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by
Lester Grinspoon and James B. Bakalar
INTRODUCTION
Most of the psychoactive drugs banned or severely restricted by law in modern industrial societies have had significant medical uses at some places and times. In the case of natural plant drugs like opium, coca, cannabis, mescaline, and psilocybin, this medical history usually reaches back thousands of years and through a variety of cultures. The general tendency has been to restrict the uses of these drugs as their dangers are more strongly emphasized and substitutes become available. Although the trend toward greater precision in the use of drugs and greater concern for safety is a medical advance, there is a danger that legal and social restrictions will prevent the realization of some genuine medical potential. As we suggest in this chapter, establishing the balance is a difficult process that has not yet been worked out adequately. (The use of illicit drugs also raises other issues, such as individual freedom of choice, that are outside the scope of this essay.)
Different drugs are assigned to different social categories in different cultures. The spectrum includes magic, religion, medicine, recreation, disease, vice, crime, and madness. in modern industrial societies, we put great emphasis on keeping these categories separated, and that is one reason why psychoactive drugs are so difficult for us to deal with. For industrial societies, medicine or therapy is one thing, fun another, religious ritual still another-an attitude reflected in separate formal and informal institutions. The distinctions among magic, religion, and medicine have not always been so clear as we make them, or at least profess to make them. The words health and holiness have a common root meaning "whole." In preindustrial societies medical diagnosis and prognosis have an aura of the occult, something resembling divination, and disease is usually considered an instrument of gods or evil spirits.
By the early nineteenth century, healers in Europe and in the United States no longer attributed illness to spirits or consciously identified the power of drugs as magical. The scientific revolution had convinced physicians that most diseases had physical and chemical causes, but a medical science created in the image of physics remained only a hope. This uncertain situation, together with the growth of manufacturing, capitalist entrepreneurship, and the spirit of liberal individualism, made the nineteenth century a great age of self-medication and competing medical authorities. The patent medicine industry therefore flowered in the late nineteenth century United States. Many of the proprietary medicines contained psychoactive drugs-alcohol, opium, cocaine, or cannabis. Orthodox physicians used them extensively as well; as late as 1910, morphine was the fourth most commonly used drug, and alcohol was the fifth. I These drugs were not specific cures for specific diseases, and little was known of their mechanism of action, but they provided relief from suffering in varied situations. They were the classic panaceas. Opium, alcohol, or cocaine, like faith in some pharmacologically inactive proprietary nostrum, actually reduced the pain while nature took its course, often toward a restoration of health.
It was a familiar fact that psychoactive drugs, like most strong medicine, could also be powerfully poisonous. Alternative, often synthetic drugs, with less apparent abuse potential, were developed in the late nineteenth century, and consciousness of the dangers of the familiar natural drugs became more intense. Problems were magnified by the isolation of drug substances in pure form and the development of such technologies as the hypodermic syringe. But the public and medical professionals also began to mistrust psychoactive drugs because of their indeterminate and apparently uncontrollable powers. Alcohol, for example, lost its status as a medicine in the first two decades of the twentieth century.
Psychoactive drugs had been used too freely in the nineteenth century, and often the distinction between use for health and use for pleasure was not carefully made. This ambiguity now began to seem dangerous, just as the primitive ambiguity between health and holiness had long been obsolete. Taking opium to relax or cocaine to feel vigorous would no longer be regarded as a cure or treatment. The common man's right to make choices about these substances (even, for a time, alcohol) was repudiated. The government and organized medicine took control over their manufacture and distribution, carefully restricting their medical uses and rejecting almost all other uses. This was part of the process by which nineteenth century liberal capitalism transformed itself into a more "orderly" state corporate system; at the same time, the organized medical and pharmaceutical professions and the larger drug companies consolidated their power. In what is now known as the Progressive Era, the Pure Food and Drug Act, the Harrison Narcotic Act, and the Volstead Act were as much characteristic legislation as the Federal Reserve Act.
The impulse to clean up society and reduce disorder was hostile to free self-medication and chaotic small-scale entrepreneurial competition. Professional hygiene required new standards for medical and pharmaceutical practice, and intellectual hygiene required clear and enforceable categories for psychoactive drugs. Changes in medicine itself were also important. Synthetic chemistry, experimental physiology, and bacteriology advanced. The promise of a materialist medicine based on the recognition of specific agents for specific diseases seemed about to be fulfilled. Psychoactive drugs, with their nonspecific and merely palliative effects, became more suspect.
The system established during the Progressive Era has persisted until the present. As the medical and allied professions expand, divide, and send out new branches, they incorporate more and more social functions. This has sometimes been called "moral entrepreneurship" or "medical imperialism." More recently, the right of medical professionals to interpret the meaning of psychoactive drug use has been challenged by scholars and social critics as well as illicit drug users. In some cases they have advocated an openly religious conception of psychoactive drug use, a recommendation that we apply the standards of preindustrial cultures. The practical merit of this idea may be dubious, but it does raise two interesting issues: the dangers of technological advance and the protective function of ritual.
Technical advances in science and manufacturing have increased the danger of drug abuse by producing chemicals in pure form and permitting their production on a vast scale. On the other hand, these products of modern industry have powers commensurate with their dangers: the face of Dr. Jekyll as well as Mr. Hyde. It could be argued that in modern industrial societies the medical profession has to provide the same kind of ritual or quasi-religious context that makes drug use relatively safe in primitive cultures. The priestly role of doctors in prescribing occasions for drug use and warning against possession by the demons in these drugs may sometimes seem arrogant, but it is doubtful whether nineteenth century individualism or a return to preindustrial cultural and technological forms would be better, even if they were possible.
Physicians are now in a good position to examine rationally how and when to use their authority in controlling psychoactive drugs. They do not have to regard the complex powers of these drugs as a challenge to their own domination of territory they have legitimately staked out. Psychoactive drugs are still an important part of the medical armamentarium, although most of those in use today are synthetic. The doctrine of specific etiology, based on infectious and dietary deficiency diseases, is the source of modern medicine's great triumphs, and yet it remains inadequate. For the vaguely defined functional problems that still account for many visits to doctors, we often still have no clear explanations and no better remedies than drugs that affect the mind. This situation naturally causes much unease. Doctors are accused by lay people and accuse one another of using pills to resolve problems of living that demand more complex and difficult adjustments. These fears are reasonable. On the other hand, there remains a large area in which diseases and problems of living overlap. What a doctor does in prescribing a tranquilizer is not always different in a fundamental way from what lay persons do in prescribing a beer or marijuana cigarette for themselves.
Twentieth century societies have kept increasing government control of therapeutic drugs on the ground that authoritative knowledge about their efficacy and safety makes free individual choice illusory. Psychoactive substances used as pleasure drugs were the first to be restricted, but all prescription medicines now have to go through an elaborate procedure of testing and certification before they are approved for medical use. Of all federal drug laws, only the Pure Food and Drug Act (1906) was designed to encourage free choice by consumers, because it was aimed at simple fraud-false statements about the contents of the package. Since the passage of the Food, Drug and Cosmetics Act of 1938, the power to decide the availability of most drugs has gradually been transferred, first from consumers to doctors and then from doctors to the government. Before allowing a drug on the market, the federal government must now judge whether it is effective as well as whether it is safe.
Although most drugs are now illicit except when taken by prescription, the common understanding of the term "illicit drugs" includes only psychoactive drugs used for pleasure, most of which are covered by the federal criminal provisions of the Controlled Substances Act of 1970 and similar state laws. It would be impossible to discuss all of them here. Some are among the most commonly used drugs and have a variety of medical applications-notably the benzodiazepine tranquilizers, the barbiturates, and the synthetic and natural opioids. We will concentrate here on four classes of drugs that have much more limited medical acceptability. All four are placed in the two most restricted schedules under the Controlled Substances Act. Cocaine and amphetamines have currently accepted medical uses; marijuana and psychedelic drugs do not. We will explore the past and present, potential and actual, experimental and established, legal and illegitimate therapeutic uses of these drugs.
COCA AND COCAINE
Cocaine is an alkaloid extracted from the leaves of the shrub Erythroxylon coca, which has long been cultivated in Bolivia and Peru as a stimulant and for medicinal purposes. For thousands of years, inhabitants of the Peruvian and Bolivian highlands and the western Amazon region have been mixing coca leaves with ash or lime, putting the wad in a cheek, and letting the juice trickle into their stomachs. In many parts of the Amazon and the Andes today, coca is the everyday stimulant drug, used more or less as coffee, tea, chewing tobacco, and khat are used in other areas of the world.
In one study of a mountain village in Peru, coca was found to be the standard remedy for symptoms of hunger and cold and for two folk illnesses: el soka, a condition of weakness, fatigue, and general malaise; and el fiero, a chronic wasting illness. Coca was also the treatment of choice for stomach upset and stomachache and for colic, or severe gastrointestinal distress including diarrhea, cramps, and nausea. 2
In the form of leaf powder or tea, coca is taken for toothache, ulcers, rheumatism, asthma, and even malaria. Coca tea is often served to tourists arriving in hotels and inns in the high Andes as a remedy for the nausea, dizziness, and headache of soroche (altitude sickness). Unlike other stimulants, coca is also a local anesthetic. The juice of the leaf can be applied to soothe eye irritations or gargled for hoarseness and sore throat. Coca leaves are also used as a topical anesthetic for mouth sores. Coca contains minerals, vitamin C, and some B vitamins, and it is sometimes said to be an important source of these nutrients in the Andean diet.
