Cannabis Research Publishing

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.

HISTORY OF THERAPEUTIC USE
The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic (Mechoulam, 1986). There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.

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.

CANNABINOID PHARMACOLOGY RELEVANT TO THERAPEUTICS
Cannabinol was isolated in 1895 and cannabidiol in 1934, but the most significant discovery was that of [DELTA]⁹-tetrahydrocannabinol (THC) in 1964. Chromatographic and spectroscopic methods subsequently uncovered many closely related compounds.

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.

CLINICAL APPLICATIONS
Nausea and vomiting
Many cytotoxic drugs are powerful emetics, and this is the major limiting factor in patients' acceptance of cancer chemotherapy (see Table 1 and Appendix).

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.

Multiple sclerosis and other neurological conditions
Drug therapy of muscle spasticity is generally only moderately effective and is limited by adverse effects (see Appendix). Spasticity is a central feature of multiple sclerosis (MS), cerebral palsy and spinal cord injury. Tremor, ataxia and incontinence also contribute to the high incidence of anxiety and depression in these conditions. Cannabis was often used to treat pain, muscle spasm, cramps and ataxia in the 19th century, and many modern sufferers have reported benefits (Grinspoon & Bakalar, 1993).

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.

Loss of appetite and weight in cancer and AIDS
Several studies have investigated effect on appetite and weight (Table 2). The appetite-stimulating effect of cannabis was confirmed in fasting and non-fasting volunteers in an RCT of oral THC with alcohol, amphetamine and placebo (Hollister, 1971). A standardised THC smoking regime over 25 days in a residential laboratory was associated with significant increases in calorie intake and frequency of eating occasions in comparison with placebo.

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.

Pain
Cannabinoids are effective analgesics in animal models with non-opiate mechanisms predominating. There are many anecdotal reports (Grinspoon & Bakalar, 1993) of benefits in bone and joint pain, migraine, cancer pain, menstrual cramps and labour.

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.

Insomnia, anxiety and depression
Randomised controlled trials investigating insomnia, anxiety and depression are given in 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).

Epilepsy
Epilepsy afflicts 1% of the world's population. Conventional anticonvulsants provide unsatisfactory control for up to 30% of patients, and all can produce disabling or even life-threatening adverse effects.

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.

Asthma
Small-scale controlled studies in volunteers with asthma show that oral, smoked and aerosolised THC has comparable bronchodilatory activity to salbutamol, although onset is quicker with the latter. Dose-related tachycardia occurred in some individuals, and subjective intoxication with higher doses. A THC aerosol was free of systemic unwanted effects, but was irritant to the lungs (Tashkin et al, 1977). Nabilone does not produce bronchodilation. Since THC-induced bronchodilation is not mediated through the sympathetic nervous system, synergistic combinations with [beta]₂-adrenoceptor stimulants might be possible.

Other possible therapeutic applications
Basic research indicates that THC and analogues inhibit opioid withdrawal (Chesher & Jackson, 1985). Anecdotal reports from patients also point to beneficial effects beyond those which could be accounted for by sedative or hypnotic activity. Cannabinoids inhibit primary tumour growth and increase survival in animal tumour models (Harris et al, 1976) by an unknown mechanism. They also show antipyretic and anti-inflammatory activity (Formukong et al, 1989). Mechoulam (1986) has drawn attention to the lack of modern research directed at possible antihelmintic, antimigraine and oxytocic applications.

DISCUSSION
Therapeutic profile on existing evidence
Tetrahydrocannabinol and nabilone are effective anti-emetics but there are no comparisons with 5-HT₃ antagonists, so a role in modern anti-emetic regimes remains to be determined. Currently, only nabilone is licensed in the UK and available for prescription and research. THC (as dronabinol) has recently been rescheduled to permit prescription but remains unlicensed and must be specially imported on a named-patient basis. Delta-8-THC looks worthy of further investigation, particularly in children, and is much simpler to synthesise than THC.

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).

The way forward
A Select Committee of the House of Lords recently examined the scientific information concerning medical cannabis and took verbal and written evidence from a wide range of witnesses. Their conclusion (House of Lords, 1998) published in November 1998, was that, although cannabis should remain a controlled drug, the law should be changed to allow doctors to prescribe "an appropriate preparation of cannabis if they saw fit". The government rejected this recommendation on the day of publication.

