Lysergic acid diethylamide

Lysergic acid diethylamide, LSD, LSD-25, or acid, is a semisynthetic psychedelic drug of the tryptamine family. Probably the best known psychedelic, it has been used mainly as a recreational drug, an entheogen, and a tool to supplement various practices for transcendence, including in meditation, psychonautics, art projects, and illicit (though at one time legal) psychedelic psychotherapy, whether self-administered or not. It is synthesized from lysergic acid derived from ergot, a grain fungus that typically grows on rye and was first synthesized by Swiss chemist Albert Hofmann. The short form LSD comes from its early codename LSD-25, which is an abbreviation for the German "Lysergsäure-diethylamid" followed by a sequential number.^[1][2]

LSD is sensitive to oxygen, ultraviolet light, and chlorine, especially in solution, though its potency may last years if it is stored away from light and moisture at low temperature. In pure form it is colorless, odorless and mildly bitter.^[2] LSD is typically delivered orally, usually on a substrate such as absorbent blotter paper, a sugar cube, or gelatin. In its liquid form, it can be administered by intramuscular or intravenous injection. The threshold dosage level needed to cause a psychoactive effect on humans is of the order of 20 to 30 µg (micrograms).

Introduced by Sandoz Laboratories as a drug with various psychiatric uses, LSD quickly became a therapeutic agent that appeared to show great promise. However, the extra-medicinal use of the drug in Western society during the mid-twentieth century led to a political firestorm that resulted in the banning of the substance for medicinal as well as recreational and spiritual uses. Despite this, the drug is still considered in some intellectual circles to show a great deal of promise as a medicinal substance.^[3] A number of organizations—including the Beckley Foundation, MAPS, Heffter Research Institute and the Albert Hofmann Foundation—exist to fund, encourage and coordinate research into its medicinal uses.^[4]

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Synthesis

LSD was first synthesized on November 16, 1938 by Swiss chemist Dr. Albert Hofmann at the Sandoz Laboratories in Basel, Switzerland, as part of a large research program searching for medically useful ergot alkaloid derivatives.^[5] Ergot is a fungus that, by infecting cereal grains used for making rye breads, causes ergotism. After Dr. Hofmann succeeded in synthesizing ergobasine (which became the preeminent uterotonic), he began working on other amide derivatives of lysergic acid. LSD (lysergic acid diethylamide) is one of the major drugs making up the hallucinogen class of drugs[4]; Lysergic acid diethylamide, the 25th lysergic acid derivative he synthesised (hence the name LSD-25) was developed initially as a probable analeptic, a circulatory and respiratory stimulant, based on its structural similarity to another known analeptic, nikethamide (nicotinic acid diethylamide). However, no extraordinary benefits of the compound were identified during animal tests (though laboratory notes briefly mention that the animals became "restless" under its effects), and its study was discontinued.^[6] Its psychedelic properties were unknown until 5 years later, when Hofmann, acting on what he has called a "peculiar presentiment," returned to work on the chemical.^[6] While re-synthesizing LSD-25 for further study, Hofmann became dizzy and was forced to stop work. In his journal, Hofmann wrote that after becoming dizzy he proceeded home and was affected by a "remarkable restlessness, combined with a slight dizziness". Hofmann stated that as he lay in his bed he sank into a not unpleasant "intoxicated like condition" which was characterized by an extremely stimulated imagination. He stated that he was in a dreamlike state, and with his eyes closed he could see uninterrupted streams of "fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors." The condition lasted about two hours after which it faded away.^[7] Hofmann had attributed the psychoactive effects he experienced to accidentally absorbing a tiny amount of LSD-25 into his skin. Three days later he would take a much larger dose in order to test its effects further; this day would later be referred to as the "Bicycle Day".^[1]

Bicycle day

On April 19, 1943 Dr. Hofmann intentionally ingested 250 µg of LSD, which he hypothesized would be at most a threshold level dose, based on his research on other ergot alkaloids. Surprisingly, the substance showed a potency orders of magnitude above almost any other substance known at the time, amounting to a much heavier dose than typically given in modern therapeutic use. After ingesting the substance Hofmann found himself struggling to speak intelligibly and asked his laboratory assistant, who knew of the self-experiment, to escort him home on his bicycle, since no vehicles were available due to wartime restrictions. On the bicycle ride home, Hofmann's condition became more severe and in his journal he stated that everything in his field of vision wavered and was distorted, as if seen in a curved mirror. Hofmann also stated that while riding on the bicycle, he had the sensation of being stationary, unable to move from where he was, despite the fact that he was moving very rapidly. Once Hofmann arrived home, he summoned a doctor and asked his neighbor for milk, believing it might help relieve the symptoms. Hofmann wrote that despite his delirious and bewildered condition, he was able to choose milk as a nonspecific antidote for poisoning.^[8] Upon arriving the attending doctor could find no abnormal physical symptoms other than extremely dilated pupils. After spending several hours terrified that his body had been possessed by a demon, that his next door neighbor was a witch, and that his furniture was threatening him, Dr. Hofmann feared he had become completely insane. In his journal Hofmann said that the doctor saw no reason to prescribe medication and instead sent him to his bed. At this time Hofmann said that the feelings of fear had started to give way to feelings of good fortune and gratitude, and that he was now enjoying the colors and plays of shapes that persisted behind his closed eyes. Hofmann mentions seeing "fantastic images" surging past him, alternating and opening and closing themselves into circles and spirals and finally exploding into colored fountains and then rearranging themselves in a constant flux. Hofmann mentions that during the condition every acoustic perception, such as the sound of a passing automobile, was transformed into optical perceptions. Eventually Hofmann slept and upon awakening the next morning felt refreshed and clearheaded, though somewhat physically tired. He also stated that he had a sensation of well being and renewed life and that his breakfast tasted unusually delicious. Upon walking in his garden he remarked that all of his senses were "vibrating in a condition of highest sensitivity, which then persisted for the entire day".^[8]