An American physician, Andrew Weil, has recently been trying to revive interest in the therapeutic uses of coca, which he believes have been neglected because of the medical profession's fascination and subsequent disillusionment with the pure alkaloid cocaine. He has found coca useful in the symptomatic relief of indigestion, gastritis, constipation, motion sickness, laryngitis, and other ailments. He believes that it could serve as a substitute for coffee in persons who find that their stomachs are upset by that stimulant. He also proposes its use as an appetite-reducing drug and as an energizer for physical labor, and he suggests that it might serve as a relatively safe substitute in treating amphetamine and cocaine dependence. He points out that coca differs from cocaine in several ways. It contains a number of related alkaloids rather than a single one, and it is less subject to abuse because it enters the body by the normal gastrointestinal route rather than intranasally, intravenously, or through the lungs. He believes that coca might best be administered in the form of a chewing gum.
Ever since the Spanish conquest there has been controversy about the health effects of habitual coca use. The evidence is unreliable, contradictory, and heavily colored by the political and social biases of observers. A number of studies have suggested that coca chewers are apathetic, subnormal in intelligence, or subject to various physical illnesses because they are weakened by the drug.' But even these results are ambiguous and inconclusive.' The biggest problem is separating cause from effect. If coca users in the high Andes seem undernourished, demoralized, and unhealthy, that is easily explained by the miserable physical and social conditions under which many of them live-conditions for which coca use apparently gives them some relief. It is significant that many Indians in the Amazon who use coca are reported to be strong and healthy.' In any case, the people of the Andes themselves, including those who do not use coca, usually reject the suggestion that it is a drug problem, a threat to health, or a danger to their community.
Cocaine was isolated from the coca leaf in 1860. Throughout the late nineteenth century, both coca itself (that is, an extract from the leaf including all of its alkaloids) and the pure chemical cocaine were popular as medicines in Europe and North America. In 1863 Angelo Mariani, a Corsican chemist, patented a preparation of coca extract and wine, which he called Vin Mariani; it became one of the most popular prescription medicines of the era, and was used by such celebrities as Thomas Edison, Ulysses Grant, Henrik Ibsen, Pope Leo XIII, Emile Zola, Jules Verne, and the Prince of Wales. Mariani wrote several articles and monographs on coca in which he combined historical, botanical, and medical information with the promotion of his company's product; he could list thousands of physicians who recommended it.'
By 1878 coca was being promoted in advertisements in the United States for young persons suffering from shyness and as a stimulant. In the same year, an American physician, W. H. Bentley, began to recommend coca as a cure for morphine addiction. Extract of coca was admitted to the United States Pharmacopoeia in 1882. In July 1884, Sigmund Freud published a famous paper, "On Coca," in which he recommended cocaine or coca extract for a variety of illnesses including the syndrome of fatigue, nervousness, and minor physical complaints then known as neurasthenia.' Referring to Freud's writings, the Parke-Davis Company declared in its pamphlet "Coca Erythroxylon and Its Derivatives": "If these claims are substantiated . . . [cocaine] will indeed be the most important therapeutic discovery of the age, the benefit of which to humanity will be incalculable."'
This article and later articles by Freud were influential, but the rediscovery of cocaine's local anesthetic properties by his colleague Karl Koller proved to be of more permanent importance. Koller introduced topical cocaine in eye operations, and soon cocaine was being used in many other forms of surgery. William Halsted of Johns Hopkins University invented nerve block or conduction anesthesia by injecting cocaine into nerve trunks. Soon regional anesthesia and spinal anesthesia were introduced. It was not until the early twentieth century that synthetic local anesthetics without the stimulant properties of cocaine were developed.
Meanwhile, cocaine was triumphing as what would now be disparagingly called a panacea. It was recommended for exhaustive and irritative conditions of the central nervous system, seasickness, trigeminal neuralgia, hay fever, head colds, and what was then called "catarrh." In 1901 the American physician W. Golden Mortimer published an encyclopedic volume, History of Coca, in which he recommended coca wine, coca extract, or cocaine for a great variety of purposes. In an appendix he cited the responses to a letter he had sent to "a selected set" of more than 5,000 physicians asking for their observations on coca. Of the 1,206 replying, 369 said that they had used coca in their own practices. They commonly observed that it increased appetite, raised blood pressure, stimulated circulation, strengthened the heart, improved digestion, stimulated the mind, and worked as an aphrodisiac. The most popular therapeutic uses were for exhaustion, overwork, and neurasthenia. Few thought there was a dangerous tendency to form a coca habit.10
One of the most popular drinks containing cocaine was CocaCola, first concocted in 1886 by a Georgia pharmacist. The Coca-Cola Company was founded in 1892, and throughout the 1890s CocaCola was advertised as a headache remedy and stimulant as well as an enjoyable drink. In 1903 coca extract was removed from Coca-Cola and replaced with caffeine. A de-cocainized extract of the coca leaf is still used for flavoring.
In the medical use of coca and cocaine, it is hard to separate the central stimulant from the digestive, respiratory, and local anesthetic effects. A singer or actor who drank Mariani's wine could hardly know how much of the improvement he or she noticed was caused by local anesthesia or constriction of blood vessels in the throat and how much by euphoria and a feeling of mastery. As for stomach and intestinal problems, the gastrointestinal system is probably the most common site of psychosomatic symptoms. The use of coca or cocaine in convalescence from long-lasting debilitating diseases represents a similar combination of central and peripheral effects.
Abuse and dependence became problems almost as soon as cocaine was introduced into medicine. Cocaine dependence first appeared in morphine addicts who took the cocaine cure recommended by Bentley and Freud. Halsted, the inventor of nerve block anesthesia, appears to have cured himself of a craving for cocaine by taking up morphine and paying the price of physical addiction. In his last paper on cocaine, published in 1887, Freud admitted that the cocaine habit could be more dangerous to health than morphine addiction." Later in life he seldom referred to cocaine.
The growing fear of cocaine changed attitudes toward coca. Advocates of coca then began to fight a rear-guard action in its defense, insisting that coca never caused the kinds of problems that were ruining the reputation of cocaine, and even saying that the effects of coca might be caused primarily by other chemicals in the leaf. But by 1900 public and medical opinion had begun to turn against both coca and cocaine. In 1906 the Pure Food and Drug Act banned food and drinks containing cocaine, and further legal restrictions soon followed, culminating in the Harrison Act of 1914, which regulated cocaine as well as opiates. Cocaine and the coca leaf were still prescribed occasionally through the 1920s for many of the same purposes as in the late nineteenth century, although criminal laws and other restraints made it less easily available. But its use gradually declined until, by 1930, it was rarely being used except as a surgical anesthetic and an illicit pleasure drug.
Today cocaine is used in medicine mainly as a topical anesthetic in eye, ear, nose, and throat surgery and fiber tube optical examinations of the upper respiratory and digestive tracts. It has a combination of properties that cannot be duplicated by any of the synthetic local anesthetics: intense constriction of blood vessels (important whenever bleeding must be prevented), long duration of anesthesia (one hour), and low toxicity. Cocaine is no longer used in infiltration anesthesia (subcutaneous injection), in nerve block anesthesia, or in spinal anesthesia. 12 Recently topical application of cocaine to the upper palate has been recommended as a way of aborting the severe pain of cluster headaches. 13
Other medical uses are rare. Cocaine is an ingredient in Brompton's mixture, a preparation used in Great Britain for treating the chronic pain of terminal cancer, but controlled studies at a hospice in England have suggested that the cocaine in this drink provides no advantage over morphine alone." Cocaine was never tested seriously as a treatment for severe depression, but this idea is unlikely to be revived because the pharmacologically similar amphetamines have proved a failure for that purpose. Today substitutes have been found for most therapeutic uses of cocaine, and in most cases its dangers are believed to outweigh its potential benefits. Despite the recent and so far uncertain signs of reviving interest, coca and cocaine will never again be so widely used in medicine as they once were.
Legally, the coca leaf and all its derivatives containing cocaine are classified under the Controlled Substances Act as Schedule 11 drugs: This means that there is a currently accepted medical use but also a high potential for abuse and dependence. Schedule 11 drugs may be prescribed under special restrictions; hospitals and pharmacies are required to keep them in a locked place.
AMPHETAMINES
Amphetamines and amphetamine congeners are a large group of chemically related central stimulant drugs; among the best known are dextroamphetamine (Dexedrine), methamphetamine (Methedrine) and methylphenidate (Ritalin). Racemic amphetamine sulfate (Benzedrine) was first synthesized in 1887, but it was not introduced as a medicine until 1932, when the Benzedrine inhaler became available over the counter in drugstores as a treatment for nasal congestion and asthma. In late 1937 the new drug was introduced in tablet form to treat narcolepsy and postencephalitic parkinsonism. It was also recommended for depression and to heighten energy and capacity for work. Soon amphetamine was receiving sensational publicity with numerous references to "brain," " pep," and "superman" pills. Even when phrased as warnings, these reports served mainly to arouse curiosity.