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.

CLINICAL IMPLICATIONS
* Cannabis and its derivatives show promise of beneficial effects in a number of medical conditions for which standard treatment is less than satisfactory, and further controlled research is fully justified.
* Cannabis is very safe in overdose, but often produces unwanted effects which are better tolerated by patients with some conditions (e.g. multiple sclerosis, chronic pain, AIDS, cancer) than others (e.g. glaucoma).
* Optimal for mutations, doses and routes of delivery have not yet been established.

LIMITATIONS
* Because of imposed time constraints, the review is not fully comprehensive, although all accessed sources were incorporated.
* Much of the evidence is anecdotal, and many of the research studies cited have serious methodological shortcomings.
* Few researchers (or reviewers) approach the subject of cannabinoid therapeutics in a spirit of dispassionate objectivity.

ACKNOWLEDGEMENT
This review was originally commissioned and funded by the Department of Health. The author thanks Dr Anthony Thorley for his support and encouragement. The views expressed in the paper are those of the author and not necessarily of the Department of Health.

APPENDIX
Existing anti-emetics
Phenothiazzines and butyrophenones can cause sedation, movement disorders which may be irreversible, neuroleptic malignant syndrome, dry mouth, blurred vision, urinary retention, hypotension, allergic reactions, jaundice, hypothermia, hormonal disturbances, irreversible eye damage and, rarely, life-threatening anaemias. Domperidone has a more benign profile but is not recommended for long-term use. Metoclopramide produces movement disorders (1% of patients), dizziness and drowsiness. Selective 5-HT₃ antagonists (ondansetron, granisetron) are newer and more expensive. Side-effects include constipation, headache, flushing, liver enzyme changes, allergic reactions, visual disturbances, chest pain and dysrhythmias.

Existing neurological treatments
Baclofen alleviates spasticity, but may accentuate muscle weakness. It produces dose-related nausea and vomiting, drowsiness, vertigo, confusion, fatigue and hypotonia. Less commonly, fits, psychiatric disorder and hypotension occur. Sudden withdrawal can cause hallucinations. Diazepam is useful but can worsen weakness or incoordination and cause drowsiness; ataxia, depression, disinhibition and dependence. Dantrolene may cause weakness, hypotonia, drowsiness, dizziness, vertigo and anxiety. Rarely, it damages the liver, and is not recommended in those with co-existing heart or lung disease.

Existing glaucoma treatments
Eye-drops. Miotics can produce blurring of vision, headache, and parasympathetic effects including sweating, bradycardia, colic and bronchospasm. Adrenaline often causes local discomfort. Dipivefrine and guanethicline may cause conjunctival fibrosis on chronic use. Beta-blockers may cause bradycardia, heart block or bronchoconstriction.

Systemic drugs (acctazolamide, dichlorphenamide) can cause hypokalaemia, appetite suppression, paraesthesiae, drowsiness, depression, rashes and, rarely, bone marrow suppression. [Context Link]

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Meek, C. (1994) Doctors want cannabis prescriptions allowed. BMA News Review, 15 February, p. 15. [Context Link]

Merritt, J. C., Crawford, W. J., Alexander, P. C., et al (1980) Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology, 87, 222-228.[Context Link]

Merritt, J. C., Olsen, J. L., Armstrong, J. R., et al (1981) Topical delta 9-tetrahydrocannabinol in hypertensive glaucomas. Journal of Pharmacy and Pharmacology, 33, 40-41.

Niederle, N., Shütte, J. & Schmidt, C. G. (1986) Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy. Klinische Wochenschrift, 64, 362-365.

Niiranen, A. & Mattson, K. (1985) A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. American Journal of Clinical Oncology, 8, 336-340.

Noyes, R. Jr, Brunk, S. F., Baram, D. A., et al (1975a) Analgesic effect of delta-9-tetrahydrocannabinol. Journal of Clinical Pharmacology, 15, 139-143.

Noyes, R. Jr, Brunk, S. F., Avery, D. A. H., et al (1975b) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clinical Pharmacology and Therapeutics, 18, 84-89.

Orr, L. E. & McKernan, J. G. (1981) Antiemetic effect of delta 9-tetrahydrocannabinol in chemotherapy-associated nausea and emesis as compared to placebo and compazine. Journal of Clinical Pharmacology, 21 (suppl. 8-9), 76S-80S.

