More than 60 years ago, the United States government, responding to stories in the press on the new “killer drug,” banned further medical use of marijuna and classed it as a dangerous narcotic. These and similar laws are still vigorously enforced on both sides of the Atlantic, and research has been used to back up arguments both for and against positions from tolerance to criminality.
Oxford University neuropharmacologist Leslie L. Iversen, Specialist Adviser to the House of Lords Select Committee on Science and Technology in its review of the medical and recreational uses of marijuana, tells us what scientists know about cannabis and suggests new public policies to reﬂect that reality. Both advocates and opponents of decriminalizing the use of marijuana will ﬁnd food for thought and debate.
As a scientist who studies drugs that act on the brain, I am often exasperated by the way both proponents and opponents in the marijuana debate use—and abuse—science in defending their positions. Marijuana has been studied in detail; there is a scientiﬁc literature on how it acts and the possible adverse effects of long-term use. The claims that marijuana has important medical applications have been researched also, albeit less thoroughly. Isn’t it about time a scientist spoke up for what he perceives to be the reality as opposed to the myth?
Marijuana accounts for almost three-quarters of all drug-related arrests in the United States and Britain—more than 500,000 a year in the United States alone. Although its medical use has been examined by the Institute of Medicine, the British Medical Association, and the House of Lords Select Committee on Science and Technology, the law in both countries treats it as a scheduled narcotic drug with no medical uses, and whose possession is a criminal offense. In public debate, marijuana has been demonized; available scientiﬁc information is largely ignored or distorted by groups that use science as a propaganda weapon. For example, in the book Marijuana Myths: Marijuana Facts1 published in 1997, the authors, Lynn Zimmer and John P. Morgan, wrote that “Marijuana’s therapeutic uses are well documented in the modern scientiﬁc literature,” while in August 1996 General Barry McCaffrey, the U.S. drug czar, said bluntly: “There is not a shred of scientiﬁc evidence that shows that smoked marijuana is useful or needed. This is not medicine. This is a cruel hoax.”2
Science can address these questions, but more to the point: Do we want to hear the answers?
Is marijuana a dangerous addictive drug with harmful side effects or a “soft drug” not harmful to health? Does it have genuine medical uses that cannot be replaced by other existing medicines? Like every drug, including aspirin, cannabis has adverse effects—but how serious are they? Do they justify prohibition of any legal use? Science can address these questions, at least to a considerable extent; but more to the point: Do we want to hear the answers?
CANNABIS AND “BLISS” IN THE BRAIN
“Marijuana” is the term for the dried leaves and ﬂowering heads of the cannabis plant. Pioneering chemical detective work by Raphael Mechoulam and his colleagues at the Hebrew University some 30 years ago showed that the principal psychoactive ingredient in cannabis is the complex chemical delta-9-tetrahydocannabinol (THC). This chemical usually accounts for 3-4% of the dry weight of the herb, although modern strains grown indoors under intensive cultivation may contain as much as 15-20% THC. Marijuana is most commonly smoked in cigarettes (joints) or pipes. Just as cigarette smoking delivers nicotine very efﬁciently, smoking marijuana rapidly delivers THC to the smoker’s brain. With this rapid feedback, and by adjusting how they smoke, users can learn to regulate the desired dose of THC accurately. THC is also absorbed when taken by mouth, but absorption is slow (as long as 3-4 hours to reach peak blood levels) and users cannot control whether they overdose or receive a less than an effective dose.
In a major advance, scientists have discovered a speciﬁc receptor protein in the brain that recognizes THC (and some closely related, biologically active derivatives). This protein, known as the cannabinoid receptor, belongs to a large family of similar receptor proteins that are part of the complex system of chemical communication in the brain—a system in which the receptors recognize and react to chemical messengers released by activated nerve cells. When a chemical messenger (either a naturally occurring molecule or a drug) binds to its particular receptor, it triggers activity in the nerve cell that has the receptor on its surface.