Early research

Early research on LSD saw its potency and noticed that even in extremely small quantities it could significantly alter the mental functioning of healthy volunteers. Due to the fact that LSD could produce changes in perceptions and emotions, early researchers hypothesized that the cause of some mental illnesses, particularly schizophrenia, were due to the human body releasing small quantities of substances identical to LSD.^[9] Much of the research during the late 1940's dealt with this hypothesis and many LSD sessions conducted for scientific study were often termed "experimental psychoses", and this is where the terms "psychoactive" , "psychotomimetic" and "hallucinogenic" were coined to refer to such drugs. Generally these studies revolved around the attempt to block the effects of LSD with premedication, which was thought to be able to lead to medical treatments for schizophrenia. The studies showed that there was no such connection (the effects of LSD and those of schizophrenia are drastically different and have different causes and functions). Some early researchers also started to suggest that LSD could have positive effects and could be used as a treatment for patients with psychiatric illnesses. Some reports suggested that even small doses of LSD could have dramatic effects on the personalities and attitudes and even lifestyles of test subjects. Early LSD research also found evidence of the drug's ability to facilitate relief of various emotional episodes related to traumatic memories from childhood of patients.^[9]

Government research

During the Cold War intelligence agencies were keenly interested in the possibilities of using LSD for interrogation and mind control, as well as for large-scale social engineering. The CIA research on LSD, most of which was done under Project MKULTRA, the code name for a CIA mind-control research program, began in the 1950s and continued until the late 1960s.^[10]

Tests were also conducted by the U.S. Army Biomedical Laboratory (now known as the U.S. Army Medical Research Institute of Chemical Defense) located in the Edgewood Arsenal at Aberdeen Proving Grounds. Subjects would take LSD (without consent) and then perform a battery of tests to investigate the effects of the drug on soldiers. Based on remaining publicly available records, the projects seem to have concluded that LSD was of little practical use as a mind control drug and moved on to other drugs.^[11]

Both the CIA and the Army experiments became highly controversial when they became public knowledge in the 1970s, as the test subjects were not normally informed of the nature of the experiments, or even that they were subjects in experiments at all.^[10] At least one person, an Army scientist named Frank Olson is thought by some to have committed suicide by leaping from a tall building as a result of his being unknowingly given LSD.^[10] Frank Olson's son, Eric Olson, believes that his father was murdered by government officials and a 1994 exhumation and examination by forensic pathologists at George Washington University of the body suggested that Olson had suffered blunt trauma to the back of his head prior to falling from the building.^[12] Most of the MKULTRA records were deliberately destroyed in 1973. The controversy contributed to President Ford's creation of the Rockefeller Commission and new regulations on informed consent.^[10]The British government also engaged in LSD testing; in 1953 and 1954, scientists working for MI6 dosed servicemen in an effort to find a "truth drug". The test subjects were not informed that they were being given LSD, and had in fact been told that they were participating in a medical project to find a cure for the common cold. One subject, aged 19 at the time, reported seeing "walls melting, cracks appearing in people's faces … eyes would run down cheeks, Salvador Dalí-type faces … a flower would turn into a slug". After keeping the trials secret for many years, MI6 agreed in 2006 to pay the former test subjects financial compensation. Like the CIA, MI6 decided that LSD was not a practical drug for mind control purposes.^[13]

Recreational use

Several mental health professionals involved in LSD research, most notably Harvard psychology professors Dr. Timothy Leary^[14] and Dr. Richard Alpert, ^[15] became convinced of LSD's potential as a tool for spiritual growth. By the spring of 1961 Dr. Timothy Leary claimed to have given psychedelic drugs to over 200 subjects, saying that eighty-five percent of his subjects reported that the experience was the most educational of their lives.^[16]

Their research became more esoteric and controversial, as Leary and Alpert alleged links between the LSD experience and the state of enlightenment sought after in many mystical traditions. They were dismissed from the traditional academic psychology community, and as such cut off from legal scientific acquisition of the drug. Drs. Leary and Alpert acquired a quantity of LSD and relocated to a private mansion, where they continued their research. The experiments lost their scientific character as the pair evolved into countercultural spiritual gurus associated with the hippie movement, encouraging people to question authority and challenge the status quo, a concept summarized in Leary's catchphrase, "Turn on, tune in, drop out".^[17]

