Methylenedioxymethamphetamine (MDMA): a.k.a. Ecstasy

As these words are written, the chemical we will call MDMA is a Schedule I drug. This means that MDMA (a) has no currently accepted medical use, (b) no currently accepted safety even under medical supervision, and (c) has a high potential for abuse. On the other hand, there are those who see great therapeutic potential in MDMA, and the Food and Drug Administration (FDA) has designated MDMA- assisted psychotherapy as a breakthrough therapy. We can foresee the day when it will be available by prescription. There is no doubt as to the chemical identity of MDMA, and much is known of its pharmacological effects in humans and in animals. The recreational drug commonly known as Ecstasy is more complicated. As is true for any illegal drug used by millions of people, demand for the drug has been met by persons not noted for their high ethical or manufacturing standards. Simply stated, short of chemical analysis, one can never be sure what street-bought Ecstasy is. For example, investigators at Vanderbilt University determined the contents of 1,214 tablets sold as Ecstasy. Only 39% contained only MDMA, while fully 46% were “substances other than MDMA.” Mixtures of MDMA and other drugs comprised the remaining 15%. On the other hand, sometimes in some places over the past several decades, nearly pure MDMA has been available on the illicit market. Nonetheless, a buyer of Ecstasy may ingest, rather than MDMA, drugs such as ketamine, gamma-hydroxybutyrate (GHB), cathinone, ephedrine, caffeine, or any one of the so-called designer drugs, many of which are amphetamine derivatives. A consequence of this pharmacological chaos is that many of the hazards associated with the use of Ecstasy have been uncritically attributed to MDMA. This fact has been a boon for those who would continue the Schedule I status of MDMA and a bane for those who would explore its therapeutic potential. However, in contrast with recreational use where purity of the drug is uncertain, MDMA in clinical trials is FDA approved and of known composition.

Hallucinogens: Magic Mushrooms, Ayahuasca, Mescal Buttons, and Dr. Hofmann’s Problem Child

There are about 400,000 species of plants in this world. Only a small fraction, perhaps 100 in number, contain hallucinogenic chemicals. Nearly a century ago, Lewis Lewin, professor of pharmacology at the University of Berlin, in speaking of drugs he called phantasticants, said “The passionate desire which . . . leads man to flee from the monotony of daily life . . . has made him discover strange substances (which) have been integral to human evolution both societal and cultural for thousands of years.” An unusual problem presents itself to me in writing about these drugs: They straddle the worlds of science and mysticism. The Encyclopedia Britannica defines mysticism as the practice of religious ecstasies (religious experiences during alternate states of consciousness), together with whatever ideologies, ethics, rites, myths, legends, and magic may be related to them. Science I am comfortable with; mysticism not so much. Yet in our exploration of the agents found in this chapter, we will encounter many persons speaking of drug-induced mystical experiences. I have attempted to get around my unease by first providing the history and the pharmacology of these agents and then touching only lightly on mysticism, allowing readers to draw their own conclusions. What shall we call these chemicals? Hallucinogen, a substance that induces perception of objects with no reality, is the term most commonly encountered and the one that I have settled on for the title of this chapter. However, it comes with a caveat. Albert Hofmann, the discoverer of LSD, our prototypic hallucinogen, has pointed out that a true hallucination has the force of reality, but the effects of LSD only rarely include this feature. Two additional terms that we will find useful are psychotomimetic and psychedelic. We have already considered the former, an ability to mimic psychosis, in our discussion of amphetamine-induced paranoid psychosis in chapter 4 and the effects of phencyclidine in chapter 6. A psychedelic was defined in 1957 by Humphrey Osmond, inventor of the word, as a drug like LSD “which enriches the mind and enlarges the vision.”

