UNIVERSITY OF CALIFORNIA
ENVIRONMENTAL TOXICOLOGY NEWSLETTER
Vol.3 Number 3 1983
The following report in the MMWR on the use of marijuana by the US population has pointed to the need for this newsletter. Marijuana use has been a topic of controversy for decades and promises to continue as such for years to come. Between 1973 to 1977 I directed laboratory research on the pharmacological and toxicological effects of one of the active ingredients of marijuana, and also gave many lectures on the topic. I am familiar with much of the scientific and popular literature published about it. Much of the controversy surrounding marijuana use has to do with moral issues which can influence scientific interpretation of objective data. Because marijuana is not a legal recreational drug, any use of it can be classified as abuse. However, once-a-day use of marijuana cannot be equated with habitual, heavy use many times per day. The same is true for alcohol and other "recreational drugs." Please keep these concepts in mind as you read and interpret this information.
THE SURGEON GENERALS WARNING ON MARIJUANA
The Surgeon General of the Public Health Service has issued the following warning on marijuana:
Marijuana use is a major public health problem in the United States. In the past 20 years, its use has increased 30- fold; it is estimated that more than a quarter of the American population has used it. The age at which persons first use marijuana has decreased gradually to the junior high school years. Until recently, nearly 11% of high school seniors used it, and although that figure has declined to 7%, its daily use still exceeds that of alcohol; more high school seniors use marijuana than smoke cigarettes. In a recent study, 32% of those surveyed had used marijuana during the previous 30 days, while 25% had smoked tobacco.
On March 24, 1982, the Department of Health and Human Services submitted to Congress a report reviewing the consequences of marijuana use. Acute intoxication with marijuana interferes with many aspects of mental functioning and has serious, acute effects on perception and skilled performance, such as driving and other complex tasks involving judgement or fine motor skills.
Among the known or suspected chronic effects of marijuana are:
Of special concern are the long-term developmental effects in children and adolescents, who are particularly vulnerable to the drug's behavioral and psychological effects. The "amotivational syndrome," characterized by a pattern of energy loss, diminished school performance, harmed parental relationships, and other behavioral disruptions, has been associated with prolonged marijuana use by young persons. Although more research is required, recent national surveys report that 40% of heavy users experience some or all of those symptoms.
Morbidity and Mortality Weekly Report August 13, 1982/Vol. 31/ No. 31
I. SOURCE AND HISTORY
Marijuana is the common name for the plant Cannabis sativa L. Marijuana is a dioecious plant (separate plants have the male and female flowers) that has a world-wide distribution, and is very often cultivated. It has been known to have pharmacological effects for centuries and its medicinal use was first reported in a Chinese monograph in 2737 B.C. In the 1800s an English Army physician wrote an article about the medicinal use of Cannabis in India and subsequently marijuana was introduced into western medicine. Certain preparations were even listed in the U.S. Pharmacopoeia from 1850 to 1942. Medicinal use of Cannabis in the United States was essentially stopped in 1937 after passage of the Marijuana Tax Act. In the last five years, marijuana has been recognized to have some unique pharmacological actions that should have a place in modern medical practice. Marijuana and the active chemicals from marijuana are classified as Schedule I drugs by the Drug Enforcement Administration (formerly the Bureau of Narcotics and Dangerous Drugs.) Schedule I Drugs are considered to have a high abuse potential and no accepted medicinal use. While the former is accepted by most people, the latter is currently a matter of contention.
II. CHEMICAL COMPOSITION
More than 400 different chemicals have been identified in crude marijuana extracts. The major psychoactive ingredient is a compound known as delta-9-tetrahydrocannabinol (THC). There are many other structurally related cannabinoids present in marijuana and some of these cannabinoids also have pharmacologic activity. THC is an oily reddish liquid at room temperatures. It is a very lipid soluble chemical that is virtually insoluble in water. THC does not exist in powdered form.*
(Ed. Note. At Washington State University we ran a street-drug analysis program and we received many samples of white powders purported to be THC. These usually turned out to be phencyclidine, a much more hazardous psychoactive chemical.)
III. PHARMACOLOGY: PHARMACOKINETICS
The usual route of exposure to THC is respiratory. Inhalation of marijuana smoke results in very fast and complete absorption of volatilized THC. This route of administration causes the most rapid effect and allows the user to "titrate" the degree of psychological effect desired . Oral administration of the plant material or actual THC results in poor, variable absorption which is not "titratable". Many of the adverse reactions to marijuana are due to oral ingestion of large amounts which have a long, slow onset of effect and result in a greater response than desired.
