Pubdate: Thu, 09 Sep 1999 Source: New England Journal of Medicine (MA) Copyright: 1999 by the Massachusetts Medical Society Contact: comments@nej.org Website: http://www.nejm.org/ Section: Book Review Author: John A. Benson, Jr., M.D. Oregon Health Sciences University

MARIHUANA AND MEDICINE

The medical use of marijuana has polarized public opinion, particularly because of its widespread recreational use over the past 30 years.

Those in favor of its medical use point to the apparent safety of this ancient and "natural" remedy, the profusion of anecdotal and survey-based evidence of marijuana's effectiveness, and the importance in today's culture of personal choice. This view has been expressed at the ballot box since November 1996 by referendums in several states. Those opposed, troubled by this potential gateway to serious drug abuse, especially among adolescents, regard acceptance of the medical use of marijuana as the camel's nose under the tent, legitimizing a dangerous relaxation of the nation's "war on drugs." Both sides come from all age groups and levels of society, and both claim their own scientific evidence.

In this rancorous climate of claim and counterclaim, both physicians and policy makers seek rational solutions based on credible evidence. Since 1986, basic science has helped enormously with discoveries of potent cannabinoid agonists; specific cannabinoid receptors and the correlation between their concentration in brain centers and their relevant functions; endogenous or natural substances that act on those receptors; and more recently, specific cannabinoid antagonists.

Regrettably, societal concerns have focused attention on drug abuse rather than on the promise of drug development. Hence, a thorough scientific exposition of the medical value of marijuana would be welcome. But this book disappoints.

MARIHUANA AND MEDICINE, EDITED BY A VETERAN IN THE FIELD, New York University's Gabriel Nahas, and his colleagues, stems from the latest (March 1998) of several international conferences held since 1974. In the preface, Nahas states that "today the verdict of marihuana in medicine is finally at hand."

In the last of 71 chapters by 109 authors, he concludes that "marihuana or THC [(Delta)9-tetrahydrocannabinol] do not qualify as safe and effective medications... [and] have no place in modern pharmacopeia," despite the interesting potential of cannabinoids described by several of the clinicians who have contributed to the book. Nahas does acknowledge that the "invaluable information" provided by the experimental use of THC and its synthetic analogues has facilitated "a better understanding of membrane signal transduction." It can be anticipated that there will be much to mine from research when its emphasis and funding shift from drug abuse to evidence-based medical use.

Structurally, this book is flawed by its dependence on annoyingly brief contributions by so many of the authorities who participated in the two-day conference. Figures that were projected as slides and embellished by the conference's speakers often lack legends to assist the reader. Instead of critical editing, there are summary reports of previous conferences and reprinted articles, which add mostly outmoded data or opinions.

Unbridled redundancy abounds, whether it concerns the history of marijuana use and regulation or the receptor story. Acronyms go unexplained, the index is incomplete, and there are scores of typographic errors. Organized progression through the chapters is frequently interrupted, too often by material unrelated to the medical use of marijuana.

Some parts of the book are valuable. Though scattered and repetitious, the historical information is interesting. The reference lists after each chapter are extraordinarily complete, with many citations from the 1970s. The new chapters begin with helpful abstracts. Parts of the book should appeal to pharmacologists, particularly as a source of references.

Molecular neurobiologists will generally be less gratified. Yet there are recognized, contemporary scientists among the contributors, including Mechoulam, Devane, and Glaser (on pharmacology), Pertwee (on receptors and their ligands), Gardner and Hiroi (on the activation of dopamine receptors to induce genes involved in brain reward systems), and Sutin and Nahas (on the interactions of THC with other drugs and anesthetics).

Although conclusions about immune suppression by cannabinoids seem premature, if not unfounded, the chapters on the pathophysiology of the cardiovascular and pulmonary systems offer useful material. Paria and colleagues offer original data suggesting that activation of embryonic CB1 receptors by natural and synthetic ligands interferes with preimplantation development in embryonic mice.

Parker and Zuckerman convincingly demonstrate that marijuana use during pregnancy is associated with impaired fetal growth and lower birth weight and that those effects are magnified by unhealthy lifestyles.

Perhaps the book's most compact and yet comprehensive chapter -- and guide to potential drug development -- is provided by Lichtman and Martin, who focus on the receptor-mediated analgesic properties of THC and endogenous anandamide in animals and humans.

They suggest coadministration of these compounds with opioids to escape the side effects of either agent and even pharmaceutical manipulation of the endogenous cannabinoid system to relieve pain. In a subsequent chapter, Clark describes an experiment in which habitual users smoked marijuana during the second of three months' surveillance in a research facility.

Both the subjects' ability to discriminate among thermal stimuli of different intensities and the response bias (which reflects attitudinal and emotional factors that influence reporting bias, or responses based on expectation) were measured.

Marijuana at low doses appeared to create both better discrimination among graded stimuli and hyperalgesia. Higher doses had no effect on the amount of pain experienced. Such sensory decision-theory models recognize the emotional side of pain and are recommended for future studies of analgesia. And analgesia has commercial value.

Practicing physicians will gain most from six well-referenced chapters that address therapy for specific symptoms. Green dismisses cannabinoids for the treatment of glaucoma, despite their effectiveness in reducing intraocular pressure through aqueous outflow pathways; perhaps receptor-independent substances that are structurally related, such as HU211, will be proved neuroprotective.

Gralla elaborates on one of the two approved uses of dronabinol (a synthetic THC): control of chemotherapy-induced nausea and vomiting, for which very effective serotonin-receptor antagonists with dexamethasone are superior therapy.

