marijuana medicine

Marijuana

and

Medicine

The Verdict is in!

This paper is in response to the coverage in the media by those with the opinion that there is a need for marijuana to be used as a medicine for the treatment of Pain, AIDS Wasting, Glaucoma, Nausea and Vomiting.

What does the world expert authorities say about marijuana being used as medicine in the monograph edited by Stig Agurell, PhD, PharmD, DSC, David Harvey, PhD, Kenneth M Sutin, MD, MS, Gabriel G Nahas, MD, PhD, DSC. Co-Editors Nicholas Pace, MD, and Robert Cancro, MD, with a total of 109 contributors. In the monograph it is clearly explained.

"The current molecular studies reported in this volume indicate that the multiple medicinal effects of Marihuana may be accounted for by an interaction of the drug with basic regulatory signalling mechanisms of the lipid bilayer and integral receptors of the cell membrane. This unique deregulation of cell membrane signalling by the THC impairs the function of brain synapses, gametes, and cells of the immune system. Therefore, today the verdict of Marihuana in medicine is finally at hand." Gabriel G Nahas.

Chronic Pain

Cannabis has also been attributed analgesic properties as confirmed in present-day pharmacologic studies of its active principles. As discussed elsewhere, these principles, notably ⁹-THC, to some extent probably act through the release of opioid peptides. It is interesting that knock-out manipulation of mice that lack a functional pro-enkephalin gene, on of the three opioid peptide precursor genes, leads to lower nociceptive thresholds, higher irritability, and aggressiveness (3). Thousands of years of folk medicine and industrial drug development have so far failed to identify alternative centrally acting analgesics of similar potency and utility as the opioids. Thus, the opioid system remains the main target for centrally induced analgesia.

Marihuana for AIDS Wasting

The association of increased appetite with smoking of Cannabis sativa has led to the anecdotal use of smoked crude marihuana in an attempt to prevent or treat AIDS wasting. This would only be justified if the therapeutic intervention was actually shown to be effective. Obviously, the adverse effects of smoking either Cannabis sativa or tobacco, particularly in an already immunosuppressed host, raise serious safety questions. Much of the literature in this area is anecdotal and therefore, subject to the bias of placebo effects and self reporting (6). As an example a study reported in 1970 showed that 91% of moderate-to-heavy marihuana users reported eating each time they smoked the drug. Eighty-five percent thought that their intake of food increased to greater quantities when under the influence of the drug than when they did not smoke, with two-thirds of the patients indicating that they would eat even though they were no longer hungry. Others have reported that smoked marihuana inhibits the sensation of satiety (6). Some controlled studies indicate an appetite-stimulating property of marihuana in healthy subjects and in patients with cancer. (7,8), although other studies could not confirm this (9). Thus, the application of smoked crude marihuana as a treatment of AIDS wasting would need to be proven by a controlled study since the disadvantages of such therapy in terms of increased risk of pulmonary infection, interaction with other drugs, and other side effects are obvious.

Because there are no scientifically acceptable data regarding smoked marihuana, this book reviews the evidence that bears on this issue from studies using oral ⁹-tetrahydrocannabinol (dronabinol), which is approved by the Food and Drug Administration (FDA) for AIDS wasting.

Whereas anecdotal information and case reports suggest that smoked crude marihuana is beneficial for treatment of AIDS patients with profound wasting syndromes, there are no data that support this use. The studies with oral dronabinol, which are the only controlled studies in this area (10-12), are disappointing. The hazards of smoking marihuana on the immune system, the risk of opportunistic infections, and the risk of neoplasia at the current time out-weigh any benefits alleged by anecdotal data to date.

