are in Research|
the Department of Psychiatry, Harvard Medical School, and the Massachusetts Mental
Health Center, Boston.
requests to Harvard Medical School, 74 Fenwood Rd, Boston, MA 02115 (Dr Grinspoon).
June 21, 1995 -- Vol. 273, No. 23 1875
Plea for Reconsideration
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.
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.
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
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
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.
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
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.
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.
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)
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.
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.
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.
B. Bakalar, JD
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.
Grinspoon L., Bakalar J. Marihuana, the Forbidden Medicine. New Haven, Conn.:
Yale University Press; 1993.
In the Matter of Marijuana Rescheduling Petition, Docket 86-22, Affidavit of Daniel
Daneac, M.D. Washington, DC: Drug Enforcement Agency; 1987.
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.
JAMA, June 21, 1995 -- Vol. 273, No. 23