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Perez-Reyes, M., Wagner, D., Wall, M. E., et al (1976) Intravenous administration of cannabinoids and intraocular pressure. In The Pharmacology of Marihuana (eds M. C. Braude & S. Szara), pp. 829 832. New York: Raven Press. [Context Link]

Pertwee, R. G. (1995) Pharmacological, physiological and clinical implications of the discovery of cannabinoid receptors: an overview. In Cannabinoid Receptors (ed. R. Pertwee), pp. 1-34. Harcourt Brace. [Context Link]

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Regelson, W., Butler, J. R., Schuiz, J., et al (1976) Delta-9-THC as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In The Pharmacology of Marihuana (eds M. C. Braude & S. Szara), pp. 763-775. New York: Raven Press. [Context Link]

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Margaret Haney et al, "Dronabinol and Marijuana in HIV-Positive Marijuana Smokers,
Caloric Intake, Mood, and Sleep," Journal of Acquired Immune Deficiency Syndromes 45, issue 5 (August 15, 2007): 545-554.

This clinical trial found that both smoked marijuana and the THC pill (Marinol, known generically as dronabinol) are effective at increasing caloric intake and weight among HIV-positive patients, with no effect on cognitive performance. Strikingly, however, it took eight times the standard dose of Marinol to approximate the effect of weak (3.9% THC) marijuana, and even at that dose, natural marijuana outperformed Marinol in some measurements.

The full study is available for free download here: http://journals.lww.com/jaids/Fulltext/2007/08150/Dronabinol_and_Marijuana_in_HIV_Positive_Marijuana.9.aspx?desktopMode=true

Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny

Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. [Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
J Clin Oncol 2006 Jul 20; 24(21):3394-400.

PURPOSE: To compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo (PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS).

PATIENTS AND METHODS: Adult patients with advanced cancer, CACS, weight loss (> or = 5% over 6 months), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2 were randomly assigned (2:2:1) to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally, twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analog scale (VAS); QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks.

RESULTS: Of 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100 patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age (mean, 61 years), sex (54% men), weight loss (32% > or = 10%), PS (13% ECOG = 2), antineoplastic treatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, or cannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patients receiving CE, THC, or PL, respectively. An independent data review board recommended termination of recruitment because of insufficient differences between study arms.

CONCLUSION: CE at the oral dose administered was well tolerated by these patients with CACS. No differences in patients' appetite or QOL were found either between CE, THC, and PL or between CE and THC at the dosages investigated.

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Patients with the severe lung disease COPD (chronic obstructive pulmonary disease) often suffer from appetite loss and cachexia (weight loss) resulting in reduced general well-being and early mortality. In an open clinical study THC improved appetite and well-being and resulted in weight gain.

18 COPD patients aged 49 to 81 years with a mean body weight of 48.5 kg were included in the study under the guidance of Dr. Karl-Christian Bergmann at the Clinic for Allergies and Asthma in Bad Lippspringe, Germany. In the six months before entering the clinic 7 participants had a constant body weight and 11 lost 2.3 kg on average.

They received 3.3-4.2 mg THC two times daily as oily drops delivered by THC Pharm, half an hour before breakfast and dinner. Mean treatment duration was 16 days resulting in a considerable improvement of appetite, general well-being and functional performance (36 per cent mean increase in walking distance) and an average gain in body weight of 1.5 kg, which is much regarding the short treatment period. Side effects were mild.

(Source: Lecture by K-C Bergmann on 17 March 2005 at the Meeting of the German Society of Pulmonology in Berlin)

ScienceDaily (Dec. 26, 2005) — Marijuana--or more specifically its active ingredient, tetrahydrocannabinol--has a well-documented tendency to stimulate hunger. And while scientists have traced this property to cannabinoid receptors in the brain, they have had little understanding of the neural circuitry underlying this effect

Understanding this circuitry has important practical implications because blocking the cannabinoid receptor, CB1, offers a promising approach to treating obesity. One such compound, rimonabant (trade name AcompliaTM) is already undergoing clinical testing.

In an article in the December 22, 2005, issue of Neuron, Young-Hwan Jo and colleagues report how the circuitry of CB1 is integrated with signaling by the appetite-suppressing hormone leptin. The CB1 receptor is normally triggered by natural regulatory molecules, called endocannabinoids.

