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.