Lysergic Acid Diethylamide (LSD) and Psychedelics
LSD is the abbreviation for lysergic acid diethylamide. It is the most potent member of a group of hallucinogenic substances called the indole-type hallucinogens. These drugs have structural similarities to another indole, the neurotransmitter serotonin.
LSD was originally synthesized at the Sandoz Pharmaceutical Company in Switzerland as part of a long project begun in the 1930s. The aim was to develop useful medications that were derived from ergot, a fungus (Claviceps purpurea) that infects such grasses as rye. Some of these compounds were found to be useful in medicine—such as methyser-gide, for the treatment of migraine headaches, and ergotamine, which is widely used in obstetrics to induce contractions of the uterus and stop bleeding after the delivery of a baby. These medications do not have hallucinogenic properties.
The chemist in charge of this drug development project was Albert Hofmann. In 1943, he synthesized a compound he called LSD-25 because it was the twenty-fifth compound made in this series of ergot derivatives. He accidentally ingested some of it and within forty minutes had the first LSD “trip.” He told his colleagues he was not feeling quite right and got on his bicycle to go home. Later, he carefully described the vividly clear flood of perceptions that are characteristic of the “mind manifesting” or psychedelic drug. This, then, was a complete surprise. Thereafter, the drug and various substitutions of different atoms on the basic molecule were extensively tested for medical uses in the late 1940s and in the 1950s. No specific medical use of LSD or its psychedelic variants has been found.
Because of its potency and the extensive reports of laboratory studies in animals and in the clinic, LSD has become the prototypical hallucinogen, or psychedelic drug. It also became the emblem of a social movement—which, in fact, was a confluence of various movements that had begun in the early 1960s; they peaked in the late 1960s. By 1973, the “acid culture” had subsided into a small but still active subculture of various psychedelic drug devotees seeking meaning and profound insights. The feeling of a “great discovery” about such drugs and the human mind had occurred as early as the nineteenth century; artists and writers, such as Baudelaire and Rimbaud in Paris, had discovered hashish and the altered, somewhat dreamy, states of consciousness and euphoria produced by this potent form of marijuana—the active ingredient of which is tetrahydrocannabinol (THC). For a period, they became absorbed with hashish and wrote about its alluring effects. The drug scene evoked the promise that the human mind must contain remarkable powers. Toward the beginning of the twentieth century, mescaline, the active hallucinogenic compound in the peyote cactus, similarly was tried by a few explorers in medicine and in the arts. In New York City, during the early part of World War I, many influential people and intellectuals took either peyote “buttons” (the dried tops of the peyote cactus) or mescaline (the synthesized active ingredient of the buttons) and called it a “dry drunk.” Similarly, after World War II, LSD caused a flurry of excitement among some professionals, and its medical value was tested in psychiatric patients. Writers such as Aldous Huxley wrote exciting books about the effects of mescaline and, later, LSD—yet there was still no widely popular movement until 1960.
Then Timothy Leary, a young psychology instructor at Harvard, explored the Mexican or “magic” mushroom, Psilocybe mexicana, and its active ingredient, psilocybin—and later LSD—claiming criminals became loving and peaceful and others more creative. He popularized this on campus and, when he was not reappointed to the faculty, proclaimed himself to be a martyr to his
cause. Between 1960 and 1966, the media repeatedly “discovered” LSD—in effect, advertising it. As publicity increased, subcultures experimenting with mushrooms and LSD grew up in the East and West Coast cities. Musicians, rock music, the hippie lifestyle, “flower children,” and many in the various protest movements against the Establishment and the Vietnam War were loosely joined to Leary's attempt to lead affluent and middle-class youth. Well-publicized festivals celebrated LSD and marijuana, such as the Summer of Love in the Haight-Ashbury section of San Francisco. Leary's challenge was for youth to “turn on, tune in and drop out” with acid. As more and more youth were curious to try experiences their parents had never dreamed of, rebellion led not only to acid experiments but to extensive polydrug abuse—the extensive use of marijuana and various street substances. Either LSD or some variant and even heroin were tried. In addition, the search for new drugs with different and improved characteristics (more or less euphoria, hallucinogenic activity, or stimulant properties), literally hundreds of so-called designer drugs were synthesized (DOM, MDMA, DMT, etc.). Because any drug can have bad effects, the unsupervised use of all of these compounds led to frequent “bad trips” (which fundamentally were panic reactions) that brought people to emergency rooms. This generated widespread concern that all American youth (and, later, those in Europe) would become dreamy and “way-out acid heads.” In 1966, the Sandoz Laboratories ceased distribution of the drug because of the often-exaggerated bad reactions and the public concern. As the claims for enduring LSD insights proved transient, research with LSD in humans essentially stopped.