Cannabis and Schizophrenia

Both schizophrenia and Cannabis appear to cause similar alterations in cognitive functions: Studies of event-related potentials in Cannabis users (13) and schizophrenics (14) have put in evidence comparable defects in P300 responses evoked by auditory cues. Theses alterations reflect a diminished ability to recognize and process irrelevant stimuli in a speedy and accurate fashion, and a recent study by Emrich et al. (15) has found that both neuroleptic-naive schizophrenics and healthy volunteers under the influence of Cannabis, present the same disturbance at a depth-perception test. The abnormality is quite peculiar in that the subjects tended to view concave objects as convex, a binocular depth inversion which represents an illusion of visual perception. Whereas the specificity of this finding has not been demonstrated-there were no comparisons made with subjects exposed to other substances-this study does show that Cannabis intoxication causes a schizophrenia-like perceptive disturbance. Once again, a greater understanding of the function of the cannabinoid system in the brain is needed in order to ascertain the nature of the relation between the two conditions.

Marihuana and Glaucoma

Several marihuana health hazards have been identified (16-18). Some responses cannot be exclusively ascribed to marihuana because of the intermittent patterns of human marihuana intake; the use of marihuana in younger age groups who are usually in better health than an elderly population; the absence of defined, controlled marihuana intake; and the difficulty in separating marihuana effects from those associated with the parallel use of alcohol, tobacco, and other drugs.

Acute marihuana effects have been documented as increased pulse rate, orthostatic hypo-tension, euphoria, conjunctival hyperemia, and reduction in intraocular pressure (IOP) (19-23). Long-term clinical effects in humans are mainly related to respiratory, hormonal, and reproductive toxicity (24-28). Marihuana smoking leads to emphysema-like changes as a result of cannabinoids or the release of tars, carcinogens, and other volatiles as found with tobacco smoke (27). Of concern are the marihuana-induced cognitive effects that assume greater significance with chronic repetitive exposure especially in the age group in which glaucoma occurs (29-30).

Each of these factors must be considered when their potential use on a chronic basis is examined as a treatment modality. This is especially true for glaucoma where continued use would be necessary to control this 24-hour-a-day disease with between 2200 and 3600 marihuana cigarettes per year.

The development of compounds such as HU211 that show a complete absence of euphoric effects, whereas retaining IOP-reducing activity (31) is a major advance. HU211 also reduces IOP through an effect on outflow of fluid from the eye (32). This compound also shows a lack of binding the CB₁ receptor (33). Increasing knowledge concerning cannabinoid receptor behavior and their relationship to pharmacological events will allow exploration of different structural analogs. Such studies may identify compounds and ligands that reduce IOP when given topically to rabbit or monkey eyes and thus might be efficacious as potential glaucoma medications (34-43). Topical administration has the clinical advantage of allowing the use of a low drug mass per delivery volume. Oral administration of cannabinoid-related compounds that lack psychoactive effects, but will reduce IOP could be a significant addition to the ophthalmic armamentarium against glaucoma.

Because cannabinoids and related substances are readily characterized chemically, they represent an area in which a focus should be make in the future. Compounds could be identified which have no, or minimal, euphoric effects. Use of these chemicals would provide drugs that reduce IOP by specific interactions with receptors or other membrane components. Furthermore, the cannabinoid-related compounds could be additive to other currently available glaucoma medications that act on aqueous humor inflow or conventional outflow pathways.

The reasons for the selection of cannabinoids versus marihuana are compelling for glaucoma studies. Such a manoeuver would allow a focus on individual chemicals rather than on a nonstandardized plant material (44). The latter has no possibility, because of the inherent variability and the plant versatility, of reaching the standards required by the FDA, or equivalent agencies in other countries or alliances, in terms of chemical identity, purity, or characterization. Furthermore, use of modalities other than smoking reduce the exposure of a cannabinoid user to undesirable side effects including smoke as well as other drugs within its plant material.

Marihuana and Medicine

Marihuana or THC do not qualify as safe and effective medications which aim at restoring or maintaining physiological function of cells, organs and organisms. They have no place in modern Pharmacopoeia from which cannabis was eliminated in the first part of the century.

However, the experimental use of THC and of its synthetic analogues in molecular physiology ahs provided invaluable information leading to a better understanding of membrane signal transduction. As a result, the relationship between allosteric receptor responsiveness, molecular configuration of proteins and regulations of cellular function may be better understood.