But amphetamine use spread mainly because the medical profession was so enthusiastic about the drugs. Many doctors regarded amphetamines as remedies with extraordinary scope, efficacy, and safety. By 1943 more than half the sales of Benzedrine went to fill prescriptions written for people who wanted to lose weight, obtain a temporary lift in spirits, or stay awake for extended periods. In 1946 W. R. Bett asserted that amphetamine had thirty-nine clinical uses, including treatment for epilepsy, postencephalitic parkinsonism, schizophrenia, alcoholism, behavior problems in children, migraine, muscular rigidity and spasm, head injuries, dysmenorrhea, and hypotension.15
Although not all these uses were generally adopted, by 1971 the total production of amphetamines had reached the equivalent of more than 10 billion 5 mg tablets. Until 1971, amphetamines were sold freely over the counter without prescription in the form of inhalers such as the Dristan inhaler. They were also easy to obtain in the form of pills, capsules, or injectable liquids, with or without a visit to the doctor for a prescription. The Army used amphetamines heavily during the Vietnam War, and amphetamine abuse became a problem among the troops. 16 From the mid-1960s on there was also a growth in both illicit bathroom laboratory synthesis of amphetamines and black market diversion of legitimately produced drugs.
Since 1970 use and abuse of amphetamines have declined because of legal restrictions and a better understanding of their dangers, which include weight loss, psychosis, severe dependence, and depression on withdrawal. It is as though the career of amphetamines from 1940 to 1970 recapitulated the career of cocaine in the late nineteenth century. Not having learned from history, we were condemned to repeat it. Although chemically different from cocaine, the amphetamines have similar stimulant effects and similar liabilities. After the first flush of enthusiasm, the range of accepted medical uses for amphetamines narrowed, just as it had for cocaine a generation earlier. The only present widely accepted medical uses for amphetamines are in treating narcolepsy and attention deficit disorder. They are occasionally used as an adjunct to tricyclic antidepressants in the treatment of depression. They are also still prescribed for weight loss, but this practice is becoming less and less common because of wellfounded doubts about their safety and effectiveness.
The amphetamines used in medicine are placed in Schedule 11 under the Controlled Substances Act of 1970 as later amended. Like cocaine, they are regarded as drugs having a currently accepted medical use but a high potential for abuse, which may lead to severe psychological or physical dependence. An applicant to manufacture such drugs must register with the attorney general. The attorney general establishes production quotas, and there are special restrictions on prescriptions.
Weight Loss
Until the early 1970s, amphetamines were overwhelmingly the drug of choice in treating overweight by appetite reduction. Their anorectic effect is apparently secondary to the stimulating effect. Controlled studies have found that amphetamines increase weight loss, at least in the first few months, by making it easy to adhere to a diet. But the user rapidly grows tolerant to the anorectic effect, and it can rarely be sustained more than a few months without an increase in the dose. 17 It also appears that most patients, once they stop using amphetamines or become tolerant to them, go back to their former eating habits and regain the weight they have lost.
The favorable results of clinical studies on the appetite reducing effects of amphetamines must also be balanced by a consideration of adverse effects, including the danger of abuse. Even if the intention is to expose the patient to amphetamine only for a short period, compulsive eaters who have a need for constant gratification may find it hard to put aside a medication that makes them feel good. They may also discover, when they no longer have the magic potion that protects them from themselves, that a psychological vacuum has developed that needs to be filled with food.
Appetite is governed by physiology, habit, and emotional state. Tension and depression, inability to delay gratification, and the substitution of food for other forms of pleasure, all of which are common in cases of overweight, increase the danger of drug dependency. A drug that reduces appetite without requiring any solution to emotional problems may seem to be a reasonable alternative at first, but the short-term weight loss may cause patients to avoid the issue of changing their eating and exercise habits. (The same problem, of course, often occurs when drugs are administered for other emotional problems and habitual behavior.)
It is doubtful whether amphetamines should be used for weight reduction under any circumstances. All anorectic drugs, and especially amphetamines, have a limited value in the treatment of obesity; because of their potential for dependence and abuse, they should be used with extreme care, if at all. The prescription of amphetamines for weight loss has properly declined in the last decade.
Narcolepsy
Narcolepsy, first described ninety years ago, is a disorder marked by an uncontrollable desire for sleep or sudden attacks of sleep during the daytime. It usually begins in adolescence, and it never completely remits. Narcolepsy is considered rare, but it is not clear just how common it is, and in any case, it is a complicated problem. It may involve either REM (dreaming) sleep or non-REM sleep, and it may be complicated by cataplexy (loss of muscle tone), sleep paralysis, or hypnagogic hallucinations. Tricyclic antidepressants are used to treat these symptoms, but they do not eliminate the sleep attacks themselves. There is no evidence of brain pathology in narcolepsy, but heredity may be a factor.
Amphetamine was first introduced as a treatment for narcolepsy in 1935, and one or another amphetamine congener continues to be the drug treatment of choice. Dextroamphetamine or methylphenidate may be necessary for a narcoleptic person whose work is dangerous, but most victims of narcolepsy can perform satisfactorily without drugs if they take at least one nap a day. The risk of dependence, toxic reactions, and psychosis must be weighed against the advantages of drug-induced wakefulness.
Depression
Depression is probably the most common complaint of adults. Its symptoms are both physical and emotional: loss of appetite and energy, insomnia, fatigue, difficulty in concentration, feelings of worthlessness and self-reproach, thoughts of death and suicide, anxiety and irritability. Amphetamines were one of the first classes of drugs to be used in the treatment of depression, beginning in 1936. Early studies sometimes led to excessive enthusiasm, because they were not controlled and the clinical symptoms of depression show a strong tendency to spontaneous remission. Even in the early stages, amphetamines were generally found to be ineffective in severe depressions and in treating the depressed phase of bipolar (manicdepressive) illness. Early studies of less serious depressions demonstrated some effectiveness but raised questions about possible dangers. Even at that time researchers mentioned the possibility of increasing the risk of suicide by heightening energy and mobility. Suicide attempts may also occur during the severe depression that sometimes follows withdrawal. Nevertheless, as late as 1958, C. D. Leake strongly recommended amphetamines for depression in an authoritative book. 18
As the dangers of insomnia and anxiety became more apparent, interest developed in using amphetamines together with sedatives such as the barbiturate sodium amytal. Each drug, it was thought, would counteract the unfortunate side effects of the other. Although doubt soon developed about the effectiveness of these combinations, they were marketed for years under various trade names and soon became sources of a new kind of drug abuse.
By the 1950s, new amphetamine congeners with fewer side effects, such as methylphenidate, had been developed, but they proved to be no more effective in treating depression. Eventually two new groups of drugs, the monoamine oxidase (MAO) inhibitors and the tricyclics, revolutionized the field. Tricyclic derivatives, along with lithium for manic-depressive illness, are now believed to be the most effective drug treatment for depression. Controlled studies comparing tricyclic antidepressants to amphetamines or placebo have found amphetamines ineffective in the treatment of all types of depression." But amphetamine-related stimulants may potentiate the effects of the tricyclics by slowing their metabolism in the body; and they may also evoke an immediate response that encourages the depressed patient to keep taking a tricyclic whose effects do not become apparent for a few weeks.20
A few other uses for amphetamines in the treatment of depression are still occasionally recommended. Methylphenidate has been proposed to treat depression in patients who are medically ill or recovering from surgery and therefore unable to tolerate the side effects of tricyclic antidepressants. This is especially true of heart patients and elderly people with organic brain disease." Amphetamines taken intravenously in combination with morphine have also been recommended in the treatment of postoperative pain." in some studies amphetamines seem to be effective in obsessive-compulsive disorder, but other drugs are available for this purpose as well."
Drugs should not be used as a substitute for reassurance and exploration of the patient's concerns in cases of mild depression, fatigue, or anxiety. If amphetamines are used to relieve symptoms that are often indistinguishable from the tensions of everyday life, they may make the patient feel good but they will only mask the underlying problem. A patient complaining of fatigue, nervousness, anxiety, or insomnia may be asking for a kind of short-term psychotherapy from a person believed to be trustworthy. When a doctor responds with a stimulant pill, he or she may be depriving the patient of a service that should be provided and may perpetuate a pattern of drug use as a substitute for coping with the problems of daily life. Fortunately, most physicians have come to recognize this, and amphetamines are no longer commonly used in treating depression.
Attention Deficit Disorder
The most controversial remaining medical use of amphetamines is the treatment of the syndrome known variously as hyperactivity, hyperkinesis, minimal brain dysfunction, and, most recently, attention deficit disorder. It is probably the most common behavioral disorder of childhood; boys are affected five to ten times as often as girls. The main symptoms are extreme physical restlessness (hyperactive children move more, even in sleep) and short attention span; other symptoms are poor coordination, intolerance for frustration, aggressive and impulsive behavior, and learning disabilities. The problem usually begins in infancy, but it becomes especially troublesome in the classroom. Hyperactive children do not usually outgrow their problems, although the symptoms may change. In adolescence they are often academic underachievers with poor social skills and low self-esteem, who may become juvenile delinquents. Many of the symptoms also persist in adult life.
