DOES MARIJUANA HAVE A PLACE IN MEDICINE?

Abstract: Few studies have been conducted on the medical efficacy of smoked
marijuana although substantial anecdotal evidence suggests smoked marijuana
has many therapeutic uses such as the ability to enhance the appetite in
AIDS patients and control nausea and vomiting due to cancer chemotherapy.

In the moral, legal, and medical realms, the use of medical marijuana is a
hotly contested issue. What do we really know about its efficacy? When, if
ever, is it recommended?

In the crude herb Cannabis sativa L. (Cannabaceae)--more commonly known as
marijuana, pot, or hemp--delta-9-tetrahydrocannabinol (THC) occurs as a
sticky, extractable, resinous oil. In total, marijuana contains more than
60 cannabinoids, most of them poorly characterized. The major psychoactive
ingredient appears to be THC, however. Whether marijuana is smoked, eaten,
brewed in a tea, or swallowed in pill form, THC is the major ingredient
affecting the CNS. This is also true of dronabinol, marijuana's chemically
synthesized THC counterpart ("medical marijuana"), which is formulated in
sesame oil and supplied in 2.5-, 5-, or 10-mg gelatin capsules.

Some argue that manufacturing dronabinol by extracting only one of many
cannabinoids produces an agent that is less effective than the
polypharmaceutical herb marijuana.[1] Others feel very strongly that as
long as dronabinol is available, the Drug Enforcement Agency (DEA) does not
need to reschedule crude marijuana as a medicinal drug. With the passage of
bills in California and Arizona recognizing marijuana as a medication,
there is increasing political and public pressure for a final decision on
the legal status of smoked marijuana as a regulated substance prescribed
for medicinal purposes. The few studies that have examined the medical
efficacy of smoked marijuana were conducted in the 1970s and 1980s. While
the debate rages, marijuana remains illegal, and dronabinol is the only
legally available THC. With the advent of serotonin antagonists, the need
for medicinal THC as an antiemetic is less clear than ever.

HOW DRONABINOL WORKS

Dronabinol, a Schedule II (prescription only) controlled substance, affects
receptors in the brain and the spinal cord. It is labeled for use in the
treatment of anorexia associated with weight loss in patients with AIDS and
for the nausea and vomiting associated with cancer chemotherapy in patients
who have failed to respond adequately to conventional antiemetic treatment.
Although it is an efficacious antiemetic, it may have significant side
effects.[2] Dronabinol is often used as a rescue medication when other
drugs do not work, rather than as a first-line treatment. It is prescribed
primarily by oncologists, although other physicians use it off-label,
either alone or as an adjunct, in treating glaucoma and epilepsy and to
relieve tremor, ataxia, and muscular spasticity in patients with multiple
sclerosis (MS).

Dronabinol is clearly most useful as a treatment option when nausea and
vomiting are uncontrolled by other means, and its stimulating effect on the
appetite may continue for 24 hours or longer after administration. It can
also be administered with a variety of medications (eg, many cytotoxic
agents, anti-infective agents, sedatives, or opioid analgesics) without
causing clinically significant drug interactions. Synthetic THC may
interact with some medications, however, through both metabolic and
pharmacodynamic mechanisms, at least theoretically. Dronabinol is highly
protein-bound, for example, and therefore might displace other
protein-bound drugs, and patients should be monitored for possible changes
in dosage requirements.

Oral THC capsules have other disadvantages. A patient suffering from nausea
and vomiting may be unable to swallow the pill or keep it down. A
suppository form appears to have been successful in clinical trials, but it
is not yet available. Trials with a dronabinol nasal inhaler are also under
way.

It is difficult to titrate dronabinol because of its erratic
bioavailability and relatively slow onset of action. Onset is delayed for
approximately 30-60 minutes, with a peak effect at 2-4 hours. The
psychoactive effects last for 4-6 hours, and side effects may be prolonged.
Dronabinol-induced parasympatholytic-like activity may result in
tachycardia or conjunctivitis. Effects on blood pressure are inconsistent,
and some patients have experienced orthostatic hypotension or syncope.

Dronabinol must be taken on a regular schedule; treatment is initiated with
a low dosage (2.5 mg/d), which is increased only as necessary. Possible
psychoactive side effects include impairment of coordination, mood, and
perception and are the biggest drawback to the medical use of THC. They may
be most severe in patients who are not experienced cannabinoid users.
Tachyphylaxis and tolerance to some of the pharmacological effects develop
with chronic use.