In their studies, the researchers concentrated on the lateral hypothalamus (LH) of the brain, known to be a center of control of food intake. Their studies involved detailed electrophysiological measurements of the effects of specific neurons that they had identified in previous studies as being important in endocannabinoid signaling.

Their studies revealed that activation of CB1 receptors, as by endocannabinoid molecules, induced these neurons to be rendered more excitable by a mechanism called "depolarization-induced suppression of inhibition" (DSI).

What's more, they found that leptin inhibits DSI. However, they found that leptin did not interfere with the CB1 receptors themselves. Rather, leptin "short-circuits" the endocannabinoid effects by inhibiting pore-like channels in the neurons that regulate the flow of calcium into the neurons. Such calcium is necessary for the synthesis of endocannabinoids.

In further studies of mice genetically altered to be leptin deficient, the researchers found the DSI to be more prolonged than in normal mice. Thus, they said, the findings "implicate this mechanism for leptin receptor/endocannabinoid signaling in contributing to the maintenance of weight balance...." The researchers also included that "upregulation of endocannabinoid signaling in the LH may explain, at least in part, the increased body weight consistent with a prior report of elevated endocannabinoids" in such leptin-deficient mice.

The researchers concluded that their findings "are consistent with the hypothesis that the integration of endocannabinoid and leptin signaling regulates the excitability of neurons on appetite-related circuits."

They also wrote that "the cellular mechanisms of recently developed antiobesity drugs, such as rimonabant, may include decreased endocannabinoid signaling and hence decreased excitability of LH circuits related to appetite, even in the context of leptin insufficiency or resistance."

The researchers included Young-Hwan Jo, Ying-Jiun J. Chen, Streamson C. Chua, Jr., David A. Talmage and Lorna W. Role of Columbia University in New York, New York. This work was supported by NS22061 and a NARSAD Grable Distinguished Investigator award to L.W.R.; by CA79737 to D.A.T.; by DK57621 to S.C.C.; and by an award from the New York Obesity Research Center to Y.-H.J.

Jo et al.: "Integration Of Endocannabinoid and Leptin Signaling in an Appetite-Related Neural Circuit." Publishing in Neuron, Vol. 48, 1055-1066, December 22, 2005, DOI 10.1016/j.neuron.2005.10.021 www.neuron.org.

E. A. Carlini, A. Hamaoui, and Regina M. W. Märtz

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Marijuana, the common name for Cannabis sativa, is a widely distributed hemp plant whose dried flowering tops and leaves have been used for medicinal purposes for 12,000 years by some estimates (1). The article by Malfait et al. (2) in this issue of PNAS is relevant to the question of whether such traditional uses of marijuana could be clinically justifiable today.

Contemporary discussions of the medical value of marijuana must be undertaken within a larger cultural, legal, and political context (Workshop on the Medical Utility of Marijuana, National Institutes of Health, http://www.nih. gov/news/medmarijuana/MedicalMarijuana.htm). The perceived behavioral and addictive effects of marijuana led to its prohibition from nonmedical uses by most states, taxation at the federal level, and eventual removal from the U.S. Pharmacopoeia in the 1930s and 1940s. Nonetheless, smoking of marijuana cigarettes continued and became the recreational drug practice of choice as well as a virtual rite of passage for young people during the Vietnam era. Some people who suffered chronic debilitating illnesses observed that marijuana eased some of their symptoms. A movement grew to redefine marijuana as a neglected, but valuable, therapeutic tool. Today, that movement has been subsumed under a more general advocacy for a whole spectrum of complementary and alternative health approaches (3).

Complementary and alternative medicine entails the use of unconventional diagnostic, preventative, and therapeutic approaches including acupuncture, chiropractic manipulation, homeopathy, and magnets, few of which have been tested according to rigorous scientific standards. Herbal and other botanical products are key components of many alternative health approaches. Numerous preparations are marketed in the United States as nutritional supplements with such promises as combating fatigue, restoring mental balance, warding off respiratory infections, losing weight, and relieving the pains of arthritis.