Dissociative Anesthetics: Angel Dust to Special K to Ketamine Clinics

We will consider just two drugs in this chapter. They are phencyclidine and ketamine. Both are widely used as anesthetic agents, ketamine in humans and phencyclidine in animals. The acronym for phencyclidine that we will use, PCP, comes from its chemical name 1-(1-PhenylCyclohexyl)-Piperidine. In addition to their medical use, both ketamine and PCP have gained roles as recreational drugs or, as others would put it, drugs of abuse. While sharing some of the properties of the depressant drugs we met in the preceding chapter, PCP and ketamine are pharmacologically and ther­apeutically unique. On March 26, 1956, V. Harold Maddox, a chemist working at the research laboratories of Parke, Davis & Company in Detroit, synthesized a novel compound later to be called phencyclidine. PCP was submitted in the autumn of that year for testing in animals. Pigeons, mice, rats, Guinea pigs, rabbits, dogs, cats, and monkeys all had their turn. Depending on the dose employed and the species in which it was tested, the effects ranged from excitement and stimulation to taming and quieting. Analgesia, that is, absence of pain without loss of consciousness, and anesthesia were common but, unlike the depressant drugs we met in the previous chapter, the anesthesia was not accompanied by depression of breathing. Studies in human subjects began in May 1957 at the Department of Anesthesiology of the Detroit Receiving Hospital. By this time, PCP had been given the trade name Sernyl. The drug initially was administered to seven volunteers. As had previously been noted in animals, there was no suppression of breathing or disturbance of cardiac rhythm, highly desirable qualities in an anesthetic agent. The investigators then moved on to 64 patients ranging in age from 18 to 78, 47 of whom were women, who were to undergo various surgical procedures, including breast biopsy, dilation and curettage, skin grafts, hysterectomy, and hernia repair. Immediately after the intravenous administration of PCP, there was what the anesthesiologists called “a profound state of analgesia” permitting surgical incision and, in many cases, completion of the operation without the use of other drugs.

Stimulants: From Coca to Caffeine

Unlike the opiates, which are a rather homogeneous group, the drugs we call stimulants come in a variety of forms. In this chapter, we will devote most of our time to the classical stimulants, cocaine and the amphetamines, but will consider as well caffeine, nicotine, ephedrine, and modafinil. All are capable of enhancing mental and physical performance, and some produce distinctly pleasurable effects that sometimes lead to addiction. About the time that humans living in what is now South America started to draw on the walls of their caves, one among them discovered the unusual properties of the coca shrub. When the leaves were chewed, wondrous things happened to the chewer: Hunger and fatigue were replaced by feelings of strength and power; the world seemed not such a bad place to live. By the time Francisco Pizarro led his conquistadors into Peru early in the 16th century, coca leaf had found an exalted place in the Incan Empire. One legend has it that coca was brought from heaven to earth by Manco Capac, son of the Sun god and the Inca from whom the ruling class traced its lineage. (Interesting how often royalty has claimed divine origins.) The Spaniards developed no great respect for coca, regarding it as but another facet of a pagan people who had no claim on civilization. But the new rulers were nothing if not practical. Coca allowed native workers to be pushed beyond the normal bounds of physical endurance. More tin and silver could be brought from the mines with fewer workers fed less food. Coca leaf lost its status as a sacrament and a pleasure of the ruling class. It became a part of the internal economy of Spanish Peru, a means of enhancing productivity, and a contributor to the destruction of the Incan people and their civilization. It was inevitable that Europeans would become familiar with the effects of coca leaf both by their observation of native use and by personal experience. In 1859, an Italian physician named Paolo Mantegazza who had spent some time among the Peruvian natives put it this way.

