Leading physicians and scientists from around the world critically examine the pharmacological and molecular basis of the therapeutic properties of marihuana and its active ingredient, THC. They detail the broad array of marihuana's effects on brain function, the immune system, male and female reproductive functions, and cardiac and pulmonary functions, as well as evaluate its clinical applications in psychiatry, glaucoma, pain management, cancer chemotherapy, and AIDS treatment. Their studies indicate that marihuana persistently impairs the brain and reproductive function, and that marihuana smoke is more toxic and damaging to the lung than tobacco smoke. Marihuana and Medicine's reports of the latest findings on the pharmacological and molecular mechanisms of marihuana and of its clinical manifestations will be essential reading for physicians, psychiatrists, pharmacologists, health-care professionals, policy makers, public health officials, and attorneys.
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In Marihuana and Medicine, leading physicians and scientists from around the world critically review the pharmacological and molecular basis of the therapeutic properties of marihuana and its active ingredient, THC. They detail the broad array of marihuana's effects on brain function, the immune system, male and female reproductive function, and cardiac and pulmonary function, as well as evaluate its clinical applications in psychiatry, glaucoma, pain management, cancer chemotherapy, and AIDS treatment. Their work indicates that marihuana impairs brain and reproductive function, is harmful to the immune system, is more damaging when smoked to the lung than tobacco smoke, and is not an effective, medically acceptable therapeutic vehicle for THC. The editors have also included key historical material tracing the controversial history of marihuana in science and medicine over the centuries.
Marihuana and Medicine's report of the latest findings on the pharmacological, pharmacodynamic, and molecular mechanisms of marihuana will be essential reading for clinicians, psychiatrists, pharmacologists, policy makers, health-care workers, and attorneys.
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.
Reviewed by John A. Benson, Jr., M.D.
Copyright © 1999 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
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