Attention deficit disorder overlaps in its symptoms with disorderly behavior and more serious developmental disorders of childhood. Symptoms found in hyperactive children are also found in some children with known brain injuries and are often associated with neurological signs of central nervous system malfunction. The term " minimal brain dysfunction" suggests an organic cause, but so far no specifically characteristic neurological disorder or brain pathology has been found. The current term "attention deficit disorder" suggests that the problem reflects the way activity is organized in response to social demands as much as it involves physical motion. Hyperactivity is probably a mixture of symptoms with different origins in different children; in many cases a genetic factor may be involved.
The use of amphetamines in treating hyperactive children began in 1937, when Charles Bradley observed that it produced striking effects on a number of schoolchildren showing various kinds of disturbance. Their problems, aside from hyperactive behavior, included specific learning disabilities, aggressiveness associated with epilepsy, and schizoid withdrawal. The drug reduced their motor activity and impulsive behavior, improved their attention, diminished mood swings, increased their interest in the surroundings, made them less anxious and irritable, and improved their school achievement. 24 Studies on the amphetamine treatment of disturbed children with a variety of diagnoses reported a substantial improvement in behavior and school performance as judged by parents, teachers, and caregivers .25
There is still much confusion about what symptoms respond to amphetamines. Some studies suggest that children who show signs of a neurological disorder do better on amphetamines than other restless children who do not show such signs. Others find that amphetamines contribute to relieving the symptoms of disturbed children in general, whether or not there is evidence of a learning disorder or brain injury.26 The apparent calming effect of these stimulant drugs on hyperactivity in children has been called paradoxical, with the implication that the effect is specifically related to the disorder. But it turns out that single doses of amphetamine affect normal boys the same way they affect hyperkinetic boys-increasing attention span and reducing motor activity.27
Amphetamines have serious limitations and dangers. The results of treatment are more variable and less spectacular than they may appear. Amphetamines probably do not help hyperkinetic preschool children or improve specific learning disorders such as reading problems .28 The symptoms usually return when the drug is withdrawn, and in any case its benefits seem to occur mainly in the first few months; long-term treatment does not lead to a better outcome.29 Attention problems, impulsiveness, and academic failure persist in adolescence among children diagnosed as hyperactive whether or not they have taken amphetamines.
Some hyperactive children even get worse on amphetamines; in one study, 16 percent of the children showed an exaggeration of the original symptoms." A few serious adverse reactions have also been reported, including an amphetamine psychosis and movement disorders." Even children who are benefited by amphetamines may suffer from loss of appetite, dizziness, pallor, and digestive troubles. These symptoms usually diminish or disappear after the first week, and they can usually be minimized by adjusting the dose. (Methylphenidate has fewer toxic side-effects than do other forms of amphetamine.) A more serious problem is that some amphetaminetreated hyperactive children fail to achieve expected gains in weight and height. The effect is statistically significant but generally not large. It might be neutralized by the spurt in growth that begins in adolescence; the evidence is not yet available. In any case, the growth of children taking stimulant drugs must be carefully monitored."
For educational psychologists who found that many disturbed children did not respond to psychotherapy and for educators interested in the relationship between learning disabilities and behavior problems, amphetamines have suggested new approaches to treatment. But children should not be given drugs as soon as they become restless or unruly. Often the problem lies in the school or home as much as in the child. Children need an educational environment that will help them come to grips with their problems without using pharmacological shortcuts unless they are absolutely necessary. Teachers, parents, and physicians should try other methods before resorting to amphetamines. Physicians must be certain that their diagnoses are accurate. At one time amphetamines may have been used excessively in treating hyperactivity because of imprecise diagnosis and overzealous promotion by drug companies and educators, but it is our impression that physicians and educators now have a better understanding of the limitations as well as the advantages of amphetamines and are using them with more care.
PSYCHEDELIC DRUGS
The psychedelics or hallucinogens are a large group of drugs, some natural and some synthetic, with a variety of chemical structures. The best known are mescaline, derived from the peyote cactus; psilocybin, found in over a hundred species of mushrooms; and the synthetic drug lysergic acid diethylamide (LSD), which is chemically related to certain alkaloids found in morning glory seeds, the lysergic acid amides. This class of drugs also includes the natural substances harmine, harmaline, ibogaine, and dimethyltryptamine (DMT), as well as a large number of synthetic drugs that are chemically described as tryptamines or methoxylated amphetamines. A few of these are diethyltryptarnine (DET), 3,4,-methylenedioxyamphetamine (MDA), and 2,5-dimethoxy-4-methylamphetamine (DOM, also known as STP).
The natural hallucinogens have long been used by preindustrial cultures, especially in Mexico and South America, for magical, religious, and healing purposes, and today the peyote cactus is the sacrament of the Native American Church, a religious organization with branches in all western states of the United States. Peyote became known in industrial society toward the end of the nineteenth century, and many other plant hallucinogens have been discovered since. LSD was first synthesized in 1938 and its psychoactive properties were discovered in 1943; since then many other synthetic psychedelic drugs have been developed in laboratories.
The psychedelic drugs differ somewhat in their subjective effects and greatly in the effective dosage. LSD is the most potent and produces the widest range of effects; it can be taken as a prototype. Although the response to LSD varies with personality, expectations, and setting, it almost always produces profound changes in perception, mood, and thinking. Perceptions become unusually brilliant and intense; normally unnoticed details capture the attention and ordinary things are seen with wonder. Synesthesia, changes in body image, and alterations in time and space perception are common. Vivid dreamlike imagery appears before closed eyes. True hallucinations are rare, but visual distortions and pseudohallucinations are common. Emotions become unusually intense and may change abruptly and often. Suggestibility is greatly heightened. The experience is suffused by a heightened sense of reality and significance, and it often produces feelings of religious and philosophical insight. The sense of self is greatly changed, sometimes to the point of merging with the external world, separation from the body, or dissolution in mystical ecstasy.
The most common adverse effect of LSD and related drugs is the "bad trip," which occasionally produces a true psychotic reaction.
Another common effect is the flashback, a spontaneous transitory recapitulation of drug-induced experience in a drug-free state. Prolonged adverse reactions, which are considerably less common, include anxiety reactions, depressive reactions, and psychoses. They are most likely to occur in schizoid and prepsychotic personalities with barely stable egos who cannot cope with the mind alterations produced by the drug trip. There is a close resemblance between people hospitalized for LSD reactions and those hospitalized for psychoses not produced by drugs."
A persistent issue has been possible genetic damage and birth defects. The available evidence suggests that LSD produces no chromosome damage in reproductive cells of a kind that is likely to cause birth defects; the same is true of other psychedelic drugs to the extent that they have been tested. There is also no evidence that LSD is teratogenic in human users at normal doses.
Ever since experimentation with psychedelic drugs began, some users and psychotherapists have maintained that a single psychedelic experience or several such experiences can provide religious insight, heightened creative capacity, psychological insight, or relief from neurotic symptoms. From 1950 to the mid-1960s, psychedelic drugs especially LSD, mescaline, and psilocybin-were used extensively in experimental psychiatry. The drugs were studied as a chemical model for natural psychoses and also used extensively in psychotherapy. More than a thousand clinical papers were published discussing forty thousand patients; there were several dozen books and six international conferences on psychedelic drug therapy. It was recommended at one time or another for a wide variety of problems, including alcoholism, obsessional neurosis, and childhood autism. Beginning in the mid-1960s, with the increase of illicit use, it became difficult to obtain the drugs or get funding for research, and professional interest declined. There is now only one legally approved project in the United States involving the therapeutic use of psychedelic drugs; it is located at the Maryland Psychiatric Research Institute in Baltimore. Maybe those two decades of psychedelic research will eventually be written off as a mistake that has only historical interest, but it might be wiser to see if something can be salvaged from them.
One source of the therapeutic interest was the belief of some experimental subjects after taking a psychedelic drug that they were less depressed, anxious, and guilty, and more self-accepting, tolerant, or sensually alert. Interest also arose from the possibility of making therapeutic use of the powerful psychedelic experiences of regression, abreaction, intense transference, and symbolic drama to improve the results of psychodynamic psychotherapy. Two kinds of therapy emerged, one making use of the mystical or conversion experience and the other exploring the unconscious in the manner of psychoanalysis. Psychedelic therapy, as the first kind was called, involved the use of a large dose (200 micrograms of LSD or more) in a single session; it was thought to be potentially helpful in reforming alcoholics and criminals as well as improving the lives of normal people. The second type, psycholytic (literally, mind-loosening) therapy, required relatively small doses and several or even many sessions; it was used mainly for neurotic and psychosomatic disorders. In practice, many combinations, variations, and special applications with some of the features of both psycholytic and psychedelic therapy evolved.
Neurotic Disorders
In a book about her LSD treatment, one woman described the result this way:
I found that in addition to being, consciously, a loving mother and a respectable citizen, I was also, unconsciously, a murderess, a pervert, a cannibal, a sadist, and a masochist. In the wake of these dreadful discoveries, I lost my fear of dentists, the clicking in my neck and throat, the arm tensions, and my dislike of clocks ticking in the bedroom. I also achieved transcendent sexual fulfillment....
At the end of nine sessions over a period of nine weeks I was cured of my hitherto incurable frigidity, and at the end of five months I felt that I had been completely reconstituted as a human being. I have continued to feel that way ever since."
These passages were written three years after a five-month period during which this woman took LSD twenty-three times. Before that she had had four years of psychoanalysis, but it was only after LSD that she became convinced of the value of Freud's theories.