Opioids: God’s Own Medicine

Albert Schweitzer called pain “a more terrible lord of mankind than even death.” Thus, it is not surprising that humans have from the earliest times attempted to identify plants which might provide pain relief. The Odyssey by Homer provides a mythic account of the use of one such agent. . . . Then Helen, daughter of Zeus, took other counsel. Straightaway she cast into the wine of which they were drinking a drug to quit all pain and strife, and bring forgetfulness of every ill. Whoso should drink this down, when it is mingled in the bowl, would not in the course of that day let a tear fall down over his cheeks, no, not though his mother and father should lie there dead . . . Such cunning drugs had the daughter of Zeus, drugs of healing, which Polydamna, the wife of Thor, had given her, a woman of Egypt, for there the earth, the giver of grain, bears the greatest store of drugs . . . . . . More than a century ago, it was suggested by Oswald Schmiedeberg, a German scientist regarded by many as the father of modern pharmacology, that the drug to which Homer refers is opium for “no other natural product on the whole earth calls forth in man such a psychical blunting as the one described.” When today, in the fields of Afghanistan or Turkey or India, the seed capsule of the opium poppy, Papaver somniferum, is pierced, a milky fluid oozes from it which, when dried, is opium. Virginia Berridge, in her elegant history of opium in England, tells us that the effects of opium on the human mind have probably been known for about 6,000 years and that opium had an honored place in Greek, Roman, and Arabic medicine. I will not dwell on that ancient history but will instead jump ahead to the 17th century by which time opium had gained wide use in European medicine.

Pharmacological Puritanism and the War on Drugs: All the King’s Horses and All the King’s Men . . .

H. L. Mencken, arguably the leading satirist of the 20th century, said that American puritanism is characterized by the haunting fear that someone, somewhere, may be happy. If the source of that happiness is a drug, we might call it pharmacological puritanism. Followers of that faith abound, but I will mention just few. “There’s no such thing as recreational drug use” were the words of William Weld, head of the criminal division of the Attorney General’s office in 1988. A year later, in the midst of a cocaine epidemic, William Bennett, the first director of the Office of National Drug Control Policy (ONDCP) under President George H. W. Bush, expressed dual goals. The first was to construct 95,000 more federal prison cells for drug abusers and the second to make Washington, D.C., a drug-free city. He believed that calls for legalization of any psychoactive drug to be “morally scandalous.” John Walters, director of the ONDCP during George W. Bush’s tenure as president, believed that religion is the answer to drug abuse. Lest we think that pharmacological puritanism is a dying faith, we need only recall Attorney General Jeff Sessions’ comment in 2016 that “Good people don’t smoke marijuana.” It does make me wonder where, on the good–bad spectrum, lie the tens of millions of Americans who live in states and in the District of Columbia where marijuana is legal for recreational use. Among the general population, pharmacological puritanism appears to be uncommon. A survey of American college students found that the prime motives for drug use were to help with concentration, to increase alertness, and to get high. From the United Kingdom, David Nutt, chairman of the Department of Neuropsychopharmacology at Imperial College London, put it this way: “Drugs are taken for pleasure.” Whatever their numbers today or in the past, it is believers in pharmacological puritanism, with the absolutism which accompanies that faith, who are major contributors to the failure of our most recent war on drugs, now nearly a half-century old.

Depressants: Sedative-Hypnotic-Tranquilizing Drugs—From Errant Yeast to Halcion and Its Relatives

The agents we will consider in this chapter are a disparate bunch, but they are united in that most can induce a mild state of intoxication that many of us find to be pleasant; social drinkers of ethyl alcohol are familiar with the phenomenon. The darker side of these drugs is that all can induce physical dependence with a characteristic and sometimes life-threatening withdrawal syndrome. In addition, they are often agents of addiction; alcoholism is a prime example. Further uniting these drugs is the relatively recent recognition of a common mechanism of action. Their current primary medical uses are in anesthesiology, as anticonvulsants, and in the treatment of anxiety and sleep disorders. For many years, drugs of this class were referred to as sedative- hypnotics. Sedation implies the induction of a state of calmness, while hypnosis refers to sleep. However, with the discovery of meprobamate (Miltown), and the benzodiazepines, for example, Valium, which we will consider later, a third term was introduced. These drugs were to be called tranquilizers to distin­guish them from earlier sedative-hypnotics. But whatever the drugs are called, the fact is that for most there is a dose-related continuum of action beginning with a state of calmness (call it tranquility, if you wish) to sleep, and, finally, for some, coma and death. An illustration of the long- recognized connectedness of sedation, hypnosis, and anxiety was provided us by Henry Behrend. He describes his patient as . . . . . . a gentleman, forty years of age. . . . He was of a most excitable and nervous temperament, and was engaged in mercantile transactions of great magnitude, the extent of which seemed quite to overwhelm him. . . . He had lost his natural sleep, was harassed and fatigued during the day, and sought my opinion as to whether he ought not at once to withdraw from business, although the sacrifice entailed thereby would be very great, and he was most anxious to avoid it. . . .