The drug was banned in the United States in 1966, with scientific therapeutic research as well as individual research also becoming prohibitively difficult. Many other countries, under pressure from the U.S., quickly followed suit. Since 1967, underground recreational and therapeutic LSD use has continued in many countries, supported by a black market and popular demand for the drug. Legal, academic research experiments on the effects and mechanisms of LSD are also conducted on occasion, but rarely involve human subjects. Despite its proscription, the hippie counterculture continued to promote the regular use of LSD, led by figures such as Leary and psychedelic rock bands such as The Doors and The Grateful Dead. "Acidhead" has been used as a (sometimes derogatory) name for people who frequently use LSD. According to Leigh Henderson and William Glass, two researchers associated with the NIDA who performed a 1994 review of the literature, LSD use is relatively uncommon when compared to the abuse of alcohol, cocaine, and prescription drugs. Over the previous fifteen years, long-term usage trends stayed fairly stable, with roughly 5% of the population using the drug and most users being in the 16 to 23 age range.^[18] Henderson and Glass found that LSD users typically partook of the substance on an infrequent, episodic basis, then "maturing out" after two to four years. Overall, LSD appeared to have comparatively few adverse health consequences, of which "bad trips" were the most commonly reported (and, the researchers found, one of the chief reasons youths stop using the drug).^[19]

Dosage

Dosages of LSD are measured in micrograms (µg), or millionths of a gram. By comparison, dosages of almost all other drugs, both recreational and medicinal, are measured in milligrams (mg), or thousandths of a gram. Hofmann determined that an active dose of mescaline, roughly 0.2 to 0.5g, has effects comparable to 100µg or less of LSD; put another way, LSD is between five to ten thousand times more active than mescaline.^[1]

While a single dose of LSD may be between 100 and 500 micrograms — an amount roughly equal to one-tenth the mass of a grain of sand — threshold effects can be felt with as little as 25 micrograms.^[20]

Generally, the dosage that will produce a threshold psychotropic effect in humans is considered to be 20 to 30µg.^[21][20] According to Glass and Henderson's review, black-market LSD is largely iterated though sometimes contaminated by manufacturing by-products. Typical doses in the 1960s ranged from 200 to 1000µg while street samples of the 1970s contained 30 to 300µg. By the 1980s, the amount had reduced to between 100 to 125 µg, lowering more in the 1990s to the 20–80 µg range. (Lower doses, Glass and Henderson found, generally produce fewer bad trips.)^[19] Dosages by frequent users can reach up to 1,200 µg (1.2 mg), although such a high dosage may precipitate severe physical and psychological effects.

Estimates for the lethal dosage (LD₅₀) of LSD range from between 200 µg/kg to more than 1 mg/kg of human body mass, though most sources report that there are no known human cases of such an overdose. Other sources note one report of a suspected fatal overdose of LSD occurring in November 1975 in Kentucky in which there were indications that ~1/3 of a gram (320 mg or 320,000 µg) had been injected intravenously, i.e., over 3,000 more typical oral doses of ~100 µg had been injected.^[22][23]

Tusko the elephant died shortly after being injected with 297 mg in 1962, but whether the LSD was the cause of his death is controversial.

LSD is not considered addictive, in that its users do not exhibit the medical community's commonly accepted definitions of addiction and physical dependence. Rapid tolerance build-up prevents regular use, and there is cross-tolerance shown between LSD, mescaline^[24] and psilocybin.^[25] This tolerance diminishes after a few days without use and is probably caused by downregulation of 5-HT_2A receptors in the brain.

Adverse effects of psychotropics are often treated with fast acting benzodiazepines like diazepam or triazolam that have calming and antianxiety effects but do not directly affect the specific actions of psychotropics. Many rumors about home remedies to counteract psychedelic effects are circulated, including sugar, calcium, orange juice or milk, but none of them have been shown to be effective and they make no sense from a pharmacological standpoint. Theoretically, specific 5-HT_2A receptor antagonists, such as Seroquel, would be direct antidotes, although reports on Erowid would state otherwise.

Effects

Pharmacokinetics

LSD's effects normally last from 8-12 hours^[2] - Sandoz's prospectus for "Delysid" warned: "intermittent disturbances of effect may occasionally persist for several days."^[1] Contrary to early reports and common belief, LSD effects do not last longer than significant levels of the drug in the blood. Aghajanian and Bing found LSD had an elimination half-life of 175 minutes,^[26] while, more recently, Papac and Foltz reported that 1 µg/kg oral LSD given to a single male volunteer had an apparent plasma half-life of 5.1 hours, with a peak plasma concentration of 1.9 ng/mL at 3 hours post-dose.^[27] Notably, Aghajanian and Bing found that blood concentrations of LSD matched the time course of volunteers' difficulties with simple arithmetic problems.

Pharmacodynamics

LSD affects a large number of the G protein coupled receptors, including all dopamine receptor subtypes, all adrenoreceptor subtypes as well as many others. LSD binds to most serotonin receptor subtypes except for 5-HT₃ and 5-HT₄. However, most of these receptors are affected at too low affinity to be activated by the brain concentration of approximate 10–20 nM.^[28] Recreational doses of LSD can affect 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT_5A, 5-HT_5B, and 5-HT₆ receptors. The psychotropic effects of LSD are attributed to its strong partial agonist effects at 5-HT_2A receptors as specific 5-HT_2A agonist drugs are psychotropics and largely 5-HT_2A specific antagonists block the psychotropic activity of LSD.^[28] Exactly how this produces the drug's effects is unknown, but it is thought that it works by increasing glutamate release and hence excitation in the cortex, specifically in layers IV and V.^[29] In the later stages, LSD might act through DARPP-32 - related pathways that are likely the same for multiple drugs including cocaine, methamphetamine, nicotine, caffeine, PCP, ethanol and morphine.^[30] A particularly compelling look at the actions of LSD was performed by Barry Jacobs recording from electrodes implanted into cat Raphe nuclei.^[31] Behaviorally relevant doses of LSD result in a complete blockade of action potential activity in the dorsal raphe, effectively shutting off the principal endogenous source of serotonin to the telencephalon.  

