LSD - Lysergic Acid Diethylamide

Synthesis
Recreational Use
Effects
Risks
Production

Lysergic acid diethylamide, LSD, LSD-25, or acid, is a semi-synthetic psychedelic drug of the ergoline 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.

LSD is sensitive to oxygen, ultraviolet light, and chlorine, especially in solution, though its potency may last for years if it is stored away from light and moisture at low temperature. In pure form it is colourless and odourless. LSD is typically delivered orally, usually on a substrate such as absorbent blotter paper, a sugar cube, or gelatine. 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. 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.

Synthesis

LSD was first synthesized on November 16, 1938 by a Swiss chemist named Dr. Albert Hofmann at the Sandoz Laboratories in Basel, Switzerland, as part of a large research program searching for medically useful ergot alkaloid derivatives. 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; 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. 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.

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. 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.

Recreational Use

Several mental health professionals involved in LSD research, most notably Harvard psychology professors Dr. Timothy Leary and Dr. Richard Alpert, 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. 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". 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. 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).

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. 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. Generally, the dosage that will produce a threshold psychotropic effect in humans is considered to be 20 to 30µg. 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.)

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.

Tusko the elephant died shortly after being injected with 300 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 and psilocybin. This tolerance diminishes after a few days without use and is probably caused by downregulation of 5-HT2A receptors in the brain. Adverse effects of psychotropics are often treated with fast acting benzodiazepines like diazepam or triazolam that have calming and anti-anxiety effects but do not directly affect the specific actions of psychotropics. Many rumours about home remedies to counteract psychedelic effects are circulated, including sugar, calcium, orange juice, milk, or niacin, but none of them have been shown to be effective and they make no sense from a pharmacological standpoint. Theoretically, specific 5-HT2A receptor antagonists, such as Seroquel, would be direct antidotes, although reports on Erowid would state otherwise. Also, some people have reported that taking a SSRI such as Prozac or Trazadone will counteract the effects of LSD and aid in sleeping.

Effects

Short-Term Effects

The short-term effects of LSD are unpredictable. They depend on the amount of the drug taken; the user's personality, mood, and expectations; and the surroundings in which the drug is used. Usually, the user feels the first effects of the drug within 30 to 90 minutes of ingestion. These experiences last for extended periods of time and typically begin to clear after about 12 hours. The physical effects include dilated pupils, higher body temperature, increased heart rate and blood pressure, sweating, loss of appetite, sleeplessness, dry mouth, and tremors. Sensations may seem to "cross over" for the user, giving the feeling of hearing colours and seeing sounds. If taken in a large enough dose, the drug produces delusions and visual hallucinations.

Long-Term Effects

LSD users often have flashbacks, during which certain aspects of their LSD experience recur even though they have stopped taking the drug. In addition, LSD users may develop long-lasting psychoses, such as schizophrenia or severe depression. LSD is not considered an addictive drug - that is, it does not produce compulsive drug-seeking behaviour as cocaine, heroin, and methamphetamine do. However, LSD users may develop tolerance to the drug, meaning that they must consume progressively larger doses of the drug in order to continue to experience the hallucinogenic effects that they seek.

Psychological Effects

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 psycho-emotional 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 colours, objects and surfaces appearing to ripple or "breathe," coloured patterns behind the eyes, a sense of time distorting (time seems to be stretching, repeating itself, changing speed or stopping), crawling geometric patterns overlaying walls and other objects, morphing objects, a sense that one's thoughts are spiralling into themselves, loss of a sense of identity or the ego (known as "ego death"), and powerful, and sometimes brutal, psycho-physical reactions interpreted by some users as reliving their own birth. Many users experience a dissolution between themselves and the "outside world". 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, 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," 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) which are used to escape from reality, LSD is seen as more of an introspective experience. Studies in the 1950s that used LSD to treat alcoholism professed a 50% success rate, five times higher than estimates near 10% for Alcoholics Anonymous. Some LSD studies were criticized for methodological flaws, and different groups had inconsistent results. Mangini's 1998 paper reviewed this history. He concluded that the efficacy of LSD in treating alcoholism remains an open question. Dr Abram Hoffer referred to Mangini's paper as "a good review of the literature" but said that, in common with many other scientists, the author has failed to grasp the important point that psychedelic therapy is a therapeutic experience.

"The critics of psychedelic therapy have not taken this into account. Thus the Toronto studies studied the drug. They made no attempt whatever to induce a psychedelic experience. I saw at least two of the patients many years after they had been treated in Toronto and they told me that it was the most horrible experience they had ever had. It was in fact a true psychotomimetic experience and probably reproduced delirium tremens more than anything else. Not surprisingly their patients did not do well. They gave them 800 micrograms which is too heavy, gave them a barbiturate in advance to prevent convulsions, tied them to the bed so that they could not run away, and had sitting with them a psychologist who wrote notes all the time and did not interact with the patients."

Abram Hoffer M.D, Ph.D, FRCP 'Comments on the article Treatment of Alcoholism Using Psychedelic Drugs'

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 Effects

LSD causes expansion and altered experience of senses, emotions, memories, time, and awareness for 6 to 14 hours, depending on dosage and tolerance. LSD does typically not produce real hallucinations as the deliriants do. Generally beginning within thirty to ninety minutes after ingestion, the user may experience anything from subtle changes in perception to overwhelming cognitive shifts. Changes in auditory and visual perception are typical. Visual effects include the illusion of movement of static surfaces ("walls breathing"), after image-like trails of moving objects ("tracers"), the appearance of moving coloured geometric patterns (especially with closed eyes), an intensification of colours 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.

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". The auditory effects of LSD 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 Effects

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 civilizations.

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 in 1962 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. 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. SSRIs are believed to interact more benignly, with a tendency to noticeably reduce LSD's subjective effects.

Similar and perhaps greater reductions have also been reported with MAOIs. 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.

Initial studies in the 1960s and 70s raised concerns that LSD might produce genetic damage or developmental abnormalities in foetuses. 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. 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.

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. 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. 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 and Naditch and Fenwick's in 1977, 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.

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. 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.

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. 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 suggest 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; 9 per 1,000 psychotherapy patients in Melleson 1971).

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.

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.

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 colour: "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 gelatine ("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, Blotter, and Lucy as well as names that reflect the designs on the sheets of blotter paper.

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 geometric in black and white patterns to exotic artwork in full four-color print.