Therapeutic Applications of Cannabinoids

The numerous pharmacological effects produced by THC led many investigators to seek some therapeutic application for this drug and other cannabinoids as well. Extensive research programs sponsored by the pharmaceutical industry (Abbott, Squibb, Lilly, and Pfizer) and by Federal agencies were initiated to establish the efficacy of THC and of its derivatives, of their mode of action, and of their main therapeutic indications. Several related synthetic molecules were designed and tested experimentally and clinically.

Among these derivatives, nabilone, a THC-like cannabinoid developed by Lilly laboratory, was approved for medical use in 1982 (45). This drug has been used in the treatment of the nausea and vomiting associated with cancer chemotherapy, in doses of 1-2 mg/day, and in the treatment of muscle spasticity.

Another THC-like synthetic derivative, levonantradol (46), was developed by Pfizer laboratory. It is a very potent substance with antalgic and antiemetic activity in the milligram dose (47,48). Its marked side effects prompted the interruption of its clinical trials in 1982.

The potential therapeutic applications of THC and related cannabinoids were reported in eleven symposia and monographs published in the 1970s and 1980s (49-59). As a result, several hundred reports were assembled in 1500 pages of text authored by organic, analytical, and pharmaceutical chemists; experimental and clinical pharmacologists, and physicians who had specialized in the chemistry, pharmacology, and therapeutic applications of the cannabinoids. The present review is an attempt to summarise, the main findings of this data reported by scientists from the United States, United Kingdom, Sweden, France, and Israel.

Antiemetic Effect

Marinol is not indicated as first-line treatment for nausea and vomiting associated with cancer chemotherapy. (It is only indicated) in patients who have failed to respond adequately to conventional antiemetic treatments. Because of the limitations of its indication, comparisons of Marinol to conventional antiemetics are inappropriate. Marinol is not a therapeutic alternative to Compazine (prochlorperazine) or other conventional antiemetic treatments (metoclopramide, ondansetron)... Patients using Marinol should be advised of possible changes in mood and other adverse behavioral or disturbing psychotominetic reactions... Marinol is a medication with a potential for abuse. Physicians and pharmacists should use the same care in prescribing and accounting for Marinol as they would morphine or other (schedule II drugs)... The risk/benefit ratio of Marinol use should be carefully evaluated in the following types of patients... patients with cardiac disorders because of occasional hypotension and hypertension, syncope, or tachycardia; patients with a history of substance abuse, including alcohol abuse or dependence; patients with manic depression, or schizophrenia because Marinol may exacerbate these illnesses; ... and patients receiving concomitant therapy with sedatives, hypnotics, or other psychoactive drugs because of the potential for additive or synergistic (central nervous system) effects.

Glaucoma

Most antiglaucoma agents are administered topically and are effective by this route. This is not the case of THC (61). Topical THC in light mineral oil vehicle (0.05-0.1%) when administered to six subjects with open-angle glaucoma was not more effective than placebo.

In summary, smoking THC containing Cannabis lowers intraocular pressure in glaucoma patients, producing unwanted psychoactive and cardiovascular side-effects, especially hypotension in older patients. The drug is ineffective when topically applied. Its oral administration is only effective in dosage associated with significant side-effects. There are many other effective preparations containing pilocarpine and beta-blockers that are available to treat glaucoma and have less systemic side-effects.

Conclusion

The THC-containing marihuana smoke, resulting from the combustion of plant material, has not been proven more effective than its oral form, marinol. It contains toxic compounds (carbon monoxide, acetaldehyde, naphthalene) and carcinogens in amounts greater than tobacco smoke. It is damaging to the lung and pulmonary defense mechanisms. Marihuana smoke has not satisfied FDA guidelines for safety and efficacy of its claimed therapeutic properties.

The acceptance of marihuana smoking as a popular medication also could present the risk of a significant diversion of the drug for recreational use by children and adolescents. Their perception of marihuana as a harmless, soft drug has been related to an increase incidence of its smoking (62).

