients and noted a significant reduction in objectively rated spasticity scores compared with placebo. Clifford(n62) studied eight patients who received 5-15mg THC orally 6 hourly for up to 18 hours. Five patients showed mild subjective but not objective improvement in tremor and well-being after THC and two showed subjective and objective improvement in tremor but not ataxia or other symptoms. Ungerleider et al.(n63) gave 13 patients (who had proved refractory to baclofen, dantrolene and diazepam) oral THC 2.5-15mg daily or b.d. for 5 days and found significant subjective improvement overall in spasticity at doses of 7.5mg THC or greater, compared with placebo, but some patients got worse. There was no change in objective measures of weakness, spasticity, coordination, gait or reflexes. Martyn et al.(n64) studied a single patient who received oral nabilone (1 mg on alternate days) or placebo for two periods of 4 weeks each. The patient noted improvement in general wellbeing, muscle spasms and frequency of nocturia during the periods on nabilone (Fig. 2). Less encouraging results were reported by Greenberg et al.,(n65) who observed the effects of smoking cannabis in a cigarette containing 1.54% THC in 10 patients with multiple sclerosis and 10 normal subjects. Cannabis impaired posture and balance in all subjects, causing greater impairment in the patients, although some reported subjective improvement.

Patients with spasticity due to spinal cord injuries or cerebral palsy often have painful muscle cramps and impaired bladder control. There appear to have been no controlled trials of cannabis or cannabinoids in these disorders, but a few questionnaire surveys(n66, n67) suggest that cannabis may be helpful for some but not all patients. Dunn & Davies(n66) questioned 10 patients with spinal cord injury, of whom five noted that cannabis improved spasticity but three reported worsening of bladder symptoms. Twenty-one of 24 patients who replied to a questionnaire sent to 48 patients reported that cannabis decreased spasticity.(n67) Isolated case reports record that cannabis relieved pain and muscle spasms in two patients with spinal cord injury(n68) and that oral THC (5 mg) had a beneficial effect on pain and spasticity in one.(n69)

With regard to movement disorders, cannabis appeared to be of no benefit to patients with Parkinson's disease(n70) or parkinsonism co-existing with dystonia in whom tremor and hypokinaesia were aggravated.(n71) Oral cannabidiol (100-600 mg daily for 6 weeks) improved dystonia in five patients with various dystonias(n72) but had no effect in 15 patients with Huntington's disease.(n73)

Patients who take cannabis illicitly and report beneficial effects are clearly a self-selected group. The results of controlled studies, few though they are, are equivocal. Some patients appear to benefit but in others there is no effect and some symptoms, such as ataxia and muscle weakness, may be worsened. Ungerleider et al.(n63) reported a high incidence of adverse reactions to THC at doses that were adequate to relieve spasticity, affecting all but one patient at the 7.5 mg dose.

Side effects consisted of weakness, dry mouth, dysphoria, mental clouding and other psychological effects. Clifford(n62) and Greenberg et al.(n65) also reported psychological effects, including a "high" or dysphoria in patients with multiple sclerosis receiving cannabinoids.

Nevertheless, the available evidence indicates a need for further investigations into the value of cannabinoids (nabilone, THC and perhaps more selective synthetic cannabinoids(n59) in spastic disorders, particularly as present drugs are often unsatisfactory. Cannabinoids seem most promising for muscle spasms and possibly tremor and bladder control, and they may find a place as adjuvant drugs in selected patients. Large controlled trials with carefully recruited patients and accurate subjective and objective measurements of efficacy are required. Treatment would need to be long-term and a further problem which requires study in chronic illness is the development of tolerance to cannabinoids.

Cannabinoids in pain conditions

Pain, particularly neuropathic pain, is often poorly controlled by available analgesics, antiinflammatory agents, anticonvulsants or antidepressants and the use of these drugs is sometimes limited by adverse effects. New drugs with analgesic efficacy and minimal toxicity are needed, and some claims have been made for cannabinoids in this context. In animal models many cannabinoids have anti-inflammatory and analgesic properties which appear to be mediated by non-opioid mechanisms.(n59, n73) There is some anecdotal evidence that cannabis alleviates various types of pain in man(n3) but very few controlled trials.