But why should nerve cells in our brain have developed a receptor that recognizes THC—a chemical found only in the cannabis plant? That question is similar to one posed by the discovery in the 1970s that some nerve cells possess receptors that selectively recognize morphine, which is derived from the opium poppy. In both cases, the answer is that these receptors exist to interact with chemical messengers that the brain itself creates and releases. For example, endogenous morphine-like chemicals in the brain, called the enkephalins and endorphins, discovered 25 years ago, are similar to the chemicals in poppies. Likewise, within the past few years, endogenous cannabis-like chemicals have been discovered—again by Mechoulam and his colleagues. These naturally occurring cannabis-like chemicals are fat-like molecules; the principal one is called “anandamide” from the Sanskrit word for “bliss.”
Discovering these naturally occurring chemicals has changed the way scientists view THC and other cannabinoid drugs. Investigations that initially asked how a plant-derived psychoactive drug worked in the brain have revealed a hitherto unrecognized naturally occurring chemical communication system in the brain. We still do not fully understand the normal physiological function of this cannabinoid system, but there are strong clues that it is important in modulating sensitivity to pain. Also, the anandamide and endorphin systems may be linked, because combining THC with morphine, at least in animal models, gives more powerful pain relief than either drug alone.
MARIJUANA IN THE MEDICINE CABINET?
Many thousand of patients in the United States and Europe are illicit users of marijuana as a medicine. They are convinced that it treats their symptoms more effectively than any conventional medicine; and they are willing to break the law and risk arrest and stern punishments. Attempting to minimize this risk, many have chosen to grow their own supplies. According to surveys of patients, they often act with the connivance—or even on the recommendation—of their physicians.
The beneﬁcial effects of cannabis most commonly reported by patients are in connection with AIDS, multiple sclerosis (MS), spasticity, and chronic pain. The “AIDS wasting syndrome” brings recurring bouts (each lasting a month or more) of appetite loss, weight loss, diarrhea, nausea, and weakness. Patients who use marijuana for this syndrome claim that it stimulates their appetite and helps to reduce or counteract weight loss. MS patients report that marijuana helps with painful muscle spasms and, by preventing these spasms at night, improves their sleep. Patients claim that marijuana helps with painful muscle spasms associated with spinal injuries. Some forms of chronic pain that do not respond to morphine or other painkillers are also reported to be treatable with marijuana. With so many patients reporting beneﬁcial effects from marijuana, is more proof needed of its effectiveness?
Scientists believe that anecdotal evidence is insufﬁcient to prove the effectiveness of a medicine. In testing new treatments in patients suffering from distressing and untreatable illnesses, there is a large element of suggestibility. For example, research has shown that as many as 60% of MS patients report some beneﬁcial response to placebo tablets (containing nothing other than sugar) for various aspects of their disease. More generally, there is a well-documented placebo response in connection with treating pain, a response that appears to result from activation of the brain’s own natural opiate (endorphin) system. Consequently, in seeking evidence that new medicines work it is customary to undertake a series of “double-blind placebo-controlled” clinical trials in which patients are randomly assigned to a placebo or an active drug group; neither the patient nor the doctor knows who received which until after the trial has been completed.
Unfortunately, there is a woeful lack of such evidence to support most medical claims for marijuana. What evidence there is relates not to marijuana but to pure THC, taken orally in capsules. A placebo-controlled trial of THC in 139 patients with AIDS wasting syndrome showed signiﬁcant stimulation of appetite, increased body weight, and reduced nausea. These results convinced the U.S. Food and Drug Administration to approve oral THC for this condition.
There seems to be a narrow window between the drug dose needed to obtain the beneﬁcial medical effect and the dose that causes psychoactive effects. For this reason, many patients prefer smoking illegal marijuana to taking the approved oral THC medicine.