After smoking marijuana the highest concentrations of THC are found in the lungs. Because THC is such a lipid soluble chemical, it has an affinity for "fatty" organs like the liver and brain. Initially the brain receives a large amount of the THC absorbed from the lungs. This is because of the proportionally large amount of blood that the brain receives compared to the rest of the body.
There is much evidence to indicate that THC is bioactivated by metabolism in the lungs and liver. The first step in THC metabolism is the addition of a hydroxyl group at the 11 position resulting in 11- hydroxy-delta-9-THC which is an active metabolite. The 11-hydroxy-delta-9-THC is further metabolized (primarily in the liver) to 8,11-dihydroxy-delta-9-THC which is an inactive product. Other metabolic reactions do take place and many other metabolites are known, however these two mechanisms are the most important.
The principal route of excretion of THC metabolites is the feces. Only very small amounts are excreted in the urine. The half-life (t1/2) in the body for the metabolites is about 50 hours. The t 1/2 in chronic users is about 28 hours which indicates that smoking marijuana induces the metabolism of THC. It is also known that chronic marijuana use can also induce the metabolism of other drugs. The induction of drug metabolism is a well known cause of drug interactions and is a potential source for interaction with therapeutic drugs.
IV. PHARMACOLOGY: PHARMACODYNAMICS
A. PHYSIOLOGICAL EFFECTS
There are a number of consistent dose-related effects that THC and marijuana have on humans. Two of the most commonly recognized effects are:
These two effects have both been used to quantitate the effects of THC given experimentally to human volunteers in psychopharmacology experiments. Other physiological effects will be covered in a discussion of the medical uses of THC.
B. PSYCHOLOGICAL EFFECTS
The acute psychological effects of marijuana and THC have been described as a "high". In clinical terms this describes a psychological state of mild euphoria, altered sense of the passage of time, slowed reaction time, disruption of short-term memory, drowsiness (at moderate doses); and visual distortions or hallucinations at very high doses. The very high doses that are required to produce hallucinations are rarely reached by recreational users of marijuana. These effects are obviously pleasurable to many users since they seek the drug in order to obtain these effects. It is interesting to note that in many studies where human volunteers were given marijuana in doses sufficient to produce physiological effects (increased heart rate), many subjects who had not ever smoked marijuana before (naive subjects) did not report a "high" while almost all experienced users did. This points to the fact that at low marijuana dose levels, the psychological effects are often subtle. At high dose levels, even naive subjects could notice the effects, however the effects were not always interpreted as pleasurable. Many users of marijuana report that it increases their appetite. This "field" observation has not been substantiated by laboratory and clinical investigations.
V. PHARMACOLOGY: MEDICINAL USES
Marijuana and derivatives of it have found medical usefulness in recent years, particularly in three areas:
THC has been found to be very effective in preventing or reducing the nausea, vomiting and anorexia (lack of appetite) associated with cancer chemotherapy and irradiation. Irradiation and the drugs used to treat cancer very commonly induce severe nausea and vomiting in cancer patients. These side effects are acceptable considering the course of untreated disease, however they can be debilitating to patients already severely ill. There are a number of antiemetics available that help somewhat with these side effects, but some patients get no relief from them. Clinical trials have shown that in many patients refractory to the usual antiemetics, THC offers significant relief from nausea and vomiting. The therapeutic effect was directly correlated with the concentration of the drug in plasma as well as with the psychological feeling of being "high".