Noyes et al.(n74, n75) carried out two double-blind placebo-controlled trials in patients with cancer pain. In the first,(n69) 10 patients received oral THC in a range of doses. Significant pain relief compared with placebo was obtained with doses of 15 mg and 20 mg THC; the analgesic effect peaked at 3 hours and lasted over 6 hours. In the second study(n75) the effect of oral THC (10 mg and 20mg) was compared with oral codeine 60mg and 120 mg. THC 20 mg and codeine 120 mg gave significant and equivalent pain relief. In a single patient with spinal cord injury 5 mg THC and codeine 50mg similarly gave equal pain relief.(n69) In a controlled study of postoperative or trauma pain in 56 patients, levonantradol given intramuscularly provided significant pain relief lasting over 6 hours after doses of 2.5mg or 3mg(n71) A few reports have described relief of phantom limb pain after cannabis.(n65, n77)

In contrast, no significant analgesic effect was found with intravenous THC in 10 patients undergoing dental surgery(n78) and oral cannabidiol provided no pain relief in 10 patients with chronic neuropathic pain.(n79) Marked sedation was a common side effect of cannabinoids in all the pain studies but other psychological effects were minimal.

Cannabinoids thus appear to have a potential for pain relief with a potency similar to that of codeine. Further research is needed, but they may prove to be helpful, probably as adjuvant drugs, in chronic and terminal pain and for various neuropathic pains, such as phantom limb pain, not well-controlled by standard analgesics. It is permissible at present to prescribe nabilone and THC for intractable pain.

Cannabinoids as appetite stimulants

Acute doses of cannabis stimulate appetite, although with chronic use the effect disappears.(n80) The anti-emetic effects may allow eating and prevent weight loss in patients undergoing cancer chemotherapy and these effects combined with appetite stimulation may benefit patients with AIDS-related diseases, many of whom are receiving antiviral drugs or have other illnesses which cause anorexia, nausea and vomiting. An open study of 10 patients with AIDS-related disease receiving antiviral therapy found that THC given daily over 5 months arrested the progressive weight loss observed in these patients prior to treatment.(n49) In a placebo-controlled study of 72 patients with advanced AIDS-related illnesses THC was found to reduce nausea, increase appetite, prevent further weight loss and improve mood compared to placebo.(n81) Following this study the American Food and Drug Administration approved the use of THC (dronabinol) for anorexia associated with AIDS. A question needing further investigation is whether immunosuppressive effects of cannabinoids may be damaging in individuals with immune systems already damaged by HIV or chemotherapy.(n82) THC was found to be ineffective in increasing appetite or weight gain in anorexia nervosa.(n83)

Cannabinoids in epilepsy

Existing anticonvulsant drugs fail to provide total protection from fits in a third of epileptic patients and all have adverse effects which can be severe. Animal work shows that cannabinoids have complex actions on seizure activity and that they can exert both convulsant and anticonvulsant effects (see references(n59, n84) for reviews). Cannabidiol appears to hold promise in human epilepsy since it has an anticonvulsant spectrum different from standard drugs. It is virtually devoid of psychoactivity since it does not react with cannabinoid receptors.(n85)

There have been three controlled trials of cannabidiol in epileptic patients. Cunha et al.(n86) found that cannabidiol (200-300 mg/day orally), when added to standard therapy, improved epileptic control in seven of eight patients while only one of seven patients improved on placebo. No psychotropic or neurological effects were noted in 16 healthy volunteers who also took cannabidiol. However, Ames & Cridland(n87) and Trembly & Sherman(n88) found no effect of this dose of cannabidiol on seizure frequency in a total of 22 epileptic patients poorly controlled on standard drugs. Added to these equivocal results are occasional case reports suggesting favourable effects of smoking cannabis in generalized or complex partial seizures.(n3, n89-n91) Although the information is sparse, further trials of cannabidiol as an add-on drug in poorly controlled epilepsy, which is often severely disabling, would seem to be merited.