The literature contains a number of such impressive case histories, but these anecdotal accounts can always be questioned; placebo effects, spontaneous recovery, special and prolonged devotion by the therapist, and the therapist's and patient's biases in judging improvement must be considered. The most serious deficiencies in psychedelic drug studies were absence of controls and inadequate follow-up. And psychedelic drug effects are so striking that it is difficult to design a double-blind study, in which neither the person administering the drug nor the person taking it knows whether it is the active substance or a placebo. No form of psychotherapy for neurotics has ever been able to justify itself under stringent controls, and LSD therapy is no exception.
Furthermore, psychiatrists did not agree about details. Should the emphasis be on expression of repressed feelings or on working through a transference attachment to the psychiatrist? How much therapy is necessary in the intervals between LSD treatments? Because of the complexity of psychedelic drug effects, there are no general answers to these questions. It appeared that LSD treatment sometimes produced spectacular improvement in neurotic symptoms, but no reliable formula for success was derived from these results. But again, in these respects psychedelic drug therapy seems to be in no better or worse position than most other forms of psychotherapy.
Alcoholism
Psychedelic therapy for alcoholism is based on the assumption that one overwhelming experience sometimes changes the self-destructive drinking habits of a lifetime, and the hope that psychedelic drugs can consistently produce such an experience. In one reported case, a 40-year-old black, unskilled laborer was brought to a hospital from jail after drinking uncontrollably for ten days. He had been an alcoholic for four years, and he was also severely anxious and depressed. He described his experiences during an LSD session as follows:
I was afraid. I started to run, but something said "Stop! Stop!" then I felt as if ten tons had fallen from my shoulders. I prayed to the Lord. Everything looked better all around me.... I changed my mind from alcohol toward Christ and the rose came back into my life.... As I sat up and looked in the mirror I could feel myself growing stronger. I feel now that my family and I are closer than ever before and I hope that our faith will grow forever and ever.
One week later his score on a questionnaire testing neurotic traits had dropped from the 88th to the 10th percentile. Six months later his psychological tests were within normal limits; he had been totally abstinent from alcohol for all that time and despite a temporary relapse when he lost his job, he was still sober after twelve months .36 LSD undoubtedly produces powerful effects on alcoholics; the question is whether they can be reliably translated into enduring change. Early studies reported dazzling success. About 50 percent of severe chronic alcoholics treated with a single high dose of LSD were said to be recovered and sober a year or two later. 37 But the early studies proved to be inadequate. When the patients were randomly assigned to drug and control groups it proved difficult to demonstrate any advantage for LSD treatment, even in studies conducted by advocates of the drug .38 The problem is that many alcoholics will improve, at least temporarily, after any treatment because excessive drinking is often sporadic and periodic relapses are common. The alcoholic who arrives at a clinic or hospital is probably at a low point in the cycle and has nowhere to go but up.
It would be wrong to conclude that a psychedelic experience can never be a turning point in the life of an alcoholic. As William James said, "Religiomania is the best cure for dipsomania." Unfortunately, psychedelic experiences have the same limitations as religious conversions. Their authenticity and emotional power are not guarantees against backsliding when the old frustrations, constraints, and emotional distress have to be faced in everyday life. Even when the revelation does seem to have lasting effects, it might have been merely a symptom of readiness to change rather than a cause of change.
The fact remains that there is no proven treatment for alcoholism.
Where so little is known, it may not make sense to give up entirely on anything that has possibilities. In the religious ceremonies of the Native American Church, periodic use of high doses of mescaline in the form of peyote is regarded as, among other things, part of a treatment for alcoholism. Both the Indians themselves and outside researchers believe that those who participate in the peyote ritual are more likely to abstain from alcohol. Peyote sustains the ritual and religious principles of the community of believers, and these sometimes confirm and support an individual commitment to give up alcohol. Even federal alcoholism clinics for Indians now recognize that peyote might have some value." If, for whatever reasons, psychedelic drugs work for at least some Indians some of the time, they might also help some non-Indian alcoholics.
Dying
There is a new consciousness today of the significance of dying as part of life. As we look for ways to change the pattern, so common in chronic illness, of constantly increasing pain, anxiety, and depression, the emphasis is shifted away from impersonal prolongation of physical existence toward a conception of dying as a psychiatric crisis, or even, in older language, a religious crisis. The purpose of giving psychedelic drugs to the dying might be stated as reconciliation: reconciliation with one's past, one's family, and one's human limitations.
Beginning in 1965, the experiment of providing a psychedelic experience for the dying was pursued at Spring Grove State Hospital in Maryland and later at the Maryland Psychiatric Research Institute. Walter Pahnke, the director of the project from 1967 until 1971, was a Doctor of Divinity as well as a psychiatrist, and he first reported on his work in an article in the Harvard Theological Review in 1969. When terminal cancer patients received LSD or DPT after appropriate preparations, about one-third were said to have improved "dramatically," one-third improved "moderately," and one-third were unchanged; the tests of improvement were reduced tension, depression, pain, and fear of death." Later experiments with
terminal cancer patients produced similar results." There were no control groups in these studies, and there is no certain way to separate the effects of the drug from those of the special therapeutic arrangements and increased attention that were part of the treatment. Nevertheless, the case histories are impressive, and it would be interesting to renew the research; the present work at the Maryland Psychiatric Research Institute is an attempt to do that.
Complications and Dangers
Like any probing psychotherapy, psychedelic drug therapy presents the danger that unconscious material will come up and be neither accepted and integrated nor totally repressed; in that case, symptoms will become worse. Psychosis and even suicide have been reported in the course of psychedelic drug treatment. On the other hand, some people who have worked with psychedelic drugs consider them more likely to prevent suicide than to cause it, and most studies questioning psychiatrists about adverse reactions to psychedelic drugs in experimental or therapeutic research have revealed a low rate of serious complications .42
All such studies have limitations. Some psychiatrists may have minimized the dangers out of therapeutic enthusiasm or reluctance to admit mistakes; some may have exaggerated the dangers under the influence of bad publicity; long-term risks may have been underestimated if follow-up was inadequate. The studies provide no basis for comparison with patients who were not treated with psychedelic drugs or not treated at all. But the fact remains that psychedelic drugs were used for more than fifteen years by hundreds of psychiatrists who considered them reasonably safe as therapeutic agents.
Conclusion
When a new kind of therapy is introduced, especially a new psychoactive drug, events often follow a pattern of spectacular success and enormous enthusiasm followed by disillusionment. But the rise and decline of psychedelic drug therapy took a somewhat unusual course. From the early 1960s on, the revolutionary proclamations and religious fervor of the nonmedical advocates of psychedelic drugs began to evoke hostile incredulity rather than simply the natural skeptical response to extravagant claims backed mainly by intense subjective experiences. Twenty years after their introduction, psychedelics were pariah drugs, scorned by the medical establishment and banned by the law. In rejecting the absurd notion that these drugs were a panacea, we have chosen to treat them as entirely worthless and extraordinarily dangerous. Maybe the time has come to find an intermediate position. If the therapeutic results have been erratic and inconsistent, that is partly because of the complexity of psychedelic drug effects. For the same reason, we may simply not yet have had enough time to sort out the best uses of these drugs.
An informal kind of research continues anyway. Illicit psychedelic drug use is an underground spring that continues to feed the stream of interest in systematic, publicly controlled experimentation. Ironically, the illicit drug use that was one of the reasons for the interruption of legitimate research now serves to keep alive efforts aimed at resuming that research. Interest also persists among some psychologists and psychiatrists. We quote a letter written in 1979 by Hanscarl Leuner of the University of Gottingen:
Though in several European countries therapists in this field could apply for licenses to continue using the drugs, the government authorities over the years started to make things difficult.... I myself was convinced that science does not depend on ideologies. This seems to be an error. The continuation of psycholytic therapy during the last years led us to new techniques and conceptions. The results in practical therapy are even more convincing than before. We would like not to stop doing psycholytic therapy. Optimistically, I hope that in time we can publish these results. For so many patients there is a tremendous need for deep probing and intensity in psychotherapy which psycholytic and related therapies could fill."
There are now dozens of known psychedelic drugs, some of them synthesized only in the last twenty years. Few have been tested seriously in human beings. Their effects are sometimes different from those of LSD and other familiar substances. These differences may be significant for the study of the human mind and for psychotherapy, but we cannot analyze them properly without more controlled human research. A Chilean psychiatrist, Claudio Naranjo, has pioneered in the use of psychedelic drugs that do not produce the same degree of perceptual and emotional change as does LSD. He has worked especially with MDA and a related shorter-acting amphetamine, MMDA, which give a heightened capacity for introspection and intimacy along with a temporary freedom from anxiety and depression.44 These and related drugs might be useful in marital counseling, in diagnostic interviews, and in helping patients decide whether they want to go through the process of psychotherapy. 45
It is a misunderstanding to regard psychedelic drug therapy as a form of chemotherapy, like giving lithium to manic patients. Patients are not maintained for a long time on psychedelic drugs, and these drugs do not produce dependence or addiction. On the other hand, the claims of psychedelic drug therapy are subject to the same doubts as those of psychoanalysis or religious conversions. The mixture of mystical and transcendental claims with therapeutic ones is an aspect of psychedelic drug therapy troubling to our culture. The pronouncements of drug enthusiasts are sometimes too much like religious testimonials to please either psychiatrists or priests and ministers. Preindustrial cultures seem to tolerate more ambiguity in this matter, and there is now a growing interest in the ideas and techniques shared by primitive shamans, Eastern spiritual teachers, and modern psychiatrists. The word "cure," after all, means both treatment for disease and the care of souls.