The only other approved indication for THC is to treat nausea and vomiting that accompanies cancer chemotherapy. During the 1970s, placebo-controlled trials for this use were conducted with more than 500 cancer patients. They showed that THC was clearly effective in reducing nausea and vomiting, and it was ofﬁcially approved for this indication. Nowadays, THC is little used in cancer patients, however; it was rapidly superseded by a new group of anti-nausea drugs that act by a different mechanism, blocking the actions of the chemical messenger serotonin. These serotonin blockers, widely used, have dramatically improved cancer chemotherapy. Unlike the water-insoluble THC, the new drugs can be dissolved and given intravenously during the initial stages of treatment; they can also be given by mouth in the later stages. The serotonin blockers also lack the unwanted psychoactive effects of THC. Patients, particularly those who have never experienced marijuana, often ﬁnd the intoxicant effects of THC disturbing, which has proved a general problem in using cannabis-based medicines. There seems to be a narrow window between the drug dose needed to obtain the beneﬁcial medical effect and the dose that causes psychoactive effects. For this reason, many patients prefer smoking illegal marijuana to taking the approved oral THC medicine. They ﬁnd that smoking provides a far more ﬂexible means of delivering the desired dose of the drug—without the risk of under- or over-dose that the oral medicine carries.
There are other medical conditions for which marijuana has been recommended. One reliable effect of the drug is reducing ﬂuid pressure in the eyeball. Patients with glaucoma have elevated pressure in the eyeball that can lead to blindness, and some have claimed beneﬁts from smoked marijuana. Indeed a few such patients in the United States were granted a special dispensation to receive marijuana to treat their condition. Although this program stopped more than a decade ago, eight patients continue to receive their free supplies of standardized marijuana cigarettes, courtesy of the government, each month. Since marijuana’s action is relatively short-lived, these patients must smoke as many as 10 marijuana joints a day. Obviously this is not a very practical form of treatment and, as with chemotherapy, new and powerful medicines have recently become available for the treatment of glaucoma.
In sum, there is scant scientiﬁc evidence for the clinical effectiveness of smoked marijuana. For conditions in which pure THC in capsules has been proven effective, it is likely that similar results could be obtained with the herbal form of the medicine. In the treatment of MS or chronic pain, however, there is very little data from controlled trials with either smoked marijuana or pure THC. Placebo-controlled trials with smoked marijuana, which are difﬁcult to conduct, involve the use of placebo marijuana cigarettes, which are made by extracting the active ingredient from the herb. We need more controlled trials if smoked marijuana is ever to meet the exacting criteria laid down for the ofﬁcial approval of medicines.
OUR MOST COMMON ILLEGAL RECREATIONAL DRUG
Marijuana is by far the most common illegal recreational drug in the Western World. About one third of the 15-50 year olds in most countries report having used marijuana at least once, and this ﬁgure rises to about 50% among seniors in high school (17-19 years old). Consumption has ﬂuctuated over the years. There was a steep rise in the 1960s and 1970s that peaked in the United States in the late 1970s, when 60 percent of 12th grade students admitted having used the drug, and 10% admitted daily use. Probably in response to health warnings, use among young people in the United States declined somewhat during the 1980s, but has climbed again during the 1990s.3 Does this perhaps indicate that a new generation of parents, many with direct experience of marijuana, are less willing to believe the strident health warnings issued by ofﬁcial sources? Among those aged 15-50, on both sides of the Atlantic, an estimated 4-5% regularly use marijuana at least once a week.4
Growing cannabis plants on farms in the United States and in other countries has an become an enterprise involving billions of dollars. Improvements in plant strains and indoor cultivation techniques have created a new cottage industry to meet the personal needs of the grower and sometimes also to make a comfortable living. For example, an investment of around $20,000 will buy the equipment for a modest sized-growing room; with a crop cycle of only 6-12 weeks, an unreported—and therefore tax-free—income of more than $100,000 per year can be generated. Home growing of cannabis, mainly for personal use, seems to be increasing rapidly in many countries. In Britain, for example, police seizures of cannabis plants rose from 11,839 in 1992 to 116,119 in 1996, a tenfold increase in less than ﬁve years.