Cannabinoids in glaucoma

Glaucoma is the commonest cause of blindness in the western world and many cases are associated with raised intraocular pressure for which treatment with miotics, adrenergic agents, beta-blockers or carbonic anhydrase inhibitors is not always satisfactory. Several investigations have shown that oral or smoked cannabis or THC, THC eye drops and some other psychoactive cannabinoids (but not the non-psychoactive cannabidiol) can reduce intraocular pressure in normal human subjects.(n92-n96) However, there is scanty information on the effects of cannabinoids in patients with glaucoma. Only two double-blind trials have been reported, both short-term. Merritt et al.(n97) studied 18 patients with glaucoma who received THC (2%) by smoking. There was a significant fall in intraocular pressure but the side effects of hypotension, palpitations and psychotropic effects occurred with such frequency as to rule out routine use with this form of administration. In a later study,(n98) eight patients with glaucoma and vascular hypertension received THC in eye drops to one eye only. There was a decrease in intraocular pressure in both eyes, suggesting that the effect was due to systemic absorption. In an open study of smoked or oral THC, seven of 11 patients with glaucoma responded with a significant drop in intraocular pressure.(n93) Remaining anecdotal reports include two patients with glaucoma who obtained symptomatic relief and lowering of intraocular pressure from smoked or orally ingested cannabis after standard pharmacotherapy had failed.(n3)

Although the evidence shows that cannabinoids can lower intraocular pressure in some patients with glaucoma, there are disadvantages to such use. First, tolerance develops within days in normal subjects and cessation of use is accompanied by a rebound in intraocular pressure to above baseline levels.(n96, n99) Secondly, although topical administration is desirable, it is difficult to prepare suitable preparations of cannabinoids since they are extremely lipid soluble and water insoluble. Topical administration of 1% THC in mineral oil had no significant effect on intraocular pressure in normal subjects.(n100, n101) The available evidence indicates that the effect of cannabinoids on intraocular pressure in man is due to systemic actions.(n102) Thirdly, all the cannabinoids which have been shown to lower intraocular pressure in man have psychoactive and cardiovascular effects. Finally, cannabinoids themselves may produce undesirable ocular effects in man, including photophobia, conjunctival hyperaemia, decreased lacrimation, corneal ulceration, conjunctivitis, keratitis and changes in pupil size.(n102) Thus, the utility of cannabinoids in glaucoma is doubtful at present,(n103) although some synthetic and semisynthetic cannabinoids have been promising in preclinical studies.(n102, n104)

Cannabinoids in asthma

Acute doses of cannabis exert a bronchodilator action on the small airways(n105) by a mechanism that appears to be different from that of betaadrenoceptor agonists and other bronchodilators used at present for asthma.(n106) Concern over risks of long-term use of potent betaadrenoceptor stimulants has renewed interest in earlier studies,(n107, n110) suggesting a possible benefit of cannabinoids in asthma. Such studies have been limited to acute administration in a small number of asthmatic patients and a few normal volunteers.

Tashkin et al.(n107) compared the effects of smoked cannabis containing 2% THC, oral THC (15mg) and inhaled isoprenaline (0.5%) in 14 asthmatic subjects. Both cannabis and THC produced bronchodilatation nearly equivalent to isoprenaline and smoked cannabis also reversed experimentally induced bronchoconstriction in three of the subjects. Similarly, smoked THC (0.9% and 1.9%) produced bronchodilatation lasting several hours in 17 asthmatic subjects (109), and an aerosol containing 200 Mu g THC produced equivalent bronchodilator effects to a salbutamol aerosol (100 Mu g) in 10 asthmatic subjects.(n110) In all these studies, effective doses of cannabinoids produced adverse effects including psychological disturbances and tachycardia. Furthermore, Tashkin et al.(n108) found that a THC aerosol caused moderate to severe bronchoconstriction, coughing and chest pain or discomfort in two of five asthmatics and three of 11 normal volunteers. These authors concluded that the irritant effect of THC on the airways make it unsuitable for therapeutic use.