Thus, one of the ways people use the effects of drugs that seem to enhance the clarity of mentation (mental activity) and perception (while not producing confusion, dreamy-euphoria, or oversedation) is to become absorbed in periods of intense exploration with a few others “in the know.” Those with such inside information form a kind of cult and then advertise, but they eventually see some bad effects (the wrong people taking the drug in the wrong circumstance with unfortunate consequences) and sooner or later see little real use for the drugs. The minor or major epidemics then die down, only to recur as later generations rediscover the compounds.
LSD is one of the most potent hallucinogens known; one-billionth of a gram of LSD per gram of brain produces profound mental changes. Although subjective effects occur in some individuals after doses as low as 50 micrograms, typical street doses range from 10 to 300 micrograms—street dosages vary widely. Misrepresentation also frequently occurs; someone will try to purchase synthetic tetrahydrocannabinol (THC), the active ingredient of marijuana, and receive LSD. Thus, the intake of LSD can be accidental as well as intentional, and the lack of quality control in illicit supplies is a hazard. Because of its high potency, LSD can be applied to paper blotters or the backs of postage stamps from which it is dissolved for consumption. Unsubstantiated reports of LSD added to stick-on tattoos for young children have caused alarm, even though absorption through skin would be far too slow to deliver enough drug to the brain to produce and sustain a trip.
The absorption of LSD from the gastrointestinal tract and other mucous membranes occurs rapidly, with drug diffusion to all tissues, including brain. The onset of psychological and behavioral effects occurs approximately 30 minutes after oral administration, peaks in the next 2 to 4 hours, depending on the dose, with gradual return to normal by 10 to 12 hours. The first 4 hours after a 200-microgram dose are called a trip. In the next 4 to 8 hours, when over half the drug has left the brain, the “TV show in the head” has stopped. At this point subjects think the drug is no longer active, but later they recognize that they, in fact, had paranoid thoughts and “ideas Page 375 | Top of Articleof reference” in the last 4 to 8 hours of the trip. This simply means that there is the feeling of being at the center of things, being hyperalert, and having a conviction that everything going on refers to oneself. This is a regular but little-publicized aftereffect, which finally dissipates 10 to 12 hours after the dose.
From 12 to 24 hours after the trip, there may be some slight letdown or feeling of fatigue—as if one had been on a long, steep roller coaster ride. After these intense and even frightening moments, the ordinary world might for a time seem drab. There is no craving to take more LSD to relieve this boredom; one trip usually produces satiation for a time, although some may want to repeat the experience. Memory for the events during the trip is quite clear. Those who revisit the experience sooner or later decide they have learned what they can and go on with the practical, daily affairs of living. In one experiment on creativity, subjects received either LSD or the stimulant amphetamine during a period of pleasant surroundings and music. The only difference between the two groups six months later was a slight tendency for those who had received LSD to buy more recordings! So the promise of lasting insight or creativity was not kept.
Drugs that make one feel different—alcohol being typical—can signal a “holiday from daily reality.” The way the effects of such drugs are interpreted is critical. Beer at the Super Bowl means “loudly letting go” and champagne at the White House means a time for graceful speech and feelings. Thus personal and social expectations (called set—or how one is set to go) and the surroundings (called setting) have much to do with the ultimate effects of drugs. This is distinctively and especially the case with psychedelics. Thus when the chemist Albert Hofmann first ingested the active ingredient of the Mexican mushroom psilocybin, the perceptions capturing his attention were related to Aztec symbols and art! For some, therefore, the trip may simply be funny and odd—for others it will have special meanings. Set and setting partially determine the character of such trips.
Fundamentally, LSD produces a heightened clarity and awareness of sensory signals—of sights, sounds, touch, lights, and colors. Similarly there is special significance given to thoughts, memories, or verbal interchanges. For example, gestures or inflections of speech or many cues that are normally in the background are felt to be more important than what is being said or usually meant—and in looking at a picture, the central figures may take on a life of their own, the small background details that are normally ignored emerging, capturing attention.