ALTERNATIVES TO THC

At least seven controlled studies comparing prochlorperazine maleate with
synthetic THC were performed more than a decade ago.[3] Several other
antiemetics have come to the fore since then, but they have not been
compared to THC in controlled clinical trials. These newer drugs include
the serotonin antagonists ondansetron HCl dihydrate and granisetron HCl,
which are more effective and cause fewer side effects than prochlorperazine
and can be administered to children.

A number of dopamine receptor blockers are currently used to treat nausea,
including metoclopramide HCl, haloperidol, and cisapride. Two studies
comparing the antiemetic effects of oral THC and metoclopramide have
yielded mixed results.[3, 4] Corticosteroids like dexamethasone and
methylprednisolone acetate and minor tranquilizers, such as lorazepam, have
proven safe and effective for the treatment of chemotherapy-induced nausea
and vomiting, especially when used in conjunction with other antinausea
medications such as scopolamine.[5] Even a combination sedative/antiemetic
in the phenothiazine family, such as chlorpromazine HCl, can be used.

INHALED MARIJUANA

Few of the more than 60 active cannabinoids found in crude marijuana have
been studied. There is speculation that some of the non-THC cannabinoids
may help confer the additional benefits reported by those who smoke or eat
marijuana, although no human trials confirm this. Little information about
the efficacy of inhaled marijuana has been derived from clinical trials,
but an abundance of anecdotal and clinical reports exist. In fact,
marijuana was widely prescribed by Western physicians in the mid-19th
century for asthma, insomnia, dysmenorrhea, convulsions, and a number of
other complaints.

Today, whole cannabis is thought to be effective in a wide range of
conditions, including appetite enhancement for the wasting syndrome of
AIDS, control of nausea and vomiting associated with cancer chemotherapy,
relief of spasticity and pain associated with MS, a decrease in intraocular
pressure in glaucoma, and control of migraine headaches and epileptic
seizures. Many of the compounds contained in marijuana have demonstrated
pain-relieving actions in animal tests, although few studies of cannabinoid
effects on pain have been conducted in humans.[6] As is the case with
dronabinol, these benefits come with possible psychotropic effects that can
impair normal activities.

Inhaling smoke, which irritates the throat and lungs, can lead to
respiratory problems. Marijuana use by patients with AIDS is discouraged
since it is not known to what extent marijuana may further compromise the
lungs' immune defenses and predispose the patient to opportunistic
pulmonary infections.[7, 8] The illegality of marijuana has made it
difficult to scientifically document a connection with lung disease or the
effects of passive exposure to marijuana smoke.

It has been suggested that alternate drug delivery devices and marijuana
extracts be studied for use in lieu of smoking an unfiltered marijuana
cigarette. Examples include different kinds of water pipes, filters, and
vaporizing devices that could selectively remove potentially harmful
elements from marijuana smoke. Water pipes have always been available as
illegal drug paraphernalia. Research has shown that THC, the active
antinausea agent in marijuana, is more quickly absorbed when marijuana is
smoked rather than ingested. According to one study, a substantial
proportion of practicing oncologists who responded to the survey regard
smoked cannabis as a safe and effective antinausea agent.[1]

COMPARING DRONABINOL AND MARIJUANA

Quality control is another factor to consider when comparing dronabinol
with smoked marijuana. The synthetic THC found in dronabinol is
manufactured under sterile, controlled conditions. There are numerous
variables in the production of illegal marijuana. The quality of the herb
is affected by soil conditions, water quality, and humidity and temperature
control. For example, like all plants, cannabis accumulates metal from the
soil, and soils in different parts of the country contain varying levels of
mercury, lithium, cadmium, and copper.

Since the crop is produced illegally, contamination by unrestricted use or
overuse of pesticides, herbicides, fungicides, or insecticides may occur.
In addition, the marijuana plant is often plagued with pathogenic fungi,
such as Aspergillus or Fusarium. It can also transmit other fungal
infections such as histoplasmosis. This problem can be eradicated by proper
sterilization, though, and baking marijuana kills Aspergillus spores with
no effect on THC content.[9]

Dronabinol can be produced in specific potencies, but variations in growing
climate and product preparation greatly affect available THC levels in
marijuana. The more potent, resinous hemp is grown in hot, moist southern
climates. Furthermore, the concentration of THC in a marijuana cigarette,
commonly called a joint, which contains dried stems, leaves, and flowers,
is much lower than the THC level in hashish--a preparation of the
unadulterated resin scraped from the flowering tops of the female hemp
plants. Hashish, or hash, is usually shaped like a bar of soap, and a piece
is broken off and used in a pipe or water pipe, or sometimes crumbled up
with marijuana and rolled into a cigarette. Like marijuana, it can be eaten.

