Commentary
 
Marihuana as Medicine
 
A Plea for Reconsideration
 
BETWEEN 1840 and 1900, European and American medical journals published
more than 100 articles on the therapeutic use of the drug known then as
Cannabis indica (or Indian hemp) and now as marihuana.  It was recommended
as an appetite stimulant, muscle relaxant, analgesic, hypnotic, and
anticonvulsant.  As late as 1913 Sir William Osler recommended it as the
most satisfactory remedy for migraine.
 
Today the 5000-year medical history of cannabis has been almost forgotten.
Its use declined in the early 20th century because the potency of
preparations was variable, responses to oral ingestion were erratic, and
alternatives became available -- injectable opiates and, later, synthetic
drugs such as aspirin and barbiturates.  In the United States, the final
blow was struck by the Marihuana Tax Act of 1937.  Designed to prevent
nonmedical use, this law made cannabis so difficult to obtain for medical
purposes that it was removed from the pharmacopeia.  It is now confined to
Schedule I under the Controlled Substances Act as a drug that has a high
potential for abuse, lacks an accepted medical use, and is unsafe for use
under medical supervision.
 
In 1972 the National Organization for the Reform of Marijuana Laws
petitioned the Bureau of Narcotics and Dangerous Drugs, later renamed the
Drug Enforcement Administration (DEA), to transfer marihuana to Schedule II
so that it could be legally prescribed.  As the proceedings continued,
other parties joined, including the Physicians Association for AIDS
[acquired immunodeficiency syndrome] Care.  It was only in 1986, after many
years of legal maneuvering, that the DEA acceded to the demand for the
public hearings required by law.  During the hearings, which lasted 2
years, many patients and physicians testified, and thousands of pages of
documentation were introduced.  In 1988 the DEA's own administrative law
judge, Francis L.  Young, declared that marihuana in its natural form
fulfilled the legal requirement of currently accepted medical use in
treatment in the United States.  He added that it was "one of the safest
therapeutically active substances known to man." His order that the
marihuana plant be transferred to Schedule II was overruled, not by any
medical authority, but by the DEA itself, which issued a final rejection of
all pleas for reclassification in Mach 1992.
 
Meanwhile, a few patients have been able to obtain marihuana legally for
therapeutic purposes.  Since 1978, legislation permitting patients with
certain disorders to use marihuana with a physician's approval has been
enacted in 36 states.  Although federal regulations and procedures made the
laws difficult to implement, 10 states eventually established formal
marihuana research programs to seek Food and Drug Administration (FDA)
approval for Investigational New Drug (IND) applications.  These programs
were later abandoned, mainly because the bureaucratic burden on physicians
and patients became intolerable.
 
Growing demand also forced the FDA to Institute an Individual Treatment IND
(commonly referred to as a Compassionate IND) for the use of physicians
whose patients needed marihuana because no other drug would produce the
same therapeutic effect.  The application process was made enormously
complicated, and most physicians did not want to become involved,
especially since many believed there was some stigma attached to
prescribing cannabis.  Between 1976 and 1988 the government reluctantly
awarded about a half dozen Compassionate INDs for the use of marihuana.  In
1989 the FDA was deluged with new applications from people with AIDS, and
the number granted rose to 34 within a year.  In June 1991, the Public
Health Service announced that the program would be suspended because it
undercut the administration's opposition to the use of illegal drugs.
After that no new Compassionate INDs were granted, and the program was
discontinued in March 1992.  Eight patients are still receiving marihuana
under the original program; for everyone else it is officially a forbidden
medicine.
 
And yet physicians and patients in increasing numbers continue to relearn
through personal experience the lessons of the 19th century.  Many people
know that marihuana is now being used illegally for the nausea and vomiting
induced by chemotherapy.  Some know that it lowers intraocular pressure in
glaucoma.  Patients have found it useful as an anticonvulsant, as a muscle
relaxant in spastic disorders, and as an appetite stimulant in the wasting
syndrome of human immunodeficiency virus infection.  It is also being used
to relieve phantom limb pain, menstrual cramps, and other types of chronic
pain, including (as Osler might have predicted) migraine.2 Polls and voter
referenda have repeatedly indicated that the vast majority of Americans
think marihuana should be medically available.
 
One of marihuana's greatest advantages as a medicine is its remarkable
safety.  It has little effect on major physiological functions.  There is
no known case of a lethal overdose; on the basis of animal models, the
ratio of lethal to effective dose is estimated as 40,000 to 1.  By
comparison, the ratio is between 3 and 50 to 1 for secobarbital and between
4 and 10 to 1 for ethanol.  Marihuana is also far less addictive and far
less subject to abuse than many drugs now used as muscle relaxants,
hypnotics, and analgesics.  The chief legitimate concern is the effect of
smoking on the lungs.  Cannabis smoke carries even more tars and other
particulate matter than tobacco smoke.  But the amount smoked is much less,
especially in medical use, and once marihuana is an openly recognized
medicine, solutions may be found.  Water pipes are a partial answer;
ultimately a technology for the inhalation of cannabinoid vapors could be
developed.  Even If smoking continued, legal availability would make it
easier to take precautions against aspergilli and other pathogens.  At
present, the greatest danger in medical use of marihuana is its illegality,
which imposes much anxiety and expense on suffering people, forces them to
bargain with illicit drug dealers, and exposes them to the threat of
criminal prosecution.
 