Some studies reviewed by Graham(n106) and Archer et al.(n111) have shown that Delta[sup 8]-THC has bronchodilator actions with little cardiovascular or psychological effects and that cannabidiol can reduce the adverse effects of THC without affecting the bronchodilator action, although neither cannabidiol nor nabilone have bronchodilator effects.

Thus, the present status of cannabinoids in asthma is doubtful. In particular, a suitable form of administration needs to be developed, possibly a metered dose inhaler.(n106) There have been no studies of long-term use and it is not clear whether tolerance to the bronchodilator effect would develop. However, combinations of cannabinoids with standard bronchodilators may have a possible use in selected patients and there may be a potential for developing synthetic cannabinoids with selective bronchodilator effects.

Other potential uses

A possible use of cannabinoids as antihypertensire agents is suggested by the observation that they cause postural hypotension. However, tolerance to this effect develops rapidly and, since they would have to be used long-term, their hypotensive properties are unlikely to be of therapeutic value.(n112)

A variety of uses for the psychotropic effects of cannabinoids have also been suggested. For example, controlled studies have shown anxiolytic effects with nabilone,(n113, n114) hypnotic actions with cannabidiol,(n115) and antidepressant effects of THC in cancer patients,(n116) although there have been no formal comparisons with standard drugs. A role in opioid withdrawal has also been suggested since animal work and a few anecdotal reports in man suggest that cannabiholds can inhibit some opioid withdrawal effects by a non-opioid mechanism.(n117)

The development of novel synthetic opioids may yet open new vistas: one such compound, (+)-HU-210, is an antagonist of NMDA (N-methyl-D-aspartate) receptors and may protect against excitotoxic effects in strokes, head injuries and neurodegenerative disorders.(n59)

Advantages and disadvantages of clinical use of cannabinoids

The major advantage of cannabinoids is that they are extremely non-toxic: no deaths have resulted from their use and their side-effects profile compares favourably with that of many drugs used for conditions in which cannabinoids have a therapeutic potential. However, for all their promise, there may be limitations to the clinical use of cannabinoids.

Sedation

The most common adverse effect in clinical trials of cannabinoids is sedation (incidence 50-100%) with drowsiness, confusion, poor memory and general cognitive and psychomotor impairment. These effects may be of importance if cannabiholds are used long-term for chronic conditions and have implications for activities such as car driving and operating machinery, especially since they are additive with other sedative drugs.(n118) Furthermore, elimination of cannabinoids is extremely slow; they are concentrated in body fat and complete elimination of a single dose may take up to 30 days.(n119) Clearly, repeated dosage results in accumulation and effects on cognitive and psychomotor performance may be long-lasting.(n82)

Psychological effects

The second most common effects in clinical trials are psychological, including euphoria, dysphoria, anxiety, depersonalization, hallucinations, paranoia and depression. Certain individuals may be particularly sensitive to these effects, and cannabis can aggravate psychosis in patients with schizophrenia, lead to loss of control with anti-psychotic drugs and possibly precipitate schizophrenia in vulnerable subjects.(n120, n121)

Physical effects

Also common are physical side-effects of cannabinoids. These include dry mouth, ataxia (incidence over 50%), general inco-ordination, muscle weakness and tremor. Tachycardia and hypotension may make cannabinoids unsuitable for patients with cardiovascular disease. Endocrine effects may preclude their use in children and in pregnancy, and immunosuppressant effects may be of importance in immunocompromised individuals.(n105, n117)

Tolerance, dependence, withdrawal effects

Tolerance develops rapidly, although incompletely and unevenly, to many of the effects of cannabis including those on mood, heart rate, blood pressure, intraocular pressure and psychomotor performance.(n99)

Such tolerance may be an advantage in overcoming unwanted effects but a disadvantage if it develops to therapeutic effects. In recreational settings cannabis can cause dependence and an abstinence syndrome on withdrawal. However, by analogy with opioids used in pain relief(n122) abuse or addiction are unlikely to become problems with prescribed dosage of cannabinoids in therapeutic settings. Nevertheless, precautions may be necessary to prevent prescribed cannabinoids being subverted like benzodiazepines, other hypnotics and amphetamines) into illicit "street" use.