Some reports indicate that although administration of chlorpromazine (Thorazine) or similar typical antipsychotic tranquilizers will not end an LSD trip, it will either lessen the intensity or immobilize and numb the patient, a side effect of the medication.^[32] While it also may not end an LSD trip, the best chemical treatment for a "bad trip" is an anxiolytic agent such as diazepam (Valium) or another benzodiazepine. Some have suggested that administration of niacin (nicotinic acid, vitamin B3) could be useful to end the LSD user's experience of a "bad trip".^[33] The nicotinic acid in niacin as opposed to nicotinamide, will produce a full body heat rash, due to widening of peripheral blood vessels. The effect is somewhat akin to a poison ivy rash. Although it is not clear to what extent the effects of LSD are reduced by this intervention, the physical effect of an itchy skin rash may itself tend to distract the user from feelings of anxiety. Indeed, nicotinic acid was experienced as a stressor by all tested persons. The rash itself is temporary and disappears within a few hours. It is questionable if this method could be effective for people having serious adverse psychological reactions.

Physical

Physical reactions to LSD are highly variable and may include the following: uterine contractions, hypothermia, fever, elevated levels of blood sugar, goose bumps, increase of heart rate, jaw clenching, perspiration, pupil-dilation, saliva production, mucus production, sleeplessness, paresthesia, euphoria, hyperreflexia, tremors and synesthesia. LSD users report numbness, weakness, trembling, and nausea.^[34] LSD was studied in the 1960s by Eric Kast as an analgesic for serious and chronic pain caused by cancer or other major trauma.^[35] Even at low (sub-psychedelic) dosages, it was found to be at least as effective as traditional opiates while being much longer lasting (pain reduction lasting as long as a week after peak effects had subsided). Kast attributed this effect to a decrease in anxiety. This reported effect is being tested (though not using LSD) in an ongoing (as of 2006) study of the effects of the psychedelic tryptamine psilocybin on anxiety in terminal cancer patients.

Furthermore, LSD has been illicitly used as a treatment for cluster headaches, an uncommon but extremely painful disorder. Researcher Peter Goadsby describes the headaches as "worse than natural childbirth or even amputation without anesthetic."^[36] Although the phenomenon has not been formally investigated, case reports indicate that LSD and psilocybin can reduce cluster pain and also interrupt the cluster-headache cycle, preventing future headaches from occurring. Currently existing treatments include various ergolines, among other chemicals, so LSD's efficacy may not be surprising. A dose-response study, testing the effectiveness of both LSD and psilocybin is currently, as of 2007, being planned at McLean Hospital. A 2006 study by McLean researchers interviewed 53 cluster-headache sufferers who treated themselves with either LSD or psilocybin, finding that a majority of the users of either drug reported beneficial effects.^[37] Unlike attempts to use LSD or MDMA in psychotherapy, this research involves non-psychological effects and often sub-psychedelic dosages; therefore, it is plausible that a respected medical use of LSD will arise.^[38]

Psychological

LSD's psychological effects (colloquially called a "trip") vary greatly from person to person, depending on factors such as previous experiences, state of mind and environment, as well as dose strength. They also vary from one trip to another, and even as time passes during a single trip. An LSD trip can have long term psychoemotional effects; some users cite the LSD experience as causing significant changes in their personality and life perspective. Widely different effects emerge based on what has been called set and setting; the "set" being the general mindset of the user, and the "setting" being the physical and social environment in which the drug's effects are experienced.

Timothy Leary and Richard Alpert considered the chemical to be of potentially beneficial application in psychotherapy. If the user is in a hostile or otherwise unsettling environment, or is not mentally prepared for the powerful distortions in perception and thought that the drug causes, effects are more likely to be unpleasant than if he or she is in a comfortable environment and has a relaxed, balanced and open mindset.

Some psychological effects may include an experience of radiant colors, objects and surfaces appearing to ripple or "breathe," colored patterns behind the eyes, a sense of time distortion, crawling geometric patterns overlaying walls and other objects, morphing objects, loss of a sense of identity or the ego [known as "ego death"], and powerful, and sometimes brutal, psycho-physical reactions described by users as reliving their own birth.

Many users experience a dissolution between themselves and the "outside world".^[39] This unitive quality may play a role in the spiritual and religious aspects of LSD. The drug sometimes leads to disintegration or restructuring of the user's historical personality and creates a mental state that some users report allows them to have more choice regarding the nature of their own personality.

Some experts hypothesize that drugs such as LSD may be useful in psychotherapy, especially when the patient is unable to "unblock" repressed subconscious material through other psychotherapeutic methods,^[40] and also for treating alcoholism. One study concluded, "The root of the therapeutic value of the LSD experience is its potential for producing self-acceptance and self-surrender,"^[41] presumably by forcing the user to face issues and problems in that individual's psyche. Many believe that, in contrast, other drugs (such as alcohol, heroin, and cocaine) are used to escape from reality. Studies in the 1950s that used LSD to treat alcoholism professed a 50% success rate,^[42] five times higher than estimates near 10% for Alcoholics Anonymous.^[43] Some LSD studies were criticized for methodological flaws, and different groups had inconsistent results. Mangini's 1998 paper reviews this history and concludes that the efficacy of LSD in treating alcoholism remains an open question.^[44]

Many notable individuals have commented publicly on their experiences with LSD. Some of these comments date from the era when it was legally available in the US and Europe for non-medical uses, and others pertain to psychiatric treatment in the 1950s and 60s. Still others describe experiences with illegal LSD, obtained for philosophic, artistic, therapeutic, spiritual, or recreational purposes.