Were botanical products merely inert food supplements or condiments, there would be little concern over their use. But the very discoveries that yielded aspirin, digoxin, vincristine, taxol, and many other valuable plant-based drugs informed us as well of their potential for harm. Despite the common belief that natural substances must be healthful, the media and scientific literature today are rife with reports of serious adverse effects of particular botanical supplements and unexpected interactions between some supplements and proprietary drugs. Thus, the public need for definitive preclinical and clinical testing of botanicals and other unconventional healing approaches led to the creation in 1999 of the National Center for Complementary and Alternative Medicine at the National Institutes of Health.

With regard to marijuana, there are data to indicate that the plant, or at least some of its constituents, conveys some clinical benefits, but a number of risks as well. Comprehensive reviews of the medical utility of marijuana were undertaken by a National Institutes of Health workshop in 1997 and by the Institute of Medicine in 1999 (http: //www.nih.gov/news/medmarijuana/MedicalMarijuana.htm and ref. 4). These reviews concluded that smoking marijuana reduces intraocular pressure in glaucoma and is claimed to ameliorate pain, cachexia, nausea, and other debilitating conditions. Unfortunately, large controlled trials have not been conducted to support the majority of such claims. Moreover, there are better, well-defined treatments for virtually all such indications.

Far more certain than reports of the benefits of marijuana smoking, however, are the health risks it imposes. Studies have described its adverse psychological, cardiovascular, and pulmonary effects, and even raised the specter of an increased risk of cancer (5, 6).

In contrast to the incomplete state of the science regarding use of the plant itself, the identity, pharmacology, and clinical effects of several of marijuana's constituents are relatively well characterized (7, 8). Marijuana contains more than 60 distinct cannabinoids, of which a series of tetrahydrocannabinols (THC) and their metabolites are the primary psychoactive ingredients and best-known components (Fig. ​(Fig.1).1). Δ⁹-THC alleviates the nausea associated with cancer chemotherapy and AIDS wasting and is available for these indications as the prescription drug dronabinol. Even the nonpsychoactive cannabinoids have been shown to have cellular and physiologic effects that could prove of clinical value.

Figure 1 The chemical structures of Δ9-THC and cannabidiol.

The paper by Malfait et al. (2) summarizes in vitro and in vivo immunological studies of the marijuana constituent cannabidiol (CBD; Fig. ​Fig.1)1) and its potential effects in the treatment of arthritis (1). Using a murine model in which arthritis is induced by immunization with type II collagen, the authors show that CBD blocks the inflammatory infiltrate and progression of joint damage. CBD appears effective both orally and intraperitoneally, but with a rather sharp dose-response peak, above or below which efficacy is less evident. A series of ex vivo studies indicate that CBD attenuates the oxidative burst in granulocytes, lymphocyte proliferation, and the release of proinflammatory cytokines.

Numerous prior studies of marijuana itself, unfractionated marijuana extracts, and individual cannabinoids revealed that they manifest a wide range of immunologic effects, both in vitro and in vivo, in animals as well as in human subjects (reviewed in ref. 9). Generally suppressive effects on T cell, B cell, macrophage, natural killer cell, and neutrophil functions have been described. Proliferation is impaired, as is release of selected cytokines and chemokines, but the findings differ by cell type, experimental conditions, and especially the concentration of the cannabinoids examined. The effects are sufficient, nonetheless, to impair host responses to animal challenges with several viral and bacterial pathogens. Moreover, the psychoactive potential of the molecule does not correlate with its immunological effects. For example, both THC and CBD were shown to inhibit release of IFN-γ and tumor necrosis factor α from cultured human peripheral blood mononuclear cells (10, 11). In some assays, the effects by one paralleled the other; in others, CBD was more potent. Importantly, the dose–response for either substance was complex, being stimulatory at concentrations of 0.01–0.1 μg/ml, the range of serum levels detected in marijuana smokers, but strongly inhibitory at 0.5–20 μg/ml. Given the tight peak response to CBD observed in the present report and its still undefined pharmacokinetics, it might be difficult to develop CBD into a useful anti-inflammatory or immunosuppressive drug.

Another issue that bears on the potential therapeutic utility of CBD, or any cannabinoid designed for prolonged use, is its toxicity, an issue that was not addressed by Malfait et al. (2). In addition to adverse effects like tremors, convulsions (12), and embryotoxicity (13) observed in formal animal studies, there are effects associated with its intended use, such as the suppression of inflammatory cytokine responses. Early experiences with the anti-tumor necrosis factor agents infliximab and etanercept revealed an increased incidence of intercurrent infections (14). Their long-term effects on dormant infections with mycobacteria or other intracellular pathogens are not known. An increased risk of lymphomas has been postulated as well (15).