Ofﬁcial policy on illicit marijuana use remains uncompromising, particularly in Britain and the United States. Elsewhere there are signs of some relaxation in attitudes. In the Netherlands it has been legal for more than two decades for anyone over the age of 18 to purchase small quantities of marijuana or cannabis resin for personal use in a system of state-registered “Coffee Shops.” The Dutch maintain an Alice in Wonderland situation, in which the marijuana sold in the Coffee Shop is legal, but the shop owner has no legal supplier. The Dutch government is also unwilling to provide marijuana for medical use. It was feared that the Dutch experiment would spur a large increase in cannabis consumption, especially among the young, but this does not seem to have happened. Levels of consumption in the Netherlands are no higher than in other European countries, and somewhat lower than in the United States.
The Dutch also maintain that their experiment in driving a wedge between the sources of supply of the “soft drug” and more dangerous drugs has worked. The rate of heroin use among young people in the Netherlands is falling, and the overall rates of heroin use are far lower than in the United States. The so-called “gateway theory,” often an argument against relaxing restrictions on marijuana use, holds that using marijuana somehow primes an individual to seek more dangerous narcotic drugs. There is no scientiﬁc basis for this idea, but exposing marijuana users to the underground world of drug suppliers may make it easier for them to obtain and experiment with other illegal drugs. It is this risk the Netherlands policy tries to address.
Not everyone in the Netherlands is happy with their liberal policy; there are concerns that Amsterdam has become the “drug tourist” capital of Europe. Nevertheless, other European countries—Switzerland, Denmark, and Greece—seem poised to adopt similar policies of decriminalizing cannabis for personal use. This has already happened in parts of Australia.
“KILLER DRUG” POLICY
Ofﬁcial attitudes to marijuana have not changed since the 1930s, when newspapers in several American cities ran scare stories on the new “killer drug.” Alarm pushed Congress, almost by default, to pass the Marijuana Tax Act in 1937, which banned further medical use of marijuana and classed it as a dangerous narcotic. This was later reafﬁrmed by classifying marijuana as a Schedule I drug, a dangerous narcotic with no medical uses. Schedule I is a classiﬁcation more severe than that of cocaine, heroin, or amphetamines, which have medical uses that have been legitimized.
Unlike alcohol users, however, cannabis users virtually never die of an overdose; nor is there evidence that the drug provokes aggressive or criminal behavior.
U.S. soldiers returning from the Vietnam War brought home a culture of marijuana use, and the drug also became immensely popular among the “ﬂower power” generation of the 1960s. Alarmed by the sudden increase in marijuana use, the U.S. government in the 1970s sponsored scientiﬁc studies of long-term use. Unfortunately, several of these studies were blatantly biased, with both the government and the scientists determined to show the dangers of the drug. Although the extensive scientiﬁc literature on marijuana is often confused and lacking objectivity, it is possible to tease out some deﬁnite conclusions.
During the acute stage of marijuana intoxication people become disoriented; they lose their sense of time and may ﬁnd it difﬁcult to maintain a coherent conversation. After large doses, they may also experience hallucinations and delusions. In this state of acute intoxication they are not capable of any work that has intellectual demands, and they should not be driving, ﬂying a plane, or operating complex machinery. Unlike alcohol users, however, cannabis users virtually never die of an overdose; nor is there evidence that the drug provokes aggressive or criminal behavior.
Alarming stories about the effects of marijuana circulated in the 1970s. It was suggested that marijuana interfered with the secretion of sex hormones in both men and women and might lead to infertility; that the drug impaired the immune system, making people less resistant to infections; and that it might damage the developing fetus. None of these has been substantiated by subsequent detailed studies.1,5
Long-term users of marijuana do show subtle deﬁcits in higher brain function, especially disorders in “executive brain function”—the ability to remember recent events and to collate and use this information to plan. These functions are thought to involve the frontal lobe, an area particularly rich in cannabinoid receptors. Also, there have been concerns that these cognitive deﬁcits might persist after marijuana use stopped—that the drug caused permanent brain damage. These fears seem not well founded; almost all studies have shown that the cognitive deﬁcits are completely or largely reversible.