Sensory / perception

LSD causes expansion and altered experience of senses, emotions, memories, time, and awareness for 6 to 14 hours, depending on dosage and tolerance. Generally beginning within thirty to ninety minutes after ingestion, the user may experience anything from subtle changes in perception to overwhelming cognitive shifts. LSD does not produce hallucinations as the deliriants do, but instead illusions and vivid daydream-like fantasies, in which ordinary objects and experiences can take on entirely different appearances or meanings.

Changes in auditory and visual perception are typical.^[39][45] Visual effects include the illusion of movement of static surfaces ("walls breathing"), after image-like trails of moving objects ("tracers"), the appearance of moving colored geometric patterns (especially with closed eyes), an intensification of colors and brightness ("sparkling"), new textures on objects, blurred vision, and shape suggestibility. Users commonly report that the inanimate world appears to animate in an unexplained way; for instance, objects that are static in three dimensions can seem to be moving relative to one or more additional spatial dimensions.^[46] Many of the basic visual effects resemble the phosphenes seen after applying pressure to the eye and have also been studied under the name "form constants". Auditory effects are not that pronounced and include echo-like distortions of sounds, a mixing of all sounds which makes it harder to discern distinct sounds, the feeling that what you're hearing is your thought, a general intensification of the experience of music, and an increased discrimination of instruments and sounds.

Higher doses often cause intense and fundamental distortions of sensory perception such as synaesthesia, the experience of additional spatial or temporal dimensions, and temporary dissociation.

Spiritual

LSD is considered an entheogen because it can catalyze intense spiritual experiences where users feel they have come into contact with a greater spiritual or cosmic order. Some users report insights into the way the mind works, and some experience long-lasting changes in their life perspective. Some users consider LSD a religious sacrament, or a powerful tool for access to the divine. Dr. Stanislav Grof has written that religious and mystical experiences observed during LSD sessions appear to be phenomenologically indistinguishable from similar descriptions in the sacred scriptures of the great religions of the world and the secret mystical texts of ancient civilisations.^[47]

Such experiences under the influence of LSD have been observed and documented by researchers such as Alan Watts, Timothy Leary and Stanislav Grof. For example, Walter Pahnke conducted the Good Friday Marsh Chapel Experiment under Leary's supervision, performing a double blind experiment on the administration of psilocybin to volunteers who were students in religious graduate programs, e.g., divinity or theology.^[48] That study provided evidence that psychotropics may induce mystical religious states.

Potential risks of LSD use

Although LSD is generally considered nontoxic, it may temporarily impair the ability to make sensible judgments and understand common dangers, thus making the user more susceptible to accidents and personal injury.

There is also some indication that LSD may trigger a dissociative fugue state in individuals who are taking certain classes of antidepressants such as lithium salts and tricyclics. In such a state, the user has an impulse to wander, and may not be aware of his or her actions, which can lead to physical injury.^[49] SSRIs are believed to interact more benignly, with a tendency to noticeably reduce LSD's subjective effects.^[50] Similar and perhaps greater reductions have also been reported with MAOIs.^[49]

As Albert Hofmann reports in LSD – My Problem Child, the early pharmacological testing Sandoz performed on the compound (before he ever discovered its psychoactive properties) indicated that LSD has a pronounced effect upon the mammalian uterus. Sandoz's testing showed that LSD can stimulate uterine contractions with efficacy comparable to ergobasine, the active uterotonic component of the ergot fungus (Hofmann's work on ergot derivatives also produced a modified form of ergobasine which became a widely accepted medication used in obstetrics, under the trade name Methergine). Therefore, LSD use by pregnant women could be dangerous and is contraindicated.^[1]

Initial studies in the 1960s and 70s raised concerns that LSD might produce genetic damage or developmental abnormalities in fetuses. However, these initial reports were based on in vitro studies or were poorly controlled and have not been substantiated. In studies of chromosomal changes in human users and in monkeys, the balance of evidence suggests no significant increase in chromosomal damage. For example, studies were conducted with people who had been given LSD in a clinical setting.^[51] White blood cells from these people were examined for visible chromosomal abnormalities. Overall, there appeared to be no lasting changes. Several studies have been conducted using illicit LSD users and provide a less clear picture. Interpretation of these data is generally complicated by factors such as the unknown chemical composition of street LSD, concurrent use of other psychoactive drugs, and diseases such as hepatitis in the sampled populations. It seems possible that the small number of genetic abnormalities reported in users of street LSD is either coincidental or related to factors other than a toxic effect of pure LSD.^[51]

Flashbacks and HPPD

There is a reported possibility of "flashbacks", a psychological phenomenon in which an individual experiences an episode of some of LSD's subjective effects long after the drug has worn off — sometimes weeks, months, or even years afterward. Flashbacks can incorporate both positive and negative aspects of LSD trips. Colloquial usage of the term flashback refers to any experience reminiscent of LSD effects, with the typical connotation that the episodes are of short duration. However, psychiatry recognizes a disorder in which LSD-like effects are persistent and cause clinically significant impairment or distress. This syndrome is called Hallucinogen Persisting Perception Disorder (HPPD), though not truly hallucinogenic, a DSM-IV diagnosis. Several scientific journal articles have described the disorder.^[52]