Withdrawal effects may be clinically undesirable. These can include psychological effects (anxiety, insomnia) and also physical effects such as a rebound rise in intraocular pressure to above baseline levels, nausea, diarrhoea and other physical symptoms.(n99) For this reason it would be advisable to taper dosage gradually on discontinuation after regular use of cannabinoids for more than a few weeks.

Modes of administration

Optimal modes of administration of cannabinoids have yet to be devised. Most clinical studies have involved the use of oral THC or nabilone, but absorption by this route is variable, slow and prolonged.(n119) Absorption of inhaled THC is rapid and almost complete but suitable aerosols of cannabinoids are not generally available. Individuals who have self-administered cannabis for medical purposes often claim that smoked herbal cannabis gives the best results, taking effect within minutes and allowing them to judge the dosage required for symptom control.(n3) However, this method cannot be recommended for long-term use since the smoke from herbal cannabis contains the same harmful constituents as tobacco smoke (apart from nicotine) and exposure to bronchial irritants, carcinogens and carbon monoxide is greater than from a tobacco cigarette.(n123, n124) Furthermore, even in herbal preparations standardized for THC content, concentrations of other cannabinoids may be variable. Rectal administration allows rapid and efficient absorption(n125) but may not be acceptable to many patients. Eye drops, buccal preparations and skin patches still require development. Finally, optimal dosage regimens, cannabinoid combinations and co-administration with standard drugs require further research.

Drug accumulation

After systemic absorption, the elimination of cannabinoids is extremely slow. The plasma elimination half-life of THC is about 56 hours in occasional cannabis users and about 28 hours in chronic users because of an increased rate of metabolism.(n126) However, because cannabinoids are highly fat soluble they are sequestered in fatty tissues, from which they are only slowly released. Thus the tissue half-life of THC is about 7 days while complete elimination of a single dose may take up to 30 days.(n119) Because of the sequestration in fat, high concentrations of cannabinoids can accumulate with repeated or chronic use and continue to reach the brain (which has a high lipid content), possibly exerting long-lasting effects. Accumulation of cannabinoids might theoretically be a problem if they are used daily for chronic conditions such as multiple sclerosis, but there have been no studies on the effects of long-term regular clinical use of cannabinoids.

Cannabinoids are metabolized in the liver. A major pharmacologically active metabolite is 11-hydroxy-THC; more than 20 other metabolites are known, some of which may be psychoactive. 11-Hydroxy-THC and many of the other metabolites have plasma elimination half-lives of the order of 50 hours. Further metabolism produces inactive metabolites, of which 15-30% are excreted in the urine. Both active and inactive metabolites are also excreted into the intestine and bile and about 15% of them are reabsorbed, prolonging the actions of cannabis, while 35-65% are finally eliminated in the faeces.(n119)

Nabilone is more rapidly eliminated than THC.(n127) The plasma half-life of the parent compound is estimated to be approximately 2 hours. It is extensively metabolized and single oral dose studies in man using radioactively labelled nabilone showed that 84% of the dose was recovered in the faeces (60%) and urine (24%) after 7 days. Tissue accumulation of nabilone or its metabolites must clearly occur if the drug is given daily, but in clinical studies of patients taking oral nabilone 3 mg daily for 21-28 days, there was no evidence of drug-related cumulative toxicity. A dose of 1 mg nabilone on alternate days was sufficient to relieve symptoms in multiple sclerosis(n64) (Fig. 2)

Conclusions

The place of cannabinoids in modern medicine remains to be evaluated and the results of clinical and pharmaceutical research will be awaited with interest. Recommendations for such research have been suggested under each indication discussed in this review. It seems that cannabinoids are unlikely to constitute a cure for any illness, but on present evidence it is possible that they could be valuable for symptom control in a variety of conditions for which available drugs are not fully satisfactory. They are most likely to find a place as adjuvants to standard agents, and it is possible that the development of novel synthetic agents with more specific actions and fewer side-effects will extend their therapeutic range. Meanwhile, several authorities(n5, n6, n128) have argued for enhanced access to cannabinoids in clinical practice and the British Medical Association report(n5) concludes: "While research is underway, police, the courts and other prosecuting authorities should be aware of the medicinal reasons for the unlawful use of cannabis by those suffering from certain medical conditions for whom other drugs have proved ineffective."