WEIGHING THE REAL DANGERS
What other dangers should we consider? No drug is completely safe, of course. Aspirin and related painkillers account for the deaths of thousands of people every year, who suffer severe gastric bleeding caused by use of these medicines. Marijuana does not kill people, but it is a powerful psychoactive drug, and there is increasing evidence that many regular users become dependent.
The cigarette smoker who ﬁnds it difﬁcult to quit and the cannabis smoker whose drug habit dominates his life are no less “addicted” than the chronic heroin user, even though they may suffer only mild withdrawal signs when drug use is stopped.
The term “addiction” once applied only to “hard” drugs such as heroin, where we see obvious signs of tolerance and physical dependence in regular users and a painful, even life-threatening physical withdrawal syndrome when use of the drug is stopped. Psychiatrists now use the term “substance dependence” for both psychological dependence (without obvious physical tolerance or a withdrawal syndrome) and physical dependence. The diagnosis of substance abuse is made by quantifying the responses to a standard set of questions. The cigarette smoker who ﬁnds it difﬁcult to quit and the cannabis smoker whose drug habit dominates his life are no less “addicted” than the chronic heroin user, even though they may suffer only mild withdrawal signs when drug use is stopped.
Using the internationally accepted deﬁnition of “substance dependence,” researchers have found that as many as a third of regular marijuana users may be classiﬁed as dependent. Marijuana comes to play a dominant role in their lives and impairs their ability to function fully at work or in their social life. Use of marijuana, however, still causes a mild form of addiction by comparison with use of heroin, cocaine, or even nicotine. We know that most cigarette smokers, once addicted, ﬁnd it very difﬁcult to stop, but a majority of marijuana smokers quit when they reach their thirties.
The most serious long-term health hazard of smoking marijuana may be the risk inherent in the smoke itself. Comparisons of the smoke from marijuana and tobacco cigarettes have shown that they contain a very similar mixture of toxic chemicals, including the respiratory poison carbon monoxide, and a series of known carcinogenic chemicals that arise from the combustion of the plant material. In addition, marijuana smokers inhale more deeply than cigarette smokers and usually hold their breath in the mistaken belief that this enhances the absorption of THC by the lungs. Thus marijuana smokers may deposit four or ﬁve times as much tar in their lungs as cigarette smokers. Like tobacco smokers, marijuana smokers are liable to develop an irritating cough and signs of bronchitis.
As yet, there is no hard evidence that marijuana smoking is associated with an increased risk of lung cancer, but there are initial reports that cancers of the mouth, tongue, and throat are more common in young users. Also, microscopic inspection of the cells lining the airways of regular marijuana smokers reveals abnormalities that suggest possible pre-cancerous changes. The problem is that respiratory cancers may take a very long time to reveal themselves. The link between lung cancer and cigarette smoking shows that the relationship between length of use and risk can be complex. The risk of lung cancer in a cigarette smoker does not increase the same amount as each year passes. In other words, someone who has smoked for 30 years as opposed to 15 years does not simply double his or her lung cancer risk; he increases it 20-fold. Smoking for 45 years as opposed to 15 years increases the cancer risk 100fold. Although a similar link has not yet been established between marijuana smoking and lung cancer, the marijuana habit has been widespread in the Western World for a relatively short time. It could take several more decades for evidence of a lung cancer link to become apparent. Meanwhile, we must hope that young people are not storing up a time bomb that will cut short their lives, as tobacco smoking has shortened the lives of previous generations.
A TIME TO DRAW NEW LINES
At the end of the twentieth century we have reached a turning point in the cannabis debate. Soon we must decide whether or not to introduce marijuana ofﬁcially into our medicine cabinets, and whether or not to accept—albeit grudgingly—that recreational use of cannabis is part of our culture.