The issues of HPPD and flashbacks are complicated and subtle, with no definitive explanations currently available. Any attempt at explanation must reflect several observations: first, over 70 percent of LSD users claim never to have "flashed back"; second, the phenomenon does appear linked with LSD use, though a causal connection has not been established; and third, a higher proportion of psychiatric patients report flashbacks than "normal" users.^[53] Several studies have tried to determine how likely a "normal" user (that is, a user not suffering from known psychiatric conditions) of LSD is to experience flashbacks. The larger studies include Blumenfeld's in 1971^[54] and Naditch and Fenwick's in 1977,^[55] which arrived at figures of 20% and 28%, respectively. A recent review suggests that HPPD (according to the DSM-IV definition) caused by LSD appears to be rare and affects a distinctly vulnerable subpopulation of users.^[56] Differences in the estimated prevalence of flashbacks may partly depend on the multiple meanings of the term and the fact that Hallucinogen Persisting Perception Disorder can only be diagnosed in a person who admits to their health care practitioner that they have used psychotropics.

Debate continues over the nature and causes of chronic flashbacks. Explanations in terms of LSD physically remaining in the body for months or years after consumption have been discounted by experimental evidence.^[53] Some say HPPD is a manifestation of post-traumatic stress disorder, not related to the direct action of LSD on brain chemistry, and varies according to the susceptibility of the individual to the disorder. Many emotionally intense experiences can lead to flashbacks when a person is reminded acutely of the original experience. However, not all published case reports of chronic flashbacks appear to describe an anxious hyper-vigilant state reminiscent of post-traumatic stress disorder.^[53]

Psychosis

There are some cases of LSD inducing a psychosis in people who appeared to be healthy prior to taking LSD. This issue was reviewed extensively in a 1984 publication by Rick Strassman.^[57] In most cases, the psychosis-like reaction is of short duration, but in other cases it may be chronic. It is difficult to determine if LSD itself induces these reactions or if it triggers latent conditions that would have manifested themselves otherwise. The similarities of time course and outcomes between putatively LSD-precipitated and other psychoses suggests that the two types of syndromes are not different and that LSD may have been a nonspecific trigger. Several studies have tried to estimate the prevalence of LSD-induced prolonged psychosis arriving at numbers of around 4 in 1,000 individuals (0.8 in 1,000 volunteers and 1.8 in 1,000 psychotherapy patients in Cohen 1960;^[58] 9 per 1,000 psychotherapy patients in Melleson 1971).^[59]

Chemistry

LSD is an ergoline derivative. It is commonly produced from reacting diethylamine with an activated form of lysergic acid. Activating reagents include phosphoryl chloride^[60] and peptide coupling reagents.^[61] Lysergic acid is made by alkaline hydrolysis of lysergamides like ergotamine, a substance derived from the ergot fungus on rye, or, theoretically, from ergine (lysergic acid amide, LSA), a compound that is found in morning glory (Ipomoea tricolor) and hawaiian baby woodrose (Argyreia nervosa) seeds. LSD is a chiral compound with two stereocenters at the carbon atoms C-5 and C-8, so that theoretically four different optical isomers of LSD could exist. LSD, also called (+)-D-LSD, has the absolute configuration (5R,8R). The C-5 isomers of lysergamides do not exist in nature and are not formed during the synthesis from D-lysergic acid. However, LSD and iso-LSD, the two C-8 isomers, rapidly interconvert in the presence of base. Non-psychoactive iso-LSD which has formed during the synthesis can be removed by chromatography and can be isomerized to LSD. A totally pure salt of LSD will emit small flashes of white light when shaken in the dark.^[62] LSD is strongly fluorescent and will glow bluish-white under UV light.

Stability

"LSD," writes the chemist Alexander Shulgin, "is an unusually fragile molecule."^[2] It is stable for indefinite amounts of time if stored, as a solid salt or dissolved in water, at low temperature and protected from air and light exposure. Two portions of its molecular structure are particularly sensitive, the carboxamide attachment at the 8-position and the double bond between the 8-position and the aromatic ring. The former is affected by high pH, and if perturbed will produce isolysergic acid diethylamide (iso-LSD), which is biologically inactive. If water or alcohol adds to the double bond (especially in the presence of light), LSD converts to "lumi-LSD", which is totally inactive in human beings, to the best of current knowledge. Furthermore, chlorine destroys LSD molecules on contact; even though chlorinated tap water typically contains only a slight amount of chlorine, because a typical LSD solution only contains a small amount of LSD, dissolving LSD in tap water is likely to completely eliminate the substance.^[2]

A controlled study was undertaken to determine the stability of LSD in pooled urine samples.^[63] The concentrations of LSD in urine samples were followed over time at various temperatures, in different types of storage containers, at various exposures to different wavelengths of light, and at varying pH values. These studies demonstrated no significant loss in LSD concentration at 25 °C for up to 4 weeks. After 4 weeks of incubation, a 30% loss in LSD concentration at 37 °C and up to a 40% at 45 °C were observed. Urine fortified with LSD and stored in amber glass or nontransparent polyethylene containers showed no change in concentration under any light conditions. Stability of LSD in transparent containers under light was dependent on the distance between the light source and the samples, the wavelength of light, exposure time, and the intensity of light. After prolonged exposure to heat in alkaline pH conditions, 10 to 15% of the parent LSD epimerized to iso-LSD. Under acidic conditions, less than 5% of the LSD was converted to iso-LSD. It was also demonstrated that trace amounts of metal ions in buffer or urine could catalyze the decomposition of LSD and that this process can be avoided by the addition of EDTA.