The prospects of THC and marihuana as therapeutic agents described by Hollister in 1984 are worth recalling (63).

"Cannabis and THC homologues should be treated like any other investigational new drug as the search for a clinical use in medicine goes on. We should expect neither less nor more in regard to the safety and efficacy than we would from other new agents. At present, Cannabis has not yet make its way back into the formularies. It is unlikely that it ever will. The ingenuity of pharmaceutical chemists in developing THC analogs may yet find a way to exploit some of these potential therapeutic uses without the side effects that make Cannabis itself undesirable."

Fourteen years later, several hundred THC analogs, agonists and antagonists have been designed and tested experimentally. The G protein coupled receptor to THC has been identified as well as its natural ligand, arachidonyl-ethanolamine AEA ("Anandamide") (64). Many synthetic agonists and antagonists of AEA have been experimentally tested (65), but have not been proven to be of any clinical use. These studies have also shown that THC deregulates the physiological signalling role of G protein receptors and the membrane lipid bilayer (66). The deregulation of membrane signalling by THC and cannabinoids explains their multiple partial and inconsistent therapeutic effects.

APFDFY Conclusion

There is no medical justification for the use of marijuana smoking in the treatment of nausea and vomiting associated with cancer or AIDS chemotherapy. Other claims formulated in the prescientific area of medicine concerning the therapeutic properties of marijuana smoking for epilepsy, multiple sclerosis, paraplegia, migraine, chronic pain, pruritus, menstrual cramps, and labor pain are purely hearsay and may even be harmful to the patient.

Marijuana smoking as a medicine is not only a cruel hoax it is also sending the wrong message to uninformed patients and health professionals who rely on safe and effective medicine. There is no medical justification for the use of marijuana smoking in the treatment of nausea and vomiting associated with cancer or AIDS chemotherapy.

Herschel Mills Baker

President

Australian Parents for Drug Free Youth

PO Box 73

Maryborough Q 4650

e-mail winner2@optusnet.com.au

Fax--- 0741 233810

Phone-0741 233810

Web Page- http://members.optusnet.com.au/~apfdfy

REFERENCES

Hökfelt, T., Zhang, X. and Wiesenfeld-Hallin, Z. (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 17, 22-30.
Manzanares, J., Corchero, J., Romero, J., Fernandez-Ruiz, J. J., Ramos, J. A. and Fuentes, J. A. (1998) Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain. Mol Brain Res 55, 126-132.