Pharmacology: The Science of Drugs

Aldous Huxley once said that man was a pharmacologist before he was a farmer. Although written records rarely go back more than 5,000 or 6,000 years, there is reason to believe that humans did indeed experience the effects of a variety of drugs much earlier, perhaps even before the rise of agriculture some 12,000 years ago in the Nile Valley. Likely drugs available to the ancients include opiates, cocaine, tetrahydrocannabinol, cathinone, and numerous hallucinogens. But these were drugs in their crude natural forms: the opium poppy, coca leaves, hemp, khat, and a variety of other plant sources. Identification of pure chemicals and a science of drugs was much slower in coming. Pharmacology had to wait for the rise early in the 19th century of or­ganic chemistry, largely in Germany, and physiology, chiefly in France and England. Pharmacology was born of the marriage of these two disciplines. Signifying its maturation in this country, the first department of pharmacology was established at Johns Hopkins University School of Medicine in 1893. Today, pharmacology is taught as a basic medical science, along with anatomy, pathology, physiology, biochemistry, and microbiology, to every medical student. Each of the drugs I mentioned earlier will be discussed in detail in the chapters that follow, but before we do this we need a basic pharmacological vocabulary and a little knowledge of how drugs act. Pharmacology deals with the interaction of chemicals with a living system: the human body. Although drugs act on every element of the body, we will be most interested in that most complex of organs, the brain. We are aware that a drug has acted upon our brains by the effects that it produces. These effects may be as direct and unequivocal as vomiting after apomorphine or convulsing after strychnine. These effects may be of such subtlety as to inspire poetry or to stimulate thoughts of God. Diffuse, relaxed pleasure or orgasmic high; tranquility or terror: Drugs can produce any of these reactions and more. Some drugs may even inspire us to love our fellow man.

Marijuana: From Reefer Madness to THC Gummy Bears

No substance better exemplifies the ambivalence of Western societies toward psychoactive drugs than marijuana. In 2017, it was estimated that there were more than 22 million current users, about 6.7% of the adult population, in the United States. For those aged 18 to 25, the figure was nearly 20%. In the United Kingdom, the prevalence of recreational use of marijuana among males aged 16–34 was put at 15.5%. Despite its widespread acceptance, many regard marijuana as a serious drug of abuse which, if set free, will destroy the fabric of our society. Others see it as one of God’s gifts to humankind and regularly call for its legalization for medical use. By 2018, the United Kingdom and 40 other countries had heeded that call. In the United States, medical marijuana has been approved in 30 states and the District of Columbia with more sure to follow. Going further, recreational use is allowed in 10 of those states. Nonetheless, marijuana possession continues to be illegal under federal law in the United States, and some physicians have been threatened with loss of their licenses for advocating medical marijuana. In 2015, combined state and federal laws led to more arrests for possession of small amounts of marijuana than those for all violent crimes combined. The word marijuana (or the alternate spelling marihuana) does not appear in American medical texts of the 19th century. Instead, the term cannabis referred to flowering tops of the female plant of Cannabis sativa. At that time, while millions of persons in Asia and Africa habitually indulged in cannabis as an intoxicant, cannabis was little used for that purpose in this country. In this chapter, I will use the term “cannabis” to refer to any active material derived from Cannabis sativa and Cannabis indica, the two species—some say subspecies—of the plant. Today’s controversies surrounding “medical marijuana” often ignore its long history in European and American medicine. Beginning in 1850, Cannabis indica and several extracts of the plant were listed in The United States Pharmacopeia, an official compilation of medically useful drugs.