While awareness is strikingly increased, control over what is being attended to is weakened. For all these reasons, unstable surroundings or confused motives at the time of drug ingestion may lead to a less-controlled trip or even a panic-generating trip. Many are aware that the trip is not quite real and fundamentally feel as if they are “spectators” of what they are so intensely experiencing. Many rely on guides, a group, or the rhythm of music to carry them through this period of altered perceptions in which control is diminished. Thus, personal intent and reliable surroundings are major factors affecting the different kinds of experiences that people will have.
While every trip has an individual characteristic, there are regularities in the trips. This has been called a “march of effects” following drug ingestion. Thus, observers note, the first sign of feeling different is like “butterflies in the stomach” or a slight nausea and feeling of “whoops, here we go” as if on a roller coaster. Parts of the body simultaneously feel strange or different. At about the same time (30–40 minutes after drug ingestion), the cheeks are slightly flushed and pupil size begins to increase, maximizing within an hour or two. These changes are due to the effects of LSD on the sympathetic and parasympathetic nervous systems. The pupils react normally but are enlarged. After 4 hours they slowly begin to return to normal size, which finally is achieved at 10 to 12 hours after taking LSD. At the beginning of the trip, all soon note that what is at the periphery of their vision suddenly seems as clear as what is normally at the center of vision. Over the next 90 minutes, there is a feeling that tension is welling up. Laughing or crying will relieve the tension. Often subjects say they are laughing because of what they see or crying because of their feelings. But this is simply based on a need to relieve the fluctuating rise of tension. The trip moves on into the second and third hours when perceptual fluctuations and intensities are mainly noted. People also report perceiving several feelings simultaneously. A Page 376 | Top of Articlecommon observation is, “I don't know if I’m anxious, thrilled, or terrified.” Just as perceptions are in flux, so are feelings, and these feelings and emotions may capture center stage in the second and third hours. Throughout the trip, people feel as if they are on the brink of an exhilarating but also dangerous experience. This intensity dies down about 4 hours after the usual dosage. If very large doses of LSD (500–1,000 micrograms) are taken, there is less capacity to be a spectator and far more intense self-absorption and fear. Some call this “dying of the ego” and relate the experience to mystical versions of death and rebirth.
Because the familiar seems novel and is seen in a different way, specialists in perception have been interested in what is called the “breakdown of constancies” that occurs with the drug. Normally we correct for what the retina sees by putting the world into order. We usually suppress the nonessential and focus on what we need to do to get about during the day. Just as with a camera, the retina sees the hand placed 6 to 8 inches in front of the eye as large. But the brain corrects for it and keeps size constant. Under LSD, corrections for constancy do not seem to happen. Many sensations that are normally dampened can thus have free play under the drug and the world will seem far less regular than it does in daily life.
One of the aftereffects in some—clearly not all—people is called “flashbacks.” Days, months, or years after tripping, with no particular trigger or with an intense sensation, there may be a sudden few minutes in which subjects feel like they are back under the drug. They also may see flashing lights and other optical illusions. These flashbacks may be very disturbing. Flashbacks can occur after only a single drug experience and unpredictably. There has been no explanation as to why or how flashbacks occur. Scientists cannot predict (by observing a trip) if flashbacks will later occur or who is vulnerable. While these aftereffects are upsetting to some, most people do not experience them or those that do are not bothered. Others simply observe that their dreams may be more intense for a time after the drug experiences. One scientist noted that riding on a train to work, he was distracted from focusing on his newspaper for several months by the telephone poles whizzing by. These were normally at the periphery of his attention as he was reading, but after LSD, he could no longer suppress this irrelevant detail. There were more reports of such phenomena after publicity about them; given the millions of trips with LSD, these aftereffects are certainly infrequent but not rare.
Perhaps the most alarming bad effects of the drug have been the panic states occurring during a trip. Native Americans note that if one is in conflict, the effects of mescaline during religious ceremonies are unpleasant and can evoke terror. They then pray with the panicked person and “talk him down.” One cannot predict whether a panic experience will occur. “One good trip does not predict a second one” is the general wisdom concerning this risk. Higher doses lead to less control and more intense effects, but panic states can occur at doses as low as 75 to 100 micrograms. For those who might be at risk for other mental disorders, hallucinogenic experiences may often destabilize them and precipitate some form of mental illness. For others, the experience may lead to a subsequent absorption with the unreal (“dropping out”), rather than coping with the challenges that the tasks of the ordinary world present. Occasional suicides or rare impulsive acting out of odd ideas arising during a trip have led some to loss of control and tragedy.