He also forecasts the potential for neurokinin-receptor antagonists. Consroe summarizes the rationale for their use and the largely anecdotal evidence that cannabinoids relieve muscle spasticity in multiple sclerosis and spinal cord injury.

In dealing with therapy for the cachexia associated with AIDS, the other approved use of cannabinoids, Timpone and colleagues carefully compare dronabinol and megestrol acetate therapy; the latter in high doses was critical for any weight gain, even though both drugs increased appetite in placebo-controlled trials. Negrete and Gill warn of troubling negative effects of marijuana in persons with schizophrenia.

The book ends with brief attention to public policy and with repetition of the editors' conclusion that THC "deregulates the physiological signaling role of a receptor protein to which it binds and of the membrane bilipid layer which it permeates.

This deregulation of membrane signaling will result in discordant and partial therapeutic effects coupled with unwanted side effects." One can agree that, to date, drugs more effective than cannabinoids have prevailed. But the editors' drug-control bias obscures the promise of drug development.

John A. Benson, Jr., M.D. Oregon Health Sciences University Portland, OR 97201-3098

Pubdate: Thu, 17 Aug 2000 Source: New England Journal of Medicine (MA) Copyright: 2000 by the Massachusetts Medical Society Contact: comments@nej.org Website: http://www.nejm.org/ Author: Gabriel Nahas, Kenneth Sutin, and William M. Bennett, M.D.s Referenced:

REVIEW OF MARIHUANA AND MEDICINE

To the Editor:

At the end of his review of Marihuana and Medicine, Benson (Sept. 9 issue) (1) states, "The editors' drug-control bias obscures the promise of drug development." Dr. Benson is the senior editor of the 1999 report by the Institute of Medicine, "Marijuana and Medicine: Assessing the Science Base," (2) which recommends medicinal use of marijuana smoking, after describing its scientific basis. This scientific basis involves the assumption that there is an endogenous anandamide cannabinoid system, D9-tetrahydrocannabinol (THC), having a basic physiologic role. This rationale is described by Lichtman and Martin, in what Benson calls "the most compact and yet comprehensive chapter" in the book. However, it is not supported by our work and that of other investigators, described in other chapters of the book (Waser and Martin, (3) Sutin and Nahas, (4) and Nahas et al. (5)). This work challenges the cannabinoid hypothesis.

Of 60 natural cannabinoids, THC is the only one that binds to a membrane receptor. This receptor (7TM) is present in every cell. In binding to it, THC displaces its natural ligand, anandamide, and persistently disrupts the physiologic signaling of the 7TM receptor. The anomalies observed clinically when THC is present in the cell membrane (i.e., impaired brain, immune, (6) cardiovascular, and reproductive (7) functions) are associated with the molecular disruption of membrane signaling. (5) Because of the disruption of this molecular mechanism by THC, it has not been possible to separate the adverse effects of THC and marijuana from their therapeutic properties.

Benson does not mention the impairment of spermatogenesis in marijuana smokers, described in four chapters of Marihuana and Medicine, including one chapter that reports the inhibitory effect of THC on the acrosome reaction and egg fertilization. (6) Benson also dismisses the immunosuppressive effect of marijuana smoke on lung macrophages, an effect that raises questions about its utility in patients with AIDS.

Acceptance of the unproved scientific basis adopted by Dr. Benson might have led to the development of THC-like drugs that lacked specificity and had adverse effects at therapeutic doses. The alternative putative molecular mechanisms of THC that we propose merit open discussion without allusion to a social bias.

Gabriel Nahas, M.D. Kenneth Sutin, M.D. New York University Medical Center New York, NY 10016

William M. Bennett, M.D. Oregon University School of Medicine Portland, OR 97201-2940

References

1. Benson JA. Review of: Marihuana and medicine. N Engl J Med 1999;341:854-5.

2. Joy JE, Watson SJ Jr, Benson JA, eds. Marijuana and medicine: assessing the science base. Washington, D.C.: National Academy Press, 1999.

3. Waser PG, Martin A. Barbiturate potentiating, temperature reducing, analgesic, and behavioral effects of some synthetic tetrahydrocannabinol derivatives in comparison with D9-tetrahydrocannabinol. In: Nahas GG, Sutin MK, Harvey DJ, Agurell S, eds. Marihuana and medicine. Totowa, N.J.: Humana Press, 1999:527-39.

4. Sutin KM, Nahas GG. Physiological and pharmacological interactions of marihuana (THC) with drugs and anesthetics. In: Nahas GG, Sutin MK, Harvey DJ, Agurell S, eds. Marihuana and medicine. Totowa, N.J.: Humana Press, 1999:253-71.

5. Nahas GG, Harvey D, Sutin K, Agurell S. Receptor and nonreceptor membrane-mediated effects of THC and cannabinoids. In: Nahas GG, Sutin MK, Harvey DJ, Agurell S, eds. Marihuana and medicine. Totowa, N.J.: Humana Press, 1999:781-805.

6. Cabral GA. Marihuana and the immune system. In: Nahas GG, Sutin MK, Harvey DJ, Agurell S, eds. Marihuana and medicine. Totowa, N.J.: Humana Press, 1999:317-25.

7. Schuel H, Chang MC, Burkman LJ, et al. Cannabinoid receptors in sperm. In: Nahas GG, Sutin MK, Harvey DJ, Agurell S, eds. Marihuana and medicine. Totowa, N.J.: Humana Press, 1999:335-45.