Pubdate: Thu, 09 Sep 1999
Source: New England Journal of Medicine (MA)
Copyright: 1999 by the Massachusetts Medical Society
Section: Book Review
Author: John A. Benson, Jr., M.D. Oregon Health Sciences University 


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.

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

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
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