For most, the experiences have few negative or positive aftereffects. Although it has often been suspected, no permanent change to the cells of the brain (brain damage) has ever been scientifically established. There is no generally accepted evidence that the drug produces chromosomal abnormalities or damage to a developing fetus (although no nonprescription drugs during pregnancy is the only safe rule to follow). The bad effects of a period of diminished control are unpredictable, and in that fact lies the real risk. Thus, it is the intensity of the experience and how well or poorly it can be managed, the unpredictable flashbacks, and how this “TV show in the head” or this “waking dream” gets woven into one's subsequent life that are at issue when hazards are considered.
One striking feature of LSD, mescaline, and related psychedelic drugs is tolerance, which is a loss of typical drug effects after repeated doses. In Page 377 | Top of Articlebrief, with daily doses the duration and intensity of effects rapidly diminish to the point where no subjective effects are perceived. After 200 micrograms per day of LSD, there is simply no detectable drug effect on the third or fourth day. After three or four days without LSD, the full initial effects can be triggered by the same dose that has been “tolerated.” Thus tolerance develops and dissipates rapidly. When subjects are tolerant to LSD, the usual dose of mescaline required for a trip is also no longer effective. This is called cross-tolerance. It is readily seen with similar dosage schedules of psilocybin, LSD, and mescaline. There is no cross-tolerance with the nonhallucinogenic stimulant drug amphetamine. Thus, there must be some common mechanism of action among the psychedelic drugs beyond their structure and similar array of mental effects.
Tolerance is seen both in humans and laboratory animals. The lack of pupil enlargement is a common sign of tolerance. In animals, some drug effects show tolerance and some do not. For example, a heightened sensitivity of rats to mild electric shock persists after daily doses and does not show tolerance. Such persisting drug effects during periods of tolerance have not been studied in humans. How and why a psychedelic drug loses and regains its potency in this fashion is not yet understood, but there is no withdrawal discomfort after stopping a psychedelic drug when it has been taken over several days. This differs from the classic effects described for opioid drugs, where an uncomfortable withdrawal with drug cessation requires more drug for relief. Such physical drug withdrawal phenomena are not found with psychedelics.
LSD AND SEROTONIN
LSD is known to affect many places in the brain where the body's neurotransmitter serotonin naturally has actions and effects, and the biochemical effects of LSD in the brain are mostly linked to those sites related to serotonin. LSD acts as a kind of impostor at receptors that recognize serotonin. LSD is like serotonin but different. Thus with LSD, the receptor signals other parts of the brain that there is too much serotonin, and these parts of the brain respond by tuning down cells that make serotonin. Yet, in fact, the chief effect of LSD is to cause less serotonin to be released in the neighborhood of the receptor—rather than too much, there is too little. This is one example of how LSD miscues the systems governing the flow of information between various brain neurons. In fact, overloading the brain with serotonin can reduce the LSD effect, and diminishing brain supplies of serotonin will increase LSD effects. Yet serotonin itself does not cause the scrambled perceptions that LSD does. How this miscue by LSD leads to the vivid effects is still unknown.
LSD, other indole-type psychedelics, and many hallucinogens related to mescaline (but surprisingly not mescaline itself) are known to act especially at a subtype of the serotonin receptor called the 5HT2 receptor. In laboratory animals, daily doses of LSD or psilocybin lead to fewer of these receptors, an effect that would be expected to produce tolerance; however, with 3 or 4 days off the drug, the number of 5HT2 receptors returns to normal. Both LSD and mescaline act at certain brain neurons, such as the locus coeruleus, and make it more responsive to inputs from the environment—such as a pinch. Researchers speak of such effects as lowering the gates to sensory input. We know the ways by which LSD affects certain brain systems but still far less than we need to know to explain the full panoply of effects.
Although many of the psychedelic drugs are known to interact with serotonergic 5HT2 receptors, and this interaction appears to be of critical importance in producing their hallucinogenic effects, the hallucinogenic drugs can bind to a subtype of serotonin receptors that is located on serotonin nerve-cell bodies and on their terminals (which release serotonin that goes to the adjacent nerves with 5HT2 receptors). Interactions with these various receptors can lead to changes in the firing rate of such cells. The designer drugs MDMA and MDA cause the release of both dopamine and serotonin, effects that might contribute to their psychostimulant properties. The differential interactions of the various hallucinogens with multiple sites and systems may underlie the qualitative differences in the experience they produce.
See also Cults and Drug Use; Hallucinogenic Plants; Monitoring the Future; Plants, Drugs From.
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DANIEL X. FREEDMAN
R. N. PECHNICK