Production

Because an active dose of LSD is astonishingly minute, a large number of doses can be synthesized from a comparatively small amount of raw material. Beginning with ergotamine tartrate, for example, one can manufacture roughly one kilogram of pure, crystalline LSD from five kilograms of the ergotamine salt. Five kilograms of LSD — 25 kilograms of ergotamine tartrate — could provide 100 million doses, sufficient for supplying the entire illicit demand of the United States. Since the masses involved are so small, concealing and transporting illicit LSD is much easier than smuggling other illegal drugs like cocaine or cannabis in equal dosage quantities.^[64]

Manufacturing LSD requires laboratory equipment and experience in the field of organic chemistry. It takes two or three days to produce 30 to 100 grams of pure compound. It is believed that LSD usually is not produced in large quantities, but rather in a series of small batches. This technique minimizes the loss of precursor chemicals in case a synthesis step does not work as expected.^[64]

Forms of LSD

LSD is produced in crystalline form and then mixed with excipients or redissolved for production in ingestible forms. Liquid solution is either distributed as-is in small vials or, more commonly, sprayed onto or soaked into a distribution medium. Historically, LSD solutions were first sold on sugar cubes, but practical considerations forced a change to tablet form. Early pills or tabs were flattened on both ends and identified by color: "gray flat", "blue flat", and so forth. Next came "domes", which were rounded on one end, then "double domes" rounded on both ends, and finally small tablets known as "microdots". Later still, LSD began to be distributed in thin squares of gelatin ("window panes", "gel tabs") and, most commonly, as blotter paper: sheets of paper which are soaked into an LSD solution, dried, and perforated into small squares of individual dosage units. The paper is then cut into small square pieces called "tabs" or "hits". The user can then absorb the LSD out of the paper using his/her tongue, or simply swallow it. Individual producers often print designs onto the paper serving to identify different makers, batches or strengths, and such "blotter art" often emphasizes psychedelic themes.

LSD has been sold under a wide variety of often short-lived and regionally restricted street names including Acid, Trips, Alice Dee, Blotter, Liquid A, Lucy, Microdots, Sunshine, Twenty-five, Windowpane, etc., as well as names that reflect the designs on the sheets of blotter paper.^[65][66] On occasion, authorities have encountered the drug in other forms — including powder or crystal, and capsule. More than 200 types of LSD tablets have been encountered since 1969 and more than 350 paper designs have been observed since 1975. Designs range from simple five-point stars in black and white to exotic artwork in full four-color print.

Legal status

United States

LSD is Schedule I in the United States.^[67] This means it is illegal to manufacture, buy, possess, process or distribute LSD without a DEA license. There can also be substantial discrepancies between the amount of chemical LSD that one possesses and the amount of possession with which one can be charged in the U.S. This is because LSD is almost always present in a medium (e.g. blotter or neutral liquid), and the amount that can be considered with respect to sentencing is the total mass of the drug and its medium. This discrepancy was the subject of 1995 United States Supreme Court case, Neal v. U.S.^[68] The United Nations Convention on Psychotropic Substances (adopted in 1971) requires its parties to prohibit LSD. Hence, it is illegal in all parties to the convention, which includes the United States, Australia, and most of Europe. However, enforcement of extant laws varies from country to country.

LSD is easy to conceal and smuggle. A tiny vial can contain thousands of doses. Not much money is made from retail-level sales of LSD, so the drug is typically not associated with the violent organized criminal organizations involved in cocaine and opiate smuggling.

Canada

In Canada, LSD is a controlled substance under Schedule III of the Controlled Drugs and Substances Act.^[69] Every person who seeks to obtain the substance without disclosing authorization to obtain such substances 30 days prior to obtaining another prescription from a practitioner is guilty of an indictable offense and liable to imprisonment for a term not exceeding 3 years. Possession for purpose of trafficking is guilty of an indictable offense and liable to imprisonment for 10 years.

Hong Kong

In Hong Kong, Lysergide and derivatives are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance, and can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10,000(HKD). The maximum penalty for trafficking or illegally manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years' imprisonment.

United Kingdom

In the United Kingdom, LSD is classed as a class A drug. This means that, without a license, possession of the drug is punishable with 7 years imprisonment and/or an unlimited fine, and trafficking is punishable with life imprisonment and an unlimited fine (see main article on drug punishments Misuse of Drugs Act 1971).

United States: Prior to 1967

Further information: Project MKULTRA

Beginning in the 1950s the Central Intelligence Agency began a research program code named Project MKULTRA. Experiments included administering LSD to CIA employees, military personnel, doctors, other government agents, prostitutes, mentally ill patients, and members of the general public in order to study their reactions, usually without the subject's knowledge. The project was revealed in the US congressional Rockefeller Commission report.

Prior to October 6th, 1966, LSD was available legally in the United States as an experimental psychiatric drug. (LSD "apostle" Al Hubbard actively promoted the drug between the 1950s and the 1970s and introduced thousands of people to it.) The US Federal Government classified it as a Schedule I drug according to the Controlled Substances Act of 1970. As such, the Drug Enforcement Administration holds that LSD meets the following three criteria: it is deemed to have a high potential for abuse; it has no legitimate medical use in treatment; and there is a lack of accepted safety for its use under medical supervision. (LSD prohibition does not make an exception for religious use.) Lysergic acid and lysergic acid amide, LSD precursors, are both classified in Schedule III of the Controlled Substances Act. Ergotamine tartrate, a precursor to lysergic acid, is regulated under the Chemical Diversion and Trafficking Act.