Our current ofﬁcial attitude that marijuana is a dangerous narcotic, comparable to cocaine and heroin, is simply not compatible with what we now know. True, there are genuine risks and concerns, but to a scientist the dangers of marijuana use seem, on the whole, no greater than those associated with tobacco or alcohol. A series of ofﬁcial inquiries over the past half century started with Mayor Fiorello LaGuardia’s detailed report on “The Marihuana Problem in the City of New York” in 1944.6 The investigators concluded:
Prolonged use of the drug does not lead to physical, mental or moral degeneration, nor have we observed any permanent deleterious effects from its continued use.
Other inquiries around the world have all come to similar conclusions: This is a drug whose use is associated with some hazards, but these do not justify punitive criminal polices. The governments who commissioned the inquiries, however, disregarded their recommendations.
We may see the ﬁrst relaxation of attitudes and practices in connection with medical use. Although it may be challenging, because of the lack of hard scientiﬁc evidence for the positive effects, to give ofﬁcial approval to use of herbal marijuana as a medicine, there seems little justiﬁcation for withholding it from dying patients who believe that they derive some beneﬁt. The 1998 U.K. House of Lords Cannabis Report recommended the rescheduling of marijuana on just such compassionate grounds. This view seems to be shared by the public, as shown by opinion polls in Britain and votes in favor of medical marijuana in recent U.S. state elections. Democratic governments can ignore the will of the electorate for only so long.
In Britain, the government has granted a commercial company permission to establish a growing facility to produce medical grade marijuana, and there are plans for large-scale controlled trials of cannabis (using a plant extract given by mouth) in the treatment of MS and chronic pain. Each of these trials will involve several hundred patients and could provide the ﬁrst scientiﬁc evidence for or against the effectiveness of cannabis-based medicines. Other investigators are looking for improved methods for the medical delivery of cannabis. Smoked marijuana may never be approved for long-term use because of the hazards of smoking, but devices that heat and then vaporize the THC or plant material without burning may provide a method of inhaling the drug that avoids the dangerous byproducts of smoke.
Relaxation of the laws on the recreational use of marijuana may happen, but this will take longer. A ﬁrst stage may be grudging tolerance of the drug as a fact of life in our culture, followed by a gradual decriminalization. Many of the anomalies in the laws on marijuana stem from its incorrect original classiﬁcation as a Schedule I narcotic, and the failure to change this when, in 1970, the U.S. Congress passed the Controlled Substances Act. Leo Hollister, a respected academic expert on psychoactive drugs testiﬁed before the U.S. House of Representatives Ways and Means Committee on this Act :
I have been unable to find any scientific colleague who agrees that the scheduling of drugs in the proposed legislation makes any sense, nor have I been able to find anyone who was consulted about the proposed schedules. The unfortunate scheduling which groups together such diverse drugs as heroin, LSD and marihuana perpetuates a fallacy long apparent to our youth. These drugs are not equivalent in pharmacological effects or in the degree of danger that they represent to individuals and to society. On the other hand, the specious criterion of medical use places amphetamines in a much lesser category, which the facts do not support. If such scheduling of drugs is retained in the legislation which is ultimately passed, the law will become a laughing stock.
He was right. The scheduling was retained in the law, and the young have largely ignored it.
I am not in favor of a complete relaxation of the laws on cannabis use. Society has been damaged badly by the health hazards of tobacco and alcohol, so the fact that marijuana may be no worse is scarcely a reason to make it freely available. In particular, the potential risks of lung cancer associated with smoked marijuana give me serious cause for concern. I believe, though, that the penalties currently meted out for the illegal personal or medical use of cannabis are not commensurate with the seriousness of the offence. There is a case for relaxing some of the current criminal restrictions on cannabis use, but not for outright legalization. Although many people have decided to ignore our present laws, the topic of marijuana is almost taboo. When polititicans discuss it at all, they only reiterate the platitudes of the past. Is it not about time that these questions were debated openly?