The main active substance in cannabis, [delta-9]-tetrahydrocannabinol
([delta-9]-THC), has been available for limited purposes as a Schedule II
synthetic drug since 1985.  This medicine, dronabinol (Marinol), taken
orally in capsule form, is sometimes said to obviate the need for medical
marihuana.  Patients and physicians who have tried both disagree.  The
dosage and duration of action of marihuana are easier to control, and other
cannabinoids in the marihuana plant may modify the action of [delta-9]-THC.
The development of cannabinoids in pure form should certainly be
encouraged, but the time and resources required are great and at present
unavailable.  In these circumstances, further isolation, testing, and
development of individual cannabinoids should not be considered a
substitute for meeting the immediate needs of suffering people.
 
Although it is often objected that the medical usefulness of marihuana has
not been demonstrated by controlled studies, several informal experiments
involving large numbers of subjects suggest an advantage for marihuana over
oral [delta-9]-THC and other medicines.  For example, from 1978 through
1986 the state research program in New Mexico provided marihuana or
synthetic [delta-9]-THC to about 250 cancer patients receiving chemotherapy
after conventional medications failed to control their nausea and vomiting.
A physician who worked with the program testified at a DEA hearing that for
these patients marihuana was clearly superior to both chlorpromazine and
synthetic [delta-9]-THC.3 It is true that we do not have studies controlled
according to the standards required by the FDA -- chiefly because legal,
bureaucratic, and financial obstacles are constantly put in the way.  The
situation is ironical, since so much research has been done on marihuana,
often in unsuccessful attempts to prove its dangerous and addictive
character, that we know more about it than about most prescription drugs.
 
Physicians should offer more encouragement to controlled research, but it
too has limitations.  Individual therapeutic responses can be obscured by
the statistical results of group experiments in which there is little
effort to identify the specific features of a patient that affect the drug
response.  Furthermore, much of our knowledge of synthetic medicines as
well as plant derivatives comes from anecdotal evidence.  For example, as
early as 1976 several small, methodologically imperfect, and relatively
obscure studies had shown that taking an aspirin a day could prevent a
second heart attack.  In 1988 a large-scale experiment demonstrated
dramatic effects.  This story is suggestive, because marihuana, like
aspirin, is a substance known to be unusually safe and to have enormous
potential health benefits.
 
Cannabis can also bring about immediate relief of suffering measurable in a
study with only one subject.  In the experimental method known as the
single patient randomized trial, active and placebo treatments are
administered randomly in alternation or succession to a patient.  The
method is often useful when large scale controlled studies are impossible
or inappropriate because the disorder is rare, the patient is atypical, or
the response to the treatment is idiosyncratic.  Many patients, either
deliberately or because of unreliable supplies, have informally carried out
somewhat similar experiments by alternating periods of cannabis use with
periods of no use in the treatment of various disorders.2(pp.133-135)
 
The American Medical Association was one of the few organizations that
raised a voice in opposition to the Marihuana Tax Act of 1937, yet today
most physicians seem to take little active interest in the subject, and
their silence is often cited by those who are determined that marihuana
shall remain a forbidden medicine.  Meanwhile, many physicians pretend to
ignore the fact that their patients with cancer, AIDS, or multiple
sclerosis are smoking marihuana for relief; some quietly encourage them.
In a 1990 survey, 44% of oncologists said they had suggested that a patient
smoke marihuana for relief of the nausea induced by chemotherapy.4 If
marihuana were actually unsafe for use even under medical supervision, as
its Schedule I status explicitly affirms, this recommendation would be
unthinkable.  It is time for physicians to acknowledge more openly that the
present classification is scientifically, legally, and morally wrong.
 
Physicians have both a right and a duty to be skeptical about therapeutic
claims for any substance, but only after putting aside fears and doubts
connected with the stigma of illicit nonmedical drug use.  Advocates of
medical use of marihuana are sometimes charged with using medicine as a
wedge to open a way for "recreational" use.  The accusation is false as
applied to its target, but expresses in a distorted form a truth about some
opponents of medical marihuana; they will not admit that it can be a safe
and effective medicine largely because they are stubbornly committed to
exaggerating its dangers when used for nonmedical purposes.
 
We are not asking readers for immediate agreement with our affirmation that
marihuana is medically useful, but we hope they will do more to encourage
open and legal exploration of its potential.  The ostensible indifference
of physicians should no longer be used as a justification for keeping this
medicine in the shadows.
 
Lester Grinspoon, MD James B. Bakalar, JD
 
1.  In the Matter of Marijuana Rescheduling Petition, Docket 86-22,
Opinion, Recommended Ruling, Findings of Fact, Conclusions of Law, and
Decision of Administrative Law Judge, September 6, 1988.  Washington, DC:
Drug Enforcement Agency; 1988.
 
2.  Grinspoon L., Bakalar J.  Marihuana, the Forbidden Medicine.  New
Haven, Conn.:  Yale University Press; 1993.
 
3.  In the Matter of Marijuana Rescheduling Petition, Docket 86-22,
Affidavit of Daniel Daneac, M.D.  Washington, DC:  Drug Enforcement Agency;
1987.
 
4.  Doblin R., Kleiman M.A.R.  Marihuana as anti-emetic medicine:  a survey
of oncologists' attitudes and experiences.  J Clin Oncol, 1991;9:1275-1290.
 
From the Department of Psychiatry, Harvard Medical School, and the
Massachusetts Mental Health Center, Boston.
 
Reprint requests to Harvard Medical School, 74 Fenwood Rd, Boston, MA 02115
(Dr Grinspoon).
 
JAMA, June 21, 1995 -- Vol. 273, No. 23, pp. 1875-1876 
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