The antiasthmatic effects of both marijuana and THC are well documented also. The acute administration of marijuana or THC by smoking or orally results in a dilation of the bronchioles (small airways that constrict during asthmatic attacks). The bronchodilation produced by smoking marijuana is relatively short-lived, whereas the effects produced by oral ingestion last longer due to the slow absorption. At the present time, marijuana is not considered a likely candidate as an antiasthmatic for the following reasons:
Glaucoma is a disease in which the pressure of the fluids inside the eye is increased to the point that it interferes with proper blood circulation to the retina. The principal result is blindness if it is not stopped. Smoking of marijuana and oral ingestion of THC both have been proven to result in a lowering of intraocular pressure in both normal and glaucomatous humans. Recently it has been shown that the instillation of THC and THC derivatives into the eye is effective in lowering the intraocular pressure and does not produce a "high". This area of research continues and is expected to be fruitful in the coming years. Marijuana also has been investigated for its potential use in the treatment of epilepsy. It has been estimated that up to one-third of all young epilepsy patients smoke marijuana. The effects of marijuana and THC in experimental animals is quite confusing in this area. The effect of marijuana is very much dependent on the animal species and the dose of marijuana used. THC is both an anticonvulsant and a convulsant, depending on these parameters. The major thrust of research in this area is on THC derivatives rather than THC itself. The old literature contained reports that marijuana was useful in treating epilepsy, but this has not been substantiated in animal trials.
There are many reports on the analgesic (pain killing) properties of marijuana. The controlled human studies that have been done have shown that while marijuana may slightly increase pain threshold (the amount of pain necessary to produce discomfort), it may decrease the tolerance of pain (the level of pain that is unbearable). Thus it cannot be considered to be a good analgesic for humans.
Marijuana may have a beneficial muscle relaxant effect in paraplegic patients, however much more work needs to be done in this area. Marijuana has also been tried in the treatment of alcohol dependence. The laboratory data does not support this assertion, at least in the acute withdrawal phase of alcohol dependence. Marijuana has also been tried in the treatment of depression, but has not been found to be effective. Marijuana has been found to be a very effective hypnotic (sleep inducing agent) however the side effects of its use ("hangover" of the "high") have eliminated it from consideration for human use.
D. PHARMACOLOGY: DRUG INTERACTIONS
Perhaps the most well documented interaction of THC is with alcohol. It has been estimated that most (over 70%) users of marijuana use it in combination with other drugs, and the most common one is alcohol. Both THC and alcohol are central nervous system depressants and they do interact additively. Perhaps the most significant area of concern in this matter is driving performance. Driving performance is adversely affected by alcohol, THC and combinations of both. This is not particularly surprising since so many drugs (e.g. antihistamines) interact with alcohol to potentiate its depressant effects. THC also interacts with other drugs of abuse such as hallucinogens and anesthetics. THC potentiates the hallucinogenic effects of LSD and mescaline, and also potentiates the effects of the anesthetic phencyclidine (PCP). Because THC can induce drug metabolism, it has the potential to interact with numerous prescription drugs.
A. TOLERANCE AND DEPENDENCE
Much has been written about the abuse potential of marijuana and its relation to tolerance and dependence. There is no doubt that tolerance can develop to many of the effects of THC. There appears to be two components to this tolerance; a behavioral one and a pharmacological one. The behavioral component is related to learning to compensate for the drug effect, similar to what takes place with learning to compensate for the effect of alcohol or any other CNS depressant. The pharmacological component is not well understood but may relate partly to metabolic induction and also to cellular tolerance.
Drug dependence is not a single entity. It has to be defined for each individual class of agents that can produce dependence. The term "addiction" is really not an appropriate term any more, now that we have good descriptions of individual drug dependence syndromes. There are three phases of drug dependence: 1) induction, or establishment of the dependence, 2) maintainence of dependence, and 3) withdrawal, or abstinence. The mechanism of dependence for two agents may be similar if they can substitute for one another in preventing an abstinence syndrome. THC does not substitute for either alcohol or true narcotics like heroin. This means that dependence produced by these agents is quite different. Drug dependence has many definitions and relates to a physiological or psychological need for the drug to insure proper function of the organism.
Physiological dependence has been demonstrated after long term administration of very large doses of THC to rats and monkeys. In a trial involving humans who were given large amounts of marijuana, abrupt cessation of access to the drug resulted in irritability or anxiety in about 75% of the subjects. However, none of the classical, physiological narcotic withdrawal signs were seen in these subjects. Marijuana does not induce a strong degree of physiological dependence since individuals who have used large quantities for long periods of time do not become violently ill like persons dependent on narcotics and alcohol. If there is a true marijuana dependence syndrome, it would entail principally a psychological "need" for the drug rather than a need to prevent unpleasant physiological effects. This is not to say that a psychological dependence may not be very strong or that it would not be without adverse effects on the welfare of the individual involved.