Correspondence to: C.H. Ashton, Department of Psychiatry, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK, Tel: 0191 222 6000, ext. 6978, Fax: 0191 227 5108.

Received for publication 11th October 1998. Accepted 21st December 1998.

Table 1. Double-blind clinical studies of cannabis or cannabinoids involving 10 or more patients

Legend for Chart:

A - Subjects
C - Drug and dose
D - Results

A
B
C
D

Anti-emetic effects in patients on cancer chemotherapy (studies since 1985)

Lane et al.(n42)

62 patients on various cancer chemotherapy

THC (dronabinol) 10 mg qds

PCP 10 mg qds

Both drugs together

No nausea or vomiting: 51% for THC,

83% for PCP; PCP and THC combined

better than either alone

Niiranan & Mattson(n31)

24 patients on various cancer chemotherapy Nabilone 2 mg 6-hourly
PCP 15 mg 6-hourly
Nabilone significantly better than PCP
for nausea and vomiting, and preferred
by most patients though more side
effects

Niederle et al.(n32)
20 patients on cisplatin
Nabilone 2 mg 6-hourly
Alizapride 150g tds
Nabilone more effective than alizapride
though more side effects

Pomeroy et al.(n33)
38 patients on various cancer chemotherapy
Nabilone 1 mg 6-hourly
Domperidone 20 mg 6-hourly
Nabilone superior to domperidone

Dalzell et al.(n18)
23 children on various cancer chemotherapy
Nabilone 0.5-1 mg bd or tds.
Domperidone 5-15 mg tds.
Nabilone superior to domperidone
Two-thirds of children preferred
nabilone

Chan et al.(n34)
30 children on various cancer chemotherapy
Nabilone
PCP
Nabilone superior to PCP

Antispastic effects in multiple sclerosis (MS)

Ungerleider et al.(n63)
13 patients with MS
Oral THC 2.5-15 mg once or
twice daily for 5 days, or
placebo
Subjective improvement in spasticity at
doses of 7.5 mg or above, but no change
in objective measures of weakness,
spasticity, coordination, gait or reflexes.
Side effects in 12 patients on THC and
5 patients on placebo

Greenberg et al.(n65)
10 patients with MS
10 normal controls
Smoking cannabis (1.54%
THC)single dose; or placebo
Cannabis impaired posture and balance
in all subjects, causing greater
impairment in MS patients. No other
objective changes but subjective
improvement with cannabis in some
patients. "High" experienced with
cannabis

Analgesic effects

Noyes et al.(n74)
10 patients with cancer pain
Oral THC 5, 10, 15, 20 mg,
or placebo
Significant pain relief with 15 and 20 mg
THC compared to placebo. Sedation
common with THC

Noyes et al.(n75)
36 patients with cancer pain
Oral THC 10 and 20mg.
Oral codeine 60 and 120 mg,
or placebo
THC 20 mg and codeine 120 mg gave
equivalent and significant pain relief
compared to placebo. THC caused
sedation

Jain et al.(n76)
56 patients with postoperative pain
IM levonantradol 1.5-3 mg or
placebo
Significant pain relief with both doses of
levonantradol compared with placebo
Drowsiness common with levonantradol

Raft et al.(n78)
10 patients undergoing dental extractions
IV THC 0.22 mg/kg and
0.44 mg/kg
IV diazepam 0.157 mg/kg or
placebo
No analgesic effects of THC detected.
THC rated as least effective, diazepam
most effective

Effects in anorexia

Gross et al.(n83)
11 patients with anorexia nervosa
Oral THC 7.5-30 mg/day
Diazepam 3-15 mg/day for 2
weeks, or placebo
No significant difference in weight gain
between THC and diazepam. Dysphoria
with THC