The role of the guide on a psychedelic drug trip, which has both religious and medical aspects, is spontaneously reproduced in all cultures where psychedelic drugs come to be used. Much of the controversy about psychedelic drugs in the 1960s was in effect concerned with the question of who was qualified to be a guide. For the moment we have made the curious decision that no one in modern industrial society is qualified for this position. Nevertheless, psychedelic drug therapy apparently still goes on underground, in one form or another. Many have regarded it as an experience worth having, some as a first step toward change, and a few as a turning point in their lives. They might be deceiving themselves, but we do not know enough to be certain; the field has potentialities that are not being allowed to reveal themselves.
A Note on Legal Status
The publicly familiar psychedelic drugs are classified in Schedule I of the Controlled Substances Act; they are regarded as having a high potential for abuse, no current medical use, and a lack of safety for use under medical supervision. They are available for medical experimentation as investigational drugs, but present research is confined almost entirely to animals. A number of psychedelic drugs that were recently synthesized or that have never been available in any quantity on the illicit market are not scheduled. It is legal for physicians to work clinically with these substances, although experimental research in human beings is not permissible until animal tests have been done.
CANNABIS
Marijuana is derived from the hemp plant (Cannabis sativa). Its most important psychoactive chemical, delta-9-tetrahydrocannabinol (delta-l-tetrahydrocannabinol in another nomenclature), is contained in a resin that covers the flower clusters and top leaves of the plant; the resin also contains many chemically related substances with lesser effects. Cannabis preparations vary widely in quality and potency depending on the type of plant, climate, soil, and methods of cultivation and manufacture. The resin can be ingested in the form of a drink or in foods, but usually the leaves and flowering tops are smoked, either in a pipe or in a cigarette called a joint.
History
Like cocaine and other psychoactive drugs derived from natural plant sources, marijuana has been used for thousands of years as a medicine as well as an intoxicant. It was listed in an herbal published by a Chinese emperor that may go back to 2800 B.C. In Jamaica, where it was introduced in the seventeenth century by African slaves, it has become the most popular folk medicine. Cannabis in the form of an alcoholic tincture was commonly used in nineteenth-century Europe and the United States as an anticonvulsant, sedative, and analgesic, and also in tetanus, neuralgia, uterine hemorrhage, rheumatism, and other conditions. It was thought to be a milder but less dangerous sedative than opium, and it was also considered an appetite stimulant. Between 1839 and 1900 more than a hundred articles appeared in scientific journals on the therapeutic uses of marijuana. After the introduction of injectable opiates in the 1850s and synthetic analgesics and hypnotics in the early twentieth century, the medical use of cannabis declined. But even as late as 1937, extract of cannabis was still a legitimate medicine marketed by drug companies. The Marijuana Tax Act of 1937 imposed a registration tax and record keeping requirements that made medical use of cannabis so cumbersome that it was dropped from the U.S. Pharmacopoeia and National Formulary.
The Marijuana Tax Act was introduced under the influence of a growing concern about the use of marijuana as an intoxicant, especially among blacks and Mexican-Americans in the South and Southwest. The law passed after a strong campaign by the Federal Bureau of Narcotics, despite a lack of empirical evidence on the harmfulness of marijuana. The legislative counsel for the American Medical Association at the time objected to the law, saying that future investigations might show substantial medical uses for cannabis. But the American Medical Association soon changed its stance and for the next thirty years maintained a position on marijuana very similar to that of the Federal Bureau of Narcotics. Recent years have seen some relaxation of legal restrictions and increasing clarification of the medical potential of cannabis and cannabis derivatives, but considerable obstacles remain and considerable research still has to be done.
Safety
The greatest advantage of cannabis as a medicine is its unusual safety. The ratio of lethal dose to effective dose is estimated on the basis of extrapolation from animal data to be about 20,000 to one. Huge doses have been given to dogs without causing death, and there is no reliable evidence of death caused by cannabis in a human being. Cannabis also has the advantage of not disturbing any physiological functions or damaging any body organs when it is used in therapeutic doses. It produces little physical dependence or tolerance; there has never been any evidence that medical use of cannabis has led to habitual use as an intoxicant.
Whole cannabis preparations have the disadvantages of instability, varying strength, and insolubility in water, which makes it difficult for the drug to enter the bloodstream from the digestive tract. Another problem is that marijuana contains so many ingredients with possible disadvantageous effects, including too high a degree of intoxication. This multitude of ingredients is also an opportunity, since it suggests the manufacture of different cannabinoids, synthetic or natural, with properties useful for particular purposes; some of these have now become available."
Depression and Pain Relief
Cannabis and synthetic cannabis derivatives have been tested as treatments for depression, so far without good evidence of effectiveness .47 It might be possible to develop synthetic cannabis preparations with a higher euphoriant-to-sedative ratio than the drugs that have been tested so far.
There are many anecdotal reports of marijuana smokers using the drug to reduce pain: postsurgery pain, headache, migraine, menstrual cramps, and so on. The disadvantage is its inconsistent effect; sometimes it actually heightens sensitivity to pain. It is possible that cannabis acts by mechanisms different from those of other analgesics, but the literature does not indicate a specific effect of cannabis on pain pathways or suggest that it is likely to be more effective than other analgesics. Again, some new synthetic derivative might prove useful as an analgesic, but this is not an immediate prospect.
Alcohol Dependence
Because of reports that some people use less alcohol when they smoke marijuana, cannabis has been proposed as an adjunct to alcoholism treatment. But so far it has not been found useful .48 Most alcoholics neither want to substitute marijuana nor find it particularly useful. But there might be some hope for use of marijuana in combination with disulfiram (Antabuse), which protects alcoholics by producing uncomfortable symptoms when they drink." Certainly a cannabis habit would be preferable to an alcohol habit for anyone who could not avoid dependence on a drug but was able to substitute one drug for another.
Spasticity and Seizures
About 20 percent of epileptics do not get much relief from conventional anticonvulsant medications. Cannabis has been explored as an alternative, at least since a case was reported in which marijuana smoking, together with the standard anticonvulsants phenobarbital and diphenylhydantoin, was apparently necessary to control seizures in a young epileptic man.50 Marijuana also reduces muscle spasm and tremors in some people who suffer from cerebral palsy or multiple sclerosis." But the effects of delta-9-tetrahydrocannabinol (hereafter called THC itself are inconsistent; it can actually heighten susceptibility to some types of seizures. The cannabis derivative that is most promising as an anticonvulsant is cannabidiol. In one controlled study, cannabidiol in addition to prescribed anticonvulsants produced improvement in seven patients with grand mal seizures; three showed great improvement. Of eight patients who received a placebo instead, only one improved. 52
Asthma
Asthma is a breathing disorder that arises when bronchial muscles go into spasm and the pathway to the lungs is blocked by mucus and swelling. A number of antiasthmatic drugs are available, but they all have drawbacks-limited effectiveness or side effects. Because marijuana dilates the bronchi and reverses bronchial spasm, cannabis derivatives have been tested as antiasthmatic drugs. Smoking marijuana would probably not be a good way to treat asthma because of chronic irritation of the bronchial tract by tars and other substances in marijuana smoke, so recent research has sought a better means of administration. THC in the form of an aerosol spray has been investigated extensively." Other cannabinoids such as cannabinol and cannabidiol may be preferable to THC for this purpose. An interesting finding for future research is that cannabinoids may affect the bronchi by a different mechanism from that of the familiar antiasthmatic drugs.
Glaucoma
A promising new medical use for cannabis is in treating glaucoma, the second leading cause of blindness in the United States. In this disease, fluid pressure within the eyeball increases until it damages the optic nerve. About a million Americans suffer from the form of glaucoma (wide angle) treatable with cannabis. Marijuana causes a dose-related, clinically significant drop in intraocular pressure that lasts several hours in both normal subjects and those with the abnormally high ocular tension produced by glaucoma. Oral or intravenous THC has the same effect, which seems to be specific to cannabis derivatives rather than simply a result of sedation. Cannabis does not cure the disease, but it can retard the progressive loss of sight when conventional medication fails and surgery is too dangerous.
It remains to be seen whether topical use of THC or a synthetic cannabinoid in the form of eyedrops will be preferable to smoking marijuana for this purpose. So far THC eyedrops have not proved effective, and in 1981 the National Eye Institute announced that it would no longer approve human research using these eyedrops.55 Studies continue on certain synthetic cannabis derivatives and other natural cannabinoids. Smoking marijuana is a better way of titrating the dose than taking an oral cannabinoid, and most patients seem to prefer it. Unfortunately, many patients, especially elderly ones, dislike the psychoactive effects of marijuana.
Cancer Treatment
Cannabis derivatives have several minor or speculative uses in the treatment of cancer, and one major use. As appetite stimulants, marijuana and THC may help to slow weight loss in cancer patients." THC has also retarded the growth of tumor cells in some animal studies, but results are inconclusive, and another cannabis derivative, cannabadiol, seems to increase tumor growth." Possibly cannabinoids in combination with other drugs will turn out to have some use in preventing tumor growth.