B. GENETIC TOXICOLOGY AND CARCINOGENESIS
Considerable research has been done in this area and the results are quite variable. There have been reports that chronic users of marijuana have a higher percentage of chromosome breaks in white blood cells than nonusers, but there have also been many reports that have not found increased numbers. It is necessary to consider that chromosome breaks in white blood cells do not necessarily indicate genetic damage that is of concern. At this time, the information on THC and genetic damage is incomplete.
Of greater concern is the question of whether THC or marijuana can cause cancer. There is no evidence to suggest that THC can cause cancer in experimental animals or humans. There is concern that long-term smoking of marijuana may expose users to known carcinogens that are produced by burning the plant material. Condensed smoke from marijuana cigarettes will induce tumors when applied to the skin of rats and rabbits. This same effect is seen with condensed tobacco smoke. Some of the carcinogens in marijuana smoke are compounds that also are found in tobacco smoke, and are known to induce drug metabolism.
D. REPRODUCTIVE TOXICITY: MALES
THC and marijuana have significant effects on reproduction in both male and female experimental animals and humans. The principal effects are due to inhibition of secretion of the hormones involved in reproduction, Follicle stimulating hormone (FSH), Luteinizing hormone (LH) and prolactin. In experimental animals all of these hormones are affected by THC. In human males the main effect is on LH secretion and the result is a transient lowering of testosterone levels in the blood which lasts up to three hours. In one chronic study using human volunteers given free access to marijuana for 5 to 6 weeks, it was found that sperm count and concentration in semen decreased due to marijuana. Increased numbers of sperm that had abnormal morphology were also found. When marijuana treatment was stopped, the morphology gradually returned to normal indicating that the effect was reversible.
E. REPRODUCTIVE TOXICITY: FEMALES
One human epidemiological study has reported some adverse effects on the human menstrual cycle. These effects were an increased number of cycles in which ovulation did not occur, lower levels of progesterone and prolactin, and higher testosterone levels in the blood. This study needs to be confirmed by a good controlled study in a research hospital ward in order to rule out other confounding factors that could affect the reported results.
F. REPRODUCTIVE TOXICITY: TERATOGENICITY
There have been many studies done to test the teratogenic effects of THC. In summary, the cannabinoids are teratogenic only at very high dose levels that produce profound effects on the mother. THC is fetotoxic at high doses, and in chronic experiments in primates did not affect conception but did increase the number of fetal losses and reduced the birth weight of male infants. Large doses given to female rats during pregnancy led to an increase in death in newborns that was attributed to inadequate milk production. It was also shown that THC is readily excreted in mothers milk and thus provides a route of exposure to suckling newborn.
G. BEHAVIORAL TOXICOLOGY
The acute effects of marijuana on humans result in decreases in performance in many tests which measure short term memory and complex motor skills (such as driving.) Tolerance does develop to the disruptive effects on motor performance. There have been reports that chronic marijuana use may lead to an "Amotivational Syndrome" characterized by a lack of motivation in many areas of life. No cause and effect relationship has been established between chronic marijuana use and "lack of motivation". It is possible that that chronic, heavy use of marijuana may be a symptom, rather than a result of "amotivation". Many studies that deal with the chronic effects of marijuana in humans are confounded by the fact that chronic users oftenutilize a variety of drugs ("poly-pharmacy").
Marijuana and its active ingredients are drugs. As such they may have therapeutic potential in addition to having abuse potential. The abuse potential is a special kind of "toxicity". Although the abuse potential of marijuana is high, the actual risk to health from marijuana is relatively low with respect to physical health. The only consistently adverse health effect seen in chronic users is bronchitis from irritation from the smoke. This is not to say that chronic marijuana use is "safe" since any agent that alters complex motor performance cannot be said to be so. There is much recent data on the endocrine (hormone) effects of marijuana that makes it reasonable to assume that it may interfere with the human reproductive process. It has not been proven to be safe for use during pregnancy. It can cross the placenta and enter the fetus.
This newsletter has presented a considerable amount of information about the health effects of marijuana. It has actually only barely scratched the surface of the mass of information on the subject. I have not compared marijuana with alcohol with respect to toxicology for a number of reasons. The biggest reason is that comparisons of this type often tend to bring out bias and eliminate objectivity. They also tend to be social issues. If you would like to receive a list of references that I used to prepare this newsletter, please write and I will gladly provide one.
Arthur L. Craigmill, Ph.D.