Konig, M., Zimmer, A. M., Steiner, H., Holmes, P. V., Crawley, J. N., Brownstein, M. J. and Zimmer, A. (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383, 535-538.
Kotler, D. P., Tierney, A. R., Wang. J., and Pierson, R. N., Jr. (1989) Magnitude of body cell-mass depletion and the timing of death from wasting in AIDS. Am. J. Clin. Nutr. 50, 444-447.
Macallan, D. C., Noble, C., Baldwin, C., Jebb, S. A., Prentice, A. M., Coward, A., Sawyer, M. S., McManus, T. J., and Griffen, G. E. Energy expenditure and wasting in human immunodeficiency virus infection. New Engl. J. Med. 333(2), 83-88.
Mattes, R. D., Engelman, K., Shaw, L. M., and Elsohly, M. A. (1994) Cannabinoids and appetite stimulation. Pharmacology Biochem. Behavior 49, 187-195.
Regelson, W., Butler, J. R., Schulz, J., Kirk, T., Peek, L., Green, M. L., and Zalis, M. O. (1976) ⁹-Tetrahydrocannabinol as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In: The Pharmacology of Marijuana (Braude, M. C., and Szara, S., eds.) Raven Press, New York, 763-776.
Sallan, S. E., Cronin, C., Zelen, M., and Zinberg, N. E. (1980) Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N. Engl. J. Med. 30, 135-138.
Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., Simon, R. M., and Rosenberg, S. A. (1979) ⁹-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate: a prospective, randomized evaluation. Ann. Int. Med. 91, 819-824.
Beal, J. E., Olson, R., Laubenstein, L., Morales, J. P., Bellman, P., Yangco, B., Lefkowitz, L., Plasse, T. F., and Shepard, K. V. (1995) Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J. Pain Symptom Manage 10(2), 89-97.
Beal, J. E., Olsen, R., Lefkowitz, L., Laubenstein, L., Bellman, P., Yangco, B., Morales, J. O., Murphy, R., Powderly, W., Plasse, T. F., Mosdell, K. W., and Shepard, K. V. (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J. Pain Symptom Manage 14(1), 7-14.
Timpone, J. G., Wright, D. J., Li, N., Egorin, M. J., Enama, M. E., Mayers, J., Galetto, G., and the DATRI 004 Study Group. (1997) The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Research and Human Retroviruses 13, 305-315.
Solowij, N. (1995) Do cognitive impairments recover following cessation of cannabis use? Life Sciences 56, 2119-2126.
Javitt, D. C. (1997) Psychophysiology of schizophrenia. Curr. Opinion in Psychiatry 10, 11-15.
Emrich, H. M., Leweke, F. M., and Schneider, U. (1997) Toward a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol. Biochem. Behav. 56(4), 803-807.
Hollister, L. E. (1986) Health aspects of cannabis. Pharmacol. Rev. 38, 1-20.
Nahas, G. G., ed. (1984) Marihuana in Science and Medicine, Raven, New York.
Agurell, S., Dewey, W. L., and Willette, R. E., eds. (1984) The Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects, Academic, New York.
Hollister, L. E. (1971) Actions of various marihuana derivatives in man. Pharmacol. Rev. 23, 349-357.
Dewey, W. L. (1986) Cannabinoid pharmacology. Pharmacol. Rev. 38,151-178.
Klonoff, H. (1983) Acute psychological effects of marihuana in man, including acute cognitive, psychomotor, and perceptual effects in driving, In: Adverse Health and Behavioral Consequences of Cannabis Use (Fehr, K. O. and Kalant, H., eds.), Addictive Research Foundation, Toronto, pp. 433-474.
Perez-Reyes, M., Lipton, M. A., Timmons, M. C., Wall, M. E., Brine, D. R., and Davis, K. H. (1973) Pharmacology of orally administered ⁹-tetrahydrocannabinol. Clin. Pharmacol. Therap. 14, 48-55.
Green, K. (1979) The ocular effects of cannabinoids, In: Current Topics in Eye Research, Vol. I (Zadunaisky, J. A. and Davson, H., eds.) Academic, New York, pp. 175-215.
Munson, A. E. and Fehr, K. O. (1983) Immunological effects of cannabis, In: Adverse Health and Behavioral Consequences of Cannabis Use (Fehr, K. O. and Kalant, H., eds.), Addictive Research Foundation, Toronto, pp. 257-353.