But the most promising use of cannabis in cancer treatment is the prevention of nausea and vomiting in patients undergoing chemotherapy. About half of patients treated with anticancer drugs suffer from severe nausea and vomiting. In about 30 percent to 40 percent of these, the commonly used antiemetics do not work." The nausea and vomiting are not only unpleasant but a threat to the effectiveness of the therapy. Retching can cause tears of the esophagus and rib fractures, prevent adequate nutrition, and lead to fluid loss.
The antiemetics most commonly used in chemotherapy are phenothiazines like prochlorperazine (Compazine). The suggestion that cannabis might be useful arose in the early 1970s when some young patients receiving cancer chemotherapy found that marijuana smoking, which was of course illegal, reduced their nausea and vomiting. In some studies, oral THC has proved effective where the standard drugs were not.59 In other studies the two types of drugs seemed to be equally effective.60 In one study nabilone, a synthetic cannabinoid, was found more effective than a phenothiazine.61 But nabilone tests have been discontinued because of animal deaths and adverse reactions in human beings.
It is generally agreed that THC is a good antiemetic, but as in the case of glaucoma, many patients reject it because they find the psychoactive effects unpleasant. There is some controversy about whether THC is best taken orally or smoked in the form of marijuana. Marijuana is related to THC in much the same way that coca is related to cocaine; it contains a variety of chemicals instead of one and enters the body by a different route. Smoking generates quicker and more predictable results in both glaucoma and cancer treatment, because it raises THC concentration in the blood more easily to the needed level. Also, it may be hard for a nauseated patient in chemotherapy to take oral medicine. But many patients dislike smoking or cannot inhale.
Conclusion
A committee of the Institute of Medicine of the National Academy of Sciences remarked in a report in 1982:
Cannabis shows promise in some of these areas, although the dose necessary to produce the desired effect is often close to one that produces an unacceptable frequency of toxic [undesirable] side effects. What is perhaps more encouraging ... is that cannabis seems to exert its beneficial effects through mechanisms that differ from those of other available drugs. This raises the possibility that some patients who would not be helped by conventional therapies could be treated with cannabis.... It may be possible to reduce side effects by synthesizing related molecules that could have a more favorable ratio of desired to undesired actions; this line of investigation should have a high priority. 62
Under federal and most state statutes, marijuana is listed as a Schedule I drug: high potential for abuse, no currently accepted medical use, and a lack of accepted safety for use under medical supervision. It cannot ordinarily be prescribed and may be used only under research conditions.
But public pressure has begun to change the situation. Several individuals have successfully argued the rare defense of medical necessity in response to criminal charges of marijuana possession; in one case glaucoma was involved and in another multiple sclerosis. Now the National Cancer Institute, the Drug Enforcement Agency, and the Food and Drug Administration have agreed to a program whereby the National Cancer Institute is making THC available through the pharmacies of about five hundred teaching hospitals and cancer centers to physicians who want to use it for chemotherapy. The legislatures of twenty-three states have also authorized special research programs that supply cannabis for the management of nausea and vomiting in chemotherapy. In effect these programs provide means for the seriously ill to gain legal access to marijuana. Physicians acting on their own can apply for permission to use marijuana, but the regulations are so complicated that physicians who want help for one or two patients may advise them to get the marijuana on the streets instead. State programs, in effect, assume responsibility for completing the paperwork required by the federal government and relieve the physician of this burden. The states make use of confiscated marijuana or marijuana cigarettes or THC pills supplied by the federal government.
The Food and Drug Administration does not approve of efforts to publicize therapies that have not gone through the standard legal process of new drug testing. Advocates of medical marijuana use want to circumvent not only the Controlled Substances Act but also the Food, Drug, and Cosmetics Act of 1938 and its amendments that establish procedures for testing and marketing new drugs. The FDA says that marijuana will never be an approved medicine because it contains so many chemicals and its composition is so variable. The requirement of a -standardized dose alone may prevent the marketing of marijuana in the ordinary way as medicine. This obstacle does not stand in the way of THC in pill form. A special form of THC in a gelatin capsule with sesame seed oil has recently been transferred to Schedule II under the Controlled Substances Act, and hearings are being held to determine whether THC in other forms should also be placed in Schedule II.
The potential of cannabis as a medicine is yet to be realized, partly because of its reputation as an intoxicant, ignorance on the part of the medical establishment, and legal difficulties involved in doing the research. Recreational use of cannabis has affected the opinions of physicians about its medical potential in various ways. When marijuana was regarded as the drug of blacks, Mexican-Americans, and bohemians, doctors were ready to go along with the Bureau of Narcotics, ignore its medical uses, and urge prohibition. For years the National Organization for the Reform of Marijuana Laws (NORML) and other groups have been petitioning the government to change this classification. Although that has not happened, cannabis derivatives have become more available for medical purposes through various devices. Now that marijuana has become so popular among a broad section of the population, we have been more willing to investigate its therapeutic value. Recreational use now spurs medical interest instead of medical hostility.
The struggle over medical marijuana use illustrates some of the issues discussed earlier: self-medication versus government control, pure chemicals versus natural drugs, the historical direction of drug policy and the present minor challenges to it, the need to find a better balance in making rules about drugs. The potential dangers of marijuana when taken for pleasure and its possible usefulness as a medicine are historically and practically interrelated issues: historically, because the arguments used to justify public and official disapproval of recreational use have had a strong influence on opinions about its medical potential; practically, because the more evidence accumulates that marijuana is relatively safe even when used as an intoxicant, the clearer it becomes that the medical requirement of safety is satisfied. Most recent research is tentative, and initial enthusiasm for drugs is often disappointed after further investigation. But it is not as though cannabis were an entirely new agent with unknown properties. Studies done during the past ten years have confirmed a centuries-old promise. With the relaxation of restrictions on research and the further chemical manipulation of cannabis derivatives, this promise will eventually be realized. The weight of past and contemporary evidence will probably prove cannabis to be valuable in several ways as a medicine.
1. Mickey C. Smith and David Knapp, Pharmacy, Drugs, and Medical Care (Baltimore: Williams and Wilkins, 1972), p. 161.
2. Horacio Fabrega and Peter K. Manning, "Health Maintenance Among Peruvian Peasants," Human Organization 31 (1973): 243-56.
3. Andrew Weil, "The Therapeutic Value of Coca in Contemporary Medicine," Journal of Ethnopharmacology 3 (1981): 367-76.
4. Carlos Gutierrez-Noriega, "El Cocaismo y la Alimentacion en el Peru," Anales de la Facultad de Medicina 31 (1948): 1-90; J. C. Negrete, "Psychological Deficit in Chewers of Coca Leaf," Bulletin on Narcotics 19, no. 4 (1967): 11-13; H. B. M. Murphy, 0. Rios, and J. C. Negrete, "The Effects of Abstinence and Retraining on the Chewer of Coca Leaf," Bulletin on Narcotics 21, no. 2 (1969): 41-47; Alfred A. Buck et al., "Coca chewing and Health: An Epidemiological Study Among Residents of a Peruvian Village," American Journal of Epidemiology 88 (1968): 159-77.
5. Lester Grinspoon and James B. Bakalar, Cocaine: A Drug and Its Social Evolution (New York: Basic Books, 1976), pp. 120-29; Andrew T. Weil, "Coca and Brain Damage," April 1978 (unpublished).
6. Weil, "Therapeutic Value of Coca," p. 374.
7. Angelo Mariani, Coca and Its Therapeutic Applications (New York: Jaros, 1890).
8. Sigmund Freud, "On Coca," in Robert Byck, ed., The Cocaine Papers (New York: Stonehill, 1974), pp. 49-73.
9. Parke Davis and Company, "Coca Erythroxylon and Its Derivatives," in Byck, Cocaine Papers, p. 144.
10. W. Golden Mortimer, History of Coca (New York: Vail, 1901), pp. 491-509. 1 1. Sigmund Freud, "Craving For and Fear Of Cocaine," in Byck, Cocaine Papers, pp. 171-76.
12. Grinspoon and Bakalar, Cocaine, pp. 161-63; Nicholas L. Schenk, "Local Anesthesia in Otolaryngology: A Reevaluation," Annals of Otology, Rhinology and Laryngology 84 (1979):65-72.
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14. R. G. Twycross, "Value of Cocaine in Opiate-containing Elixirs," British Medical Journal 2 (1977): 1348.
15. W. R. Bett, "Benzedrine Sulfate in Clinical Medicine: A Survey of the Literature," Postgraduate Medical Journal 22 (1946): 205-18.
16. See Lester Grinspoon and Peter Hedblom, The Speed Culture: Amphetamine Use and Abuse in America (Cambridge: Harvard University Press, 1975), pp. 19-20.
17. D. Adlersberg and M. E. Mayer, "Results of Prolonged Medical Treatment of Obesity with Diet Alone, Diet and Thyroid Preparations, and Diet and Amphetamine," Journal of Clinical Endocrinology 9 (1949): 275-84.