Beal et al.(n81)
72 patients with AIDS-related illness
THC 2.5 mg bd or placebo
for 6 weeks
Significant reduction in nausea and
weight loss, increased appetite and
improved mood with THC compared to
placebo

Anticonvulsant effects

Cunha et al.(n86)
15 patients with poorly controlled
generalised epilepsy 16 healthy volunteers
Oral cannabidiol 200-300 mg/
day added to standard therapy
in patients
Oral cannabidiol 3 mg/kg/day
in controls, or placebo in both
groups.
Treatment for 4-5 months
Cannabidiol improved control in 7 of 8
patients; 1 of 7 patients improved on
placebo. Sedation in 4 patients on
cannabidiol.
No adverse effects in controls

Ames & Cridland(n87)
12 epileptic patients poorly controlled
on standard drugs
Oral cannabidiol 200-300 mg/
day for 4 weeks or placebo
No significant effect on seizure
frequency

Trembly & Sherman(n88)
10 patients with poorly controlled
epilepsy, mixed types
Oral cannabidiol 300 mg/day
added to standard drugs for 6
months or placebo
No effect on seizure pattern or
frequency

Effects on glaucoma

Merritt et al.(n97)
18 patients with glaucoma
Smoking THC 2%, or placebo
Reduction in intraocular pressure with
THC but palpitations, hypotension and
psychotropic effects

Bronchodilator effects in asthma

Tashkin et al.(n108)
14 asthmatic subjects
Smoked THC 2%, oral THC
15 mg, isoprenaline 0.5%, or
placebo.
Bronchodilation with THC nearly
equivalent to isoprenaline
Smoked THC reversed experimentally
induced bronchospasm in 3 patients

Vachon et al.(n109)
17 asthmatic subjects
Smoked THC 0.9% and 1.9%
(single-blind)
THC produced bronchodilation lasting
several hours, tachycardia at higher dose

Williams et al.(n110)
10 asthmatic subjects
THC 200 Mu g in metered dose
inhaler
Salbutamol aerosol 100 Mu g, or
placebo
THC and salbutamol improved
ventilation, equivalent at 1 hour

PCP = prochlorperazine.

Table 2. Properties of some natural and synthetic cannabinoids

Legend for Chart:

A - Plant cannabinoids

A
B

Delta[sup 9]-tetrahydrocannabinol (Delta[sup 9]-THC)
(available in synthetic form as dronabinol)
Main psychoactive cannabinoid in Cannabis
sativa. Largely responsible for psychological
and physical effects

Delta[sup 8]-tetrahydrocannabinol (Delta[sup 8]-THC)
(available in synthetic form)
Slightly less potent than Delta[sup 9]-THC.
Appears to have fewer psychotropic effects

Cannabinol
Less potent than Delta[sup 9]-THC

Cannabidiol
Does not interact with cannabinoid receptors.
No psychotropic effects but may have anticonvulsant
and analgesic properties; may attenuate
psychotropic effects of Delta[sup 9]-THC

Endogenous cannabinoids

Anandamide (arachidonyl ethanolamide), one of a
family of similar endogenous cannabinoids
Interacts with cannabinoid receptors and mimics
actions of Delta[sup 9]-THC in animals. Has
not been tested in man

Synthetic cannabinoids

Nabilone
Similar properties to Delta[sup 9]-THC but
more potent. Higher incidence of dysphoria but
less euphoria and lower abuse potential

Levonantradol
Similar properties to Delta[sup 9]-THC but
more potent analgesic effects. High incidence
of dysphoria and sedation

DIAGRAMS: Figure 1. Chemical structure of main cannabinoids in
Cannabis sativa.

GRAPH: Figure 2. Symptoms while receiving nabilone or placebo in a
patient with multiple sclerosis (with permission form Martyn et
al.(n39)

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~~~~~~~~

By C. H. Ashton, Department of Psychiatry, University of Newcastle
upon Tyne, UK