Bloch, E. (1983) Effects of marihuana and cannabinoids on reproduction, endocrine function, development, and chromosomes, In: Adverse Health and Behavioral Consequences of Cannabis Use (Fehr, K. O. and Kalant, H., eds.). Addictive Research Foundation, Toronto, pp. 355-432.
Rosenkrantz, H. (1983) Cannabis, marihuana and cannabinoid toxicological manifestations in man and animals, In: Adverse Health and Behavioral Consequences of Cannabis Use (Fehr, K. O. and Kalant, H., eds.), Addictive Research Foundation, Toronto, pp. 91-175.
Tashkin, D. P., Shapiro, B. J., Ramanna, L., Taplin, G. V., Lee Y. E., and Harper, C. E. (1976) Chronic effects of heavy marihuana smoking on pulmonary function in healthy young males, In: The Pharmacology of Marihuana (Braude, M. C. and Szara, S., eds.), Raven, New York, pp. 291-295.
Dornbush, R. L. and Kokkevi, A. (1976) The acute effects of various cannabis substances on cognitive, perceptual, and motor performance in very long-term hashish users, In: The Pharmacology of Marihuana (Braude, M. C. and Szara, S., eds.), Raven, New York, pp. 421-427.
Fletcher, J. M., Page, J. B., Francis, D. J., Copeland, K., Naus, M. J., Davis, C. M., Morris, R., Krauskopf, D., and Satz, P. (1996) Cognitive correlates of long-term cannabis use in Costa Rican men. Arch. Gen. Psych. 53, 1051-1057.
Solowij, N., Michie, P. T., and Fox, A. M. (1995) Differential impairments of selective attention due to frequency and duration of cannabis use. Biol. Psych. 37, 731-739.
Beilin, M., Aviv, H., Friedman, D., Vered, M., Belkin, M., Neumann, R., Amselem, S., Schwarz, J., and Bar-Zlan, A. (1993) HU211, a novel synthetic, non-psychotropic cannabinoid with ocular hypotensive activity. Invest. Ophthalmol. Vis. Sci. 34(suppl), 1113.
Beilin, M., Neumann, R., Belkin, M., Green, K., and Bar-Zlan, A. (1998) Pharmacology of the intraocular pressure (IOP) lowering effect of systemic HU-211, a non-psychotropic cannabinoid. J. Ocular Pharmacol. Therap. Submitted for publication.
Little, P. J., Compton, D. R., Mechoulam, R., and Martin, B. R. (1989) Stereochemical effects of 11-OH-8-THC-dimethylheptyl in mice and dogs. Pharmacol. Biochem. Behav. 32, 661-666.
Green, K. and Kim, K. (1977) Acute dose response of intraocular pressure to topical and oral cannabinoids. Proc. Soc. Exp. Biol. Med. 154, 228-231.
Newell, F. W., Stark, P., Jay, W. M., and Schanzlin, D. J. (1979) Nabilone: A pressure reducing synthetic benzopyran in open angle glaucoma. Ophthalmology 86, 156-160.
Mechoulam, R., Lander, N., Varkony, T. H., Kimmel, I., Recker, O., Ben-Zvi, Z., Edery, H., and Parath, G. (1980) Stereochemical requirements for cannabinoid activity. J. Med. Chem. 23: 1068-1072.
Lemberger, L. (1980) Potential therapeutic usefulness of marihuana. Ann. Rev. Pharmacol. Toxicol. 20, 151-172.
Weber, P. A. and Howes, J. F. (1981) Lowering of intraocular pressure in normotensive human volunteers by naboctate. Invest. Ophthalmol. Vis. Sci. 20(suppl), 196.
Razdan, R. K. (1986) Structure-activity relationships in cannabinoids. Pharmacol. Rev. 38, 75-149.
Sugrue, M. F., Funk, H. A., Leonard, Y., O'Neill-Davis, L., and Labelle, M. (1996) The ocular hypotensive effects of synthetic cannabinoids. Invest. Ophthalmol. Vis. Sci. 37(suppl), 831.
Pate, D. W., Jarvinen, K., Urtti, A., Harho, P., and Jarvinen, T. (1995) Arachidonylethanolamide decreases intraocular pressure in normotensive rabbits. Curr. Eye Res. 14, 791-797.
Pate, D. W., Jarvinen, K., Urtti, A., Harho, P., and Jarvinen, T. (1996) Effects of topical anandamides on intraocular pressure in normotensive rabbits. Life Sci. 58, 1849-1860.