18. C. D. Leake, The Amphetamines: Their Actions and Uses (Springfield, Ill.: Thomas, 1958), pp. 67-69.
19. E. H. Hare, J. Dominian, and L. Sharpe, "Phenelzine and Dexamphetamine in Depressive Illness: A Comparative Trial," British Medical Journal (1962): 9-12; J. E. Overall et al., "Drug Therapy in Depressions: Controlled Evaluation of Imipramine, Isocarboxazine, Dextroamphetamine-Amobarbital, and Placebo," Clinical Pharmacology and Therapeutics 3 (1962): 16-21.
20. Eric J. Drimmer, Michael J. Gitlin, and Harry E. Gwirtsman, "Desipramine and Methylpheniclate Combination Treatment for Depression: Case Report," American Journal of Psychiatry 140 (1983): 241-42; R. N. Wharton, et al., "A Potential Clinical Use for Methy1phenidate with Tricyclic Antidepressants," American Journal of Psychiatry 127 (1971): 161925.
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22. W. H. Forest et al., "Dextroamphetamine with Morphine for the Treatment of Postoperative Pain," New England Journal of Medicine 296 (1977): 712-15.
23. Thomas R. Insel et al., "Amphetamine in Obsessive-Compulsive Disorder," Psychopharmacology 80 (1983): 231-35.
24. Charles Bradley, "The Behavior of Children Receiving Benzedrine," American Journal of Psychiatry 94 (1937): 577-85.
25. C. K. Conners et al., "Dextroamphetamine Sulfate in Children with Learning Dis-
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26. Peggy T. Ackerman et al., "Methylphenidate Effects on Cognitive Style and Reaction Time in Four Groups of Children," Psychiatry Research 7 (1982): 199-213; Roscoe A. Dykman, Peggy T. Ackerman, and David S. McCray, "Effects of Methylpheniclate on Selective and Sustained Attention in Hyperactive, Reading-Disabled, and Presumably Attention-Disordered Boys," Journal of Nervous and Mental Disease 168 (1980): 745-52.
27. J. L. Rapaport et al., "Dextroamphetamine: Cognitive and Behavioral Effects in Normal Prepubescent Boys," Science 199 (1978): 560-63.
28. C. K. Conners, "Controlled Trial of Methylpheniclate in Preschool Children with Minimal Brain Dysfunction," International Journal of Mental Health 4 (1975): 61-74; Rachel Gittelman, "Indications for the Use of Stimulant Treatment in Learning Disorders," Journal of the American Academy of Child Psychiatry 19 (1980): 623-36.
29. Linda Charles and Richard Schain, "A Four-Year Follow-Up Study of the Effects of Methylpheniclate on the Behavior and Academic Achievement of Hyperactive Children," Journal of Abnormal Child Psychology 9 (1981): 495-505.
30. Charles Bradley, "Benzedrine and Dexedrine in the Treatment of Children's Behavior Disorders," Pediatrics 5 (1950): 24-36.
31. R. H. Mattson and J. R. Calverly, "Dextroamphetamine Sulfate-Induced Dyskinesias," Journal of the American Medical Association 2O4(1968): 400-2; P. G. Ney, "Psychosis in a Child Associated with Amphetamine Administration," Canadian Medical Association Journal 97 (1967): 1026-29.
32. Jeffrey A. Mattes and Rachel Gittelman, "Growth of Hyperactive Children on Maintenance Regimen of Methylphenidate," Archives of General Psychiatry 40 (1983): 317-21.
33. Lester Grinspoon and James B. Bakalar, Psychedelic Drugs Reconsidered (New York: Basic Books, 1979), pp. 163-66, 168-71.
34. Norman 1. Dishotsky et al., "LSD and Genetic Damage," Science 172 (1971): 43140; Sally Y. Long, "Does LSD Induce Chromosomal Damage and Malformations? A Review of the Literature," Teratology 6 (1972): 75-90.
35. Constance A. Newland, My Self and I (New York: New American Library, 1962), pp. 20-47.
36. Albert A. Kurland, "The Therapeutic Potential of LSD in Medicine," in R. DeBold and R. Leaf, eds., LSD, Man, and Society (Middletown, Corm.: Wesleyan University Press, 1967), pp. 20-35.
37. Abram Hoffer, "A Program for the Treatment of Alcoholism: LSD, Malvaria, and Nicotinic Acid," in Harold A. Abramson, ed., The Use of LSD in Psychotherapy and Alcoholism (New York: Bobbs-Merrill, 1967), pp. 353-402.
38. Reginald G. Smart et at., "A Controlled Study of Lysergicle in the Treatment of Alcoholism," Quarterly Journal of Studies on Alcohol 27 (1966): 469-82; Frances E. Cheek et al., "Observations Regarding the Use of LSD-25 in the Treatment of Alcoholism," Journal of Psychopharmacology 1, no. 1 (1966): 56-74.
39. Bernard J. Albaugh and Philip 0. Anderson, "Peyote in the Treatment of Alcoholism Among American Indians," American Journal of Psychiatry 131 (1974): 1247-51.
40. Walter N. Pahnke, "The Psychedelic Mystical Experience in the Human Encounter with Death," Harvard Theological Review 62 (1969): 1-21.
41. Stanislav Grof et al., "LSD-Assisted Psychotherapy in Patients with Terminal Cancer," International Pharmacopsychiatry 8 (1973): 129-41.
42. Walter Houston Clark and G. Ray Funkhouser, "Physicians and Researchers Disagree on Psychedelic Drugs," Psychology Today 3, no. 11: 48-50, 70-73; Sidney Cohen, "Lysergic Acid Diethylamide: Side Effects and Complications," Journal of Nervous and Mental Disease 130 (1960): 30-40; Nicholas Malleson, "Acute Adverse Reactions to LSD in Clinical and Experimental Use in the United Kingdom," British Journal of Psychiatry 188 (1971): 229-30.
43. Personal communication, 1979.
44. Claudio Naranjo, The Healing Journey (New York: Ballantine, 1975).
45. George Greer, "MDMA: A New Psychotropic Compound and Its Effects in Humans," 1983 (unpublished).
46. R. Mechoulam and E. A. Carlini, "Toward Drugs Derived from Cannabis," Naturwissenschaften 65 (1978): 174-79.
47. J. Kotin, R. M. Post, and F. K. Goodwin, "Delta-9-tetrahydrocannabinol in Depressed Patients," Archives of General Psychiatry 28 (1973): 345-48.
48. C. M. Rosenberg, J. R. Gerrein, and C. Schnell, "Cannabis in the Treatment of Alcoholism," Journal of Studies on Alcohol 39 (1978): 155-58.
49. C. M. Rosenberg, "The Use of Marihuana in the Treatment of Alcoholism," in S. Cohen and R. C. Stillman, eds. The Therapeutic Potential of Marihuana (New York andLondon: Plenum, 1976).
50. Paul F. Consroe, George C. Wood, and Harvey Buchsbaum, "Anticonvulsant Natureof Marihuana Smoking," Journal of the American Medical Association 234 (1975): 306-7.
51. D. J. Petro, "Marihuana as a Therapeutic Agent for Muscle Spasm or Spasticity," Psychosomatics 21 (1980): 81-85.
52. J. M. Cunha et al., "Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients," Pharmacology 21 (1980): 175-85.
53. D. P. Tashkin et at., "Effects of Smoked Marijuana in Experimentally Induced Asthma," American Review of Respiratory Diseases 112 (1975): 377-86; D. B. Tashkin et at., "Bronchial Effects of Aerosolized Delta-9-tetrahydrocannabinol in Healthy and Asthmatic Subjects," American Review of Respiratory Diseases 115 (1977): 57-65.
54. R. S. Hepler, I. M. Frank, and R. Petrus, "Ocular Effects of Marihuana Smoking," in M. C. Braude and S. Szara, eds., Pharmacology of Marihuana (New York: Raven Press, 1976).
55. Roger A. Roffman, Marihuana as Medicine (Seattle: Madrona, 1982), P. 99.
56. W. Regelson et al., "Delta-9-tetrahydrocannabinol as an Effective Antidepressant and Appetite-Stimulating Agent in Advanced Cancer Patients," in Braude and Szara, eds., Pharmacology of Marihuana, pp. 763-76.
57. A. C. White et al., "Effects of Delta-9-tetrahydrocannabinol in Lewis Lung Adenocarcinoma Cells in Tissue Culture," Journal of the National Cancer Institute 56 (1976): 65558.
58. Roffman, Marijuana as Medicine, pp. 82-83.
59. V. S. Lucas and J. Laszlo, "Delta-9-tetrahydrocannabinol for Refractory Vomiting Induced by Cancer Chemotherapy," Journal of the American Medical Association 243 (1980): 1241-43; S. E. Sallan, N. E. Zinberg, and E. Frei, "Antiemetic Effect of Delta-9-tetrahydrocannabinol in Patients Receiving Cancer Chemotherapy," New England Journal of Medicine 293 (1975): 795-97. 60. S. Frytak et al., "Delta-9-tetrahydrocannabinol as an Antiemetic for Patients Receiving Cancer Chemotherapy: A Comparison with Prochlorperazine and a Placebo," Annals of Internal Medicine 91 (1979): 825-30.
61. T. S. Herman et al., "Superiority of Nabilone Over Prochlorperazine as an Antiemetic in Patients Receiving Cancer Chemotherapy," New England Journal of Medicine 300 (1979): 1295-97.
62. Institute of Medicine, Marijuana and Health (Washington, D.C.: National Academy
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