LSD has been manufactured illegally since the 1960s. Historically, LSD was distributed not for profit, but because those who made and distributed it truly believed that the psychedelic experience could do good for humanity, that it expanded the mind and could bring understanding and love. A limited number of chemists, probably fewer than a dozen, are believed to have manufactured nearly all of the illicit LSD available in the United States. The best known of these is undoubtedly Augustus Owsley Stanley III, usually known simply as Owsley. The former chemistry student set up a private LSD lab in the mid-Sixties in San Francisco and supplied the LSD consumed at the famous Merry Pranksters parties held by Ken Kesey and his Merry Pranksters, and other major events such as the Gathering of the tribes in San Francisco in January 1967. He also had close social connections to leading San Francisco bands the Grateful Dead, Jefferson Airplane and Big Brother and The Holding Company, regularly supplied them with his LSD and also worked as their live sound engineer and made many tapes of these groups in concert. Owsley's LSD activities — immortalized by Steely Dan in their song "Kid Charlemagne" — ended with his arrest at the end of 1967, but some other manufacturers probably operated continuously for 30 years or more. Announcing Owsley's first bust in 1966, The San Francisco Chronicle's headline "LSD Millionaire Arrested" inspired the rare Grateful Dead song "Alice D. Millionaire."

United States: 1970 to the present

American LSD usage declined in the 1970s and 1980s, then experienced a mild resurgence in popularity in the 1990s. Although there were many distribution channels during this decade, the U.S. DEA identified continued tours by the psychedelic rock band The Grateful Dead and the then-burgeoning rave scene as primary venues for LSD trafficking and consumption. American LSD usage fell sharply circa 2000, following a single major DEA operation. Because of the huge drop in LSD availability, combined with the simultaneous increased availability of Research Chemicals, much of what has been, and is currently sold as LSD since 2000, is in fact, not LSD but other hallucinogens like DOI, DOB, or 5-MeO-AMT.^{[70][citation needed]} These other drugs are sold by unscrupulous dealers because they are hallucinogenic and are potent enough that a single dose can fit on one or more blotter tabs and thus achieving the same appearance as typical blotter acid would. The duration of action of DOI and especially DOB is typically longer than LSD, but all of these drugs can last 12 hours or more. Importantly, the toxicity of 5-MeO-AMT and all of the hallucinogenic amphetamines such as DOI, are either unknown, or much higher than LSD, and thus the consumption of large quantities of these other drugs, under the guise of being LSD, can be potentially dangerous.

Pickard and Apperson

The decline in prevalence of LSD is correlated with (but not necessarily caused by) the arrest of two chemists, William Leonard Pickard, a Harvard educated organic chemist, and Clyde Apperson. According to DEA reports, black market LSD availability dropped by 95% after the two were arrested in 2000. These arrests were a result of one of the largest LSD manufacturing raids in DEA history.^[71]

Pickard was an alleged member of the Brotherhood of Eternal Love group that produced and sold LSD in California during the late 1960s and early 1970s. It is believed he had links to other "cooks" associated with this group — an original source of the drug back in the 1960s — and his arrest may have forced other operations to cease production, leading to the large decline in street availability.

The DEA claims that these two individuals were responsible for supplying a third of the LSD in the United States and maybe the world,^[72] however, the government quoted seizure amounts in connection with this case have been seriously questioned.^[73]

In November of 2003, Pickard was sentenced to life imprisonment without parole, and Apperson was sentenced to 30 years imprisonment without parole, after being convicted in Federal Court of running a large scale LSD manufacturing operation out of several clandestine laboratories, including a former missile silo near Wamego, Kansas.

Modern distribution

LSD manufacturers and traffickers can be categorized into two groups: A few large scale producers, such as the aforementioned Pickard and Apperson, and an equally limited number of small, clandestine chemists, consisting of independent producers who, operating on a comparatively limited scale, can be found throughout the country. As a group, independent producers are of less concern to the Drug Enforcement Administration than the larger groups, as their product reaches only local markets.

See also

• Mind at Large
• ALD-52
• Bogle-Chandler case, deaths mistakenly attributed to LSD overdoses
• Drug urban legends
• Entheogen
• Psychedelic psychotherapy
• United States v. Stanley, US Supreme Court case
• Related chemical compounds: ergolines, LSA, psilocybin, DMT, serotonin

References

Further reading

• Stevens, Jay. Storming Heaven: LSD And The American Dream ([5])
• Marks, John. The Search for the Manchurian Candidate: The CIA and Mind Control (1979), 0-8129-0773-6
• Grof, Stanislav. LSD Psychotherapy. (April 10, 2001)
• Lee, Martin A. and Bruce Shlain. Acid Dreams: The Complete Social History of LSD: The CIA, the Sixties, and Beyond [6]

• Erowid -> LSD Information
• The Lycaeum Archive -> LSD
• TIHKAL entry for LSD¶
• The Neurochemistry of Psychedelic Experience, Science & Consciousness Review¶
• Current LSD Research – MAPS¶
• International 3 day conference on LSD in Basel¶
• Talk to FrankUK government anti-drug site on LSD¶
• Scholarly bibliography on the histories of LSD use¶
• Huxley, Aldous, "The Doors of Perception".¶