Hodges, L. C., Reggio, P. H., and Green, K. (1997) Evidence against cannabinoid receptor involvement in intraocular pressure effects of cannabinoids in rabbits. Ophthalmic Res. 29, 1-5.
Green, K. (1998) Marihuana smoking vs. cannabinoids for glaucoma therapy. Arch. Ophthalmal. Submitted.
Archer, R. A., Hanasono, G. K., Lemberger, L. and Sullivan, H. R. (1981) Update on nabilone research: the relationship of metabolism to toxicity in dogs. In: Treatment of Cancer Chemotherapy Induced Nausea and Vomiting (Poster, D. S., Penta, J. S. and Bruno, S. eds.) Moser, New York, pp. 119-127.
Milne, G. M., Koe, B. K. and Johnson, M. R. (1979) Stereospecific and potent analgetic activity for nantradol: Astructurally novel, cannabinoid-related analgetic 1980. In: Problems of Drug Dependence (Harris, L. S. ed.) NIDA Research Monograph 27, Rockville, MD.
Cronin, C. M., Sallan, S. E., Belger, R., Lucs, V. and Laszlo, J. (1981) Antiemetic effect of intramuscular levonantradol inpatients receiving anticancer chemotherapy. J. Clin. Pharmacol. 21, 43S-85S.
Diasio, R. B., Ettinger, D. S. and Satterwhite, B. E. (1981) Oral levonantradol in the treatment of chemotherapy-induced emesis; preliminary observations. J. Clin.Pharmacol. 21, 81S-85S.
Therapeutic potential (1976) In 'Pharmacology of Marihuana' (Braude, M. and Szara, S., eds.) Mason, New York.
Cohen, S. and Stillman, R. (1976) The Therapeutic Potential of Marihuana, Plenum, New York.
Lemberger, L. (1980) Potential therapeutic usefulness of marihuana, Ann. Rev. Pharmacolo. Toxicolo. 20, 151.
Treatment of Cancer Chemotherapy-Induced Nausea and Vomiting (Poster) (Penta, J. S. and Bruno, S. eds.) Mason, New York.
Therapeutic Progress in Cannabinoid Research (Pfizer symposium) Clin. Pharmacol. 21, Nos. 8-9 supplement p. 487.
Clinical and therapeutic aspects (1985) In: Marihuana, 1984 Oxford Symposium (Harvey, D., Paton, W. D. M. and Nahas, G. G. eds.) Academic New York.
'The medical use of cannabis' (1984) In: Marihuana in Science and Medicine (Nahas, G., Paris, M and Harvey, D., eds.) Raven, New York, pp. 247-261.
'The cannabinoids, chemical, pharmacological and therapeutic aspects' (1984) (Agurell, S., Dewey, W. L. and Willette, R. E., eds.) Academic New York.
Mechoulam, R. (1986) Cannabinoids as Therapeutic Agents CRC Press, Boca Raton, FL, p. 186.
Therapeutic and clinical effects of marihuana (1988) In: International Research Report, Melbourne Symposium on Cannabis (Consroe, P. and Musty, R., eds.) Australian Government Publishing Service, Canberra, pp. 119-167.
Consroe, P. and Sandy, R. (1992) 'Potential role of cannabinoids for therapy of neurological disorders'. In: Marihuana/Cannabinoids, Neurobiology and Neurophysiology (Murphy, L. and Bartke, A., eds.) CRC Press, Boca Raton, FL, pp. 459-524.
Neelman, M. P. (1996) Marihuana, soft drug or medicine? Pain Clinic 9, 243-248.
Green, K., Wynn, H. and Bowman, K. A. (1978) A comparison of topical cannabinoids on intraocular pressure. Exp. Eye Res. 27, 239-256.
(1996) The National Drug Control Strategy. The White House. Increased adolescent drug use 1991-1995. p. 19.
Hollister, L. (1984) Health aspects of cannabis use, In: The Cannabinoids: Chemical, Pharmacologic, and Therapeutic Aspects. (Agurell, S., Dewey, W. L. and Willette, R. E. eds.) Academic New York, p. 15.
Pertwee, R. (1995) Cannabinoid Receptors, Academic Press, New York.
Mechoulam, R., Hanus, L., Ben-Shabat, S., Fride, E. and Weidenfeld, J. (1994) The anandamides, a family of endogenous cannabinoid ligands-chemical and biological studies. Neuropschychopharmacology 10, 145S-145S.
Nahas, G. G., Sutin, K. E., Turndorf, H., Cancro, R. (1998) Cannabinoids and regulation of membrane signal transduction. ACNP 37^th Annual Meeting, Porto Rico.

Information is supplied by the APFDFY PO Box 73 Maryborough Qld 4650 Australia Phone/Fax 0741 233 810