Government-produced cigarettes sponsored by the National Institute on Drug
Abuse are reported to be bacteria- and fungus-free as well as consistent in
THC level. Many supporters of marijuana for medical use, therefore, support
governmental control of the production of cannabis for safety and
consistency of THC levels and the elimination of fungi and bacteria.

The bioavailability of dronabinol and marijuana vary tremendously in
individuals and from day to day in the same person. Even though synthetic
THC is available in three strengths, it can be very difficult to define
appropriate dose and determine what time day the patient needs to take it.
Some stud suggest that smoking is a more efficient delivery system for THC
than dronabinol because the patient gets near-immediate results and can
self-titrate--although the ability to self-titrate has been questioned.[10]
Smoking marijuana appears to surpass eating crude marijuana in terms of
control of titration. In addition, eating marijuana may be difficult for
patients who are anorectic, nauseated, or vomiting.[10, 11]

Smoking a cannabis cigarette is associated with a nearly fivefold increase
in the carboxyhemoglobin concentration compared to that associated with
smoking a tobacco cigarette. More tar is also inhaled and retained in the
respiratory tract when smoking marijuana.[12] It's true too, however, that
the medicinal use of inhaled marijuana entails smoking far fewer cigarettes
than the number typically smoked by a tobacco user.

Cardiac effects such as tachycardia and hypotension are common with both
dronabinol and smoked marijuana. Although these effects may be of minimal
consequence in younger persons, elderly patients may be more sensitive to
them. The adverse reactions can also be more prominent in the inexperienced
marijuana user.

Proponents of smoked marijuana for medical use believe that
government-approved marijuana would be less expensive than dronabinol or
the new antiemetics. For example, ondansetron costs $120-$160 for oral
administration but, because of nausea and vomiting, especially in AIDS
patients, IV administration is often required at a cost of about $600.[13]
Without the black market, the price of government-grown marijuana
cigarettes could be quite low.

WHAT'S NEXT

Supporters of smoked marijuana for medical use believe that governmental
control over marijuana as a Schedule I substance (no currently accepted
medical use) has prevented an objective evaluation of the drug in
controlled clinical trials. In fact, no major trials to assess marijuana's
safety or efficacy have been conducted. Some people believe that the
federal government should remove legal barriers to research, provide direct
or indirect financial support to research, and, in the meantime, allow
continued and expanded use of the drug on a compassionate-use basis. [14, 15]

Many physicians say that if cannabinoids are found to be as effective as
other available medications, they would prescribe them. At the least, many
physicians would like to put the issue to rest once and for all. Many
doctors believe that the greatest danger in the medical use of marijuana is
its illegality, which imposes much anxiety and expense on suffering people,
forces them to bargain with illicit drug dealers, and exposes them to
threats of criminal prosecution. Only clinical research comparing
dronabinol to other tetrahydro-cannabinoids and cannabinoids for
therapeutic efficacy can clarify this controversy. The National Institutes
of Health are open to receiving research grant applications for studies of
the medical efficacy of marijuana, and they have recently provided a $1
million grant to the Institute of Medicine to review scientific and
laboratory tests on marijuana.

RELATED ARTICLE: Drugs mentioned in this article

Chlorpromazine HCI (Thorazine)

Cisapride (Propulsid

Dexamethasone (Decadron, Hexadrol)

Granisetron HCI (Kytril)

Haloperidol (Haldol)

Lorazepam (Ativan)

Methylprednisolone acetate (Deop-Medrol)

Metoclopramide HCI (Zofran)

Prochlorperazine maleate (Compazine)

Scopolamine HBr (injectable)

REFERENCES

[1.] Doblin RE, Kleiman MAR: Marijuana as antiemetic medicine: A survey of
oncologists' experiences and attitudes. J Clin Oncol 1991;9:1314-1319.

[2.] Beal JE, Olson DO, Laubenstein L, et al: Dronabinol as a treatment for
anorexia associated with weight loss in patients with AIDS. J Pain Sympton
Manage 1995;10:89-97.

[3.] Ekert H, Waters KD, Jurk IH, et al: Amerlioration of cancer
chemotherapy-induced nausea and vomiting by delta-9-tetrahyrdocannabinol.
Med J Aust 1979;2:657-659.