Regardless of its eventual utility and safety, CBD is a potential lead to new classes of agents that would interfere with inflammatory pathways. Although one could only speculate as to why a common weed like Cannabis would evolve to contain THC and CBD, we do know something of the cellular mechanisms by which it acts on the mammalian immune and nervous systems. Two related cannabinoid receptors have been described: CB1 and CB2 (Table ​(Table1;1; refs. 16 and 17). They are both widely distributed G-coupled protein receptors. High densities of CB1 are found in the cortex, limbic system, and hippocampus, where endogenous ligands like anandamide serve as neurotransmitters. CB2 also is expressed in the brain, but is found in relatively higher concentrations than CB1 in various lymphocyte subpopulations, especially B cells. That CBD does not bind to either CB1 or CB2 implies that additional receptors remain to be discovered. The evolving work suggests that the differential expression of cannabinoid receptors, and the particular endogenous ligands accessible to them in specific tissues, constitute a rich regulatory network (18, 19).

Table 1 The distribution and ligand affinitives of cannabinoid receptors

Many proponents of complementary and alternative medicine find the discovery of neuro-immune effector molecules, such as the cannabinoid receptors and their endogenous ligands, to be an exciting validation of their traditional beliefs about the unity of mind and body. They extol the proverbial wisdom of nature in providing medicinal plants whose components can affect human cells through evolutionarily conserved biochemical mechanisms. They believe, as well, that the multiplicity of related constituents in medicinal plants act collectively to enhance overall beneficial effects while tempering adverse ones.

It is conceivable that marijuana contains a series of cannabinoids that, in the aggregate, could alleviate arthritis as implied in the present report (2), yet remain well tolerated. Remarkably, the claim that marijuana does so also was made 4,000 years ago by the Chinese emperor Shen-nung whose pharmacobotanical compendium, the Pen-ts'ao Ching, concluded that cannabis “undoes rheumatism” (cited in ref. 20). These are ideas that are now susceptible to critical scrutiny through controlled trials in which purified plant constituents are compared, alone and in combination, with whole-plant products.

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A study in the Proceedings of the National Academy of Sciences finds that endocannabinoids, compounds naturally found in the body related to pot's active ingredient, could inform the effort to control appetite. Cynthia Graber reports

Could there be a substance that both gives us the munchies and can help combat obesity? There may indeed be, according to research published in the Proceedings of the National Academy of Sciences.

The Monell Center in Pennsylvania partnered with Kyushu University in Japan to study compounds called endocannabinoids. These occur naturally in our body and are similar to THC, the compound primarily responsible for marijuana’s psychoactive effects.

Researchers studied endocannabinoids in mice, and they say that the chemicals have a one-two punch—in your brain, they increase your appetite. And on your tongue, they enhance the response to sweet flavors. The compounds had no effect on salty, sour, bitter or umami tasting.

It turns out that sweetness receptors are present in the same cells as cannabinoid receptors on our tongues. But how could such an effect contribute to combating obesity? According to the scientists, there are similar sweet receptors in hormone-producing cells in the intestine and pancreas. There, they affect metabolism and the absorption of nutrients. Scientists say that if endocannabinoids also act on those receptors it could lead to new compounds to moderate metabolism. Which might stop the development of the pot belly.

—Cynthia Graber

 December 29, 2009

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Caloric Intake, Mood, and Sleep," Journal of Acquired Immune Deficiency Syndromes 45, issue 5 (August 15, 2007): 545-554.

This clinical trial found that both smoked marijuana and the THC pill (Marinol, known generically as dronabinol) are effective at increasing caloric intake and weight among HIV-positive patients, with no effect on cognitive performance. Strikingly, however, it took eight times the standard dose of Marinol to approximate the effect of weak (3.9% THC) marijuana, and even at that dose, natural marijuana outperformed Marinol in some measurements.

The full study is available for free download here: http://journals.lww.com/jaids/Fulltext/2007/08150/Dronabinol_and_Marijuana_in_HIV_Positive_Marijuana.9.aspx?desktopMode=true