[4.] Gralia RJ, Tyson LB, Clark RA, et al: Antiemetic trials with high dose
metoclopramide: Superiority over THC, preservation of efficacy in
subsequent chemotherapy courses, abstracted. Proceedings of the American
Society of Clinical Oncology 1982;1:58.

[5.] Grunberg SM, Hesketh PJ: Control of chemotherapy-induced emesis. N
Engl J Med 1993;24:1790-1796.

[6.] Hardman JG (ed): Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, Ninth Edition. New York, McGraw-Hill, 1996.

[7.] Sherman MP, Campbell LA, Gong H Jr, et al: Antimicrobial and
respiratory burst characteristics of pulmonary alveolar macrophages
recovered from smokers of marijuana alone, smokers of tobacco alone,
smokers of marijuana and tobacco, and nonsmokers. Am Rev Respir Dis
1991;144:1351-1356.

[8.] Baldwin GC, Tashkin DP, Buckley DM, et al: Marijuana and cocaine
impair alveolar macrophage function and cytokine production. Am J Respir
Care Med 1997;156:1606-1613.

[9.] Levitz SM, Diamond RD: Aspergillosis and marijuana. Ann Intern Med
1991; 115:578-579.

[10.] Matthias P, Tashkin DP, Marques-Magallanes JA, et al: Effects of
varying marijuana potency on deposition of tar and [Delta][9]-THC in the
lung during smoking. Pharmacol Biochem Behav 1997;58:1045-1050.

[11.] Mattes RD, Engelman K, Shaw LM, et al: Cannabinoids and appettite
stimulation. Pharmacol Biochem Behav 1994;49:187-195.

[12.] Nahas G, Latour C: The human toxicity of marijuana. Med J Aust 1992;
156:495-497.

[13.] Nelan EH: Medical marijuana: Research priority, hoax or civil right?
Gay Men's Health Crisis Treatment Issues 1997;11:1-3.

[14.] Kassirer JP: Federal foolishness and marijuana, editorial, N Engl J
Med 1997; 336-336-367.

[15.] Annas GJ: Reefer madness: The federal response to California's
medical-marijuana law. N Engl J Med 1997;337:435-439.

SUGGESTED READING

Grinspoon L, Bakalar JB: Maruhuana as medicine: a plea for reconsideration.
http://206.61.184.43/schaffer/hemp/medical/grinjama/htm

Grinspoon L, Bakalar J: Marihuana, the Forbidden Medicine, New Haven, Conn,
Yale Univ Pr, 1993.

Major studies of drugs and drug policy,
http://206.61.184.43/schaffer/library/ studies/studies.com

Report of the US National Commission of Marihuana and Drug Abuse, 1972:
History of marijuana use: Medical and antoxicant.
http://206.61.184.43/schaffer/ library/studies/nc/nc1a.htm

Rosenthal E, Mikuriya T, Gieringer D: Marijuana Medical Handbook: A guide
to therapeutic use. Oakland, Calif, Quick American Archives, 1997.

Schwartz RH, Beveridge RA: Marijuana as an antiemetic drug: How useful is
it today? Opinions from clinical oncologists. J Addict Dis 1994;13:53-65.

Schwartz RH, voth EA, Sheridan MJ: Marijuana to prevent neusea and vomiting
in cancer patients: A survey of clinical oncologists. South Med J
1997;90:167-172.

Voth EA, Schwartz RH: Medicinal applications of
delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 1997;126-791-798.

Wu T-C, Tashkin DP, Djahed B, et al: Pulmonary hazards of smoking marijuana
as compared with tobacco. N Engl J Med 1988;318:347-351.

ARTICLE CONSULTANTS

LISA CAPADINI, MD is Associate clinical Professor of Medicine, University
of California, San Francisco, School of Medicine; and Director, Castro
Medical Clinic, San Francisco.

DONALD TASHKIN, MD, is Professor of Medicine, Division of Pulmonary and
Critical Care Medicine, Department of Medicine, University of California,
Los Angeles, UCLA School of Medicine; and a researcher for the National
Institute on Drug Abuse, Bethesda, Md.

WILLIAM VILENSKY, RPh, DO, is Clinical Associate Professor, Department of
Family Medicine, Robert Wood Johnson Medical School, University of Medicine
and Dentistry of New Jersey, Piscataway; Clinical Associate Professor,
Department of Psychiatry. UMDMJ--New Jersey Medical School, Newark; and
Executive Medical Director, Forensic and Educational Consultants, Margate,
N.J.

Full Text COPYRIGHT 1998 Medical Economics Publishing