Lysergic acid diethylamide (LSD)

Lysergic acid diethylamide, LSD, LSD-25, or acid, is a semisynthetic psychedelic drug of the ergoline family. Its unusual psychological effects, which include visuals of colored patterns behind the eyes in the mind, a sense of time distorting, and crawling geometric patterns, have made it one of the most widely known psychedelic drugs.

It has been used mainly as a recreational drug, an entheogen, and as a tool to supplement various practices for transcendence, including in meditation, psychonautics, art projects, and illicit (formerly legal) psychedelic therapy. Formally, LSD is classified as a hallucinogen of the psychedelic type.

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 code name 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 colorless, odorless, and mildly bitter

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 between 20 and 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.

The European Monitoring Centre for Drugs and Drug Addiction reports that LSD retail prices range between €5 and €11 per unit in most European countries.

LSD was first synthesized on November 16, 1938, by Swiss chemist 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. Lysergic acid diethylamide, the 25th lysergic acid derivative Hofmann 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 five years later, when Hofmann, acting on what he has called a "peculiar presentiment," returned to work on the chemical.

While re-synthesizing LSD-25 for further study on April 16, 1943, 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.

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".

Bicycle dayOn April 19, 1943, Dr. Albert 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 wartime restrictions made automobiles unavailable.

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.

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".
Early researchEarly researchers on LSD saw its potency and noticed that even in extremely small quantities it could significantly alter the mental functioning of healthy volunteers.

Since LSD could produce changes in perceptions and emotions, early researchers hypothesized that the cause of some mental illnesses, particularly schizophrenia, were caused by endogenous compounds with a similar activity to LSD.

Much of the research during the late 1940s 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.[citation needed] Generally these studies revolved around the attempt to block the effects of LSD with premedication in order to find 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, 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.

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.

Tests were also conducted by the U.S. Army Biomedical Laboratory (now known as the United States Army Medical Research Institute of Chemical Defense) located in the Edgewood Arsenal at Aberdeen Proving Grounds. The government would administer LSD to subjects (without consent) and then perform a battery of tests to investigate the effects of the drug on soldiers.

Further CIA-funded testing was carried out at the Allan Memorial (Psychiatric) Institute in Montreal, a division of the Royal Victoria Hospital, which is a teaching hospital of McGill University. Most of the results of these experiments remain classified. Based on remaining publicly available records, the projects were said to be inconclusive.

Both the CIA and the Army experiments caused controversy 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.

In 1961, Paul Robeson attempted suicide in a Moscow hotel room. His son claimed this was precipitated by a CIA agent who placed some synthetic hallucinogen in his drink
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.

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.

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.

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" that could be used in interrogations. 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.

Current researchToday, most research with LSD involves animals or cells. However, a few groups are exploring LSD effects in humans. The Multidisciplinary Association for Psychedelic Studies has an eight-person study in Switzerland to see if a large dose of LSD (200 µg) is more helpful as part of psychotherapy for cancer patients than a lower dose (20 µg).

The Beckley Foundation is studying the effects of LSD on mental activity and consciousness in LSD-experienced volunteers, in order to gain insight into its reported effects on creativity and insight

It is hypothesised that LSD could be used in the treatment of obsessive-compulsive disorder due to the substance's stimulation of the 5-HT2A receptors

There has been additional interest in studying the effects of LSD on cluster headaches, although the current status of this research is uncertain. While some of these studies could be criticized for being too small to lead to strong conclusions, they may represent the beginnings of renewed scientific interest into LSD.

Effects
PharmacokineticsLSD's effects normally last from 6–12 hours depending on dosage, tolerance, body weight and age - Sandoz's prospectus for "Delysid" warned: "intermittent disturbances of affect may occasionally persist for several days."

Contrary to early reports and common belief, LSD effects do not last longer than the amount of time significant levels of the drug are present in the blood. Aghajanian and Bing found LSD had an elimination half-life of 175 minutes,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 5 ng/mL at 3 hours post-dose

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.

Recreational doses of LSD can affect 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5B, and 5-HT6 receptors. The psychotropic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors as specific 5-HT2A agonist drugs are psychotropics and largely 5-HT2A specific antagonists block the psychotropic activity of LSD.

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 cerebral cortex, specifically in layers IV and V.

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.

One experiment studying the actions of LSD was performed by Barry Jacobs recording from electrodes implanted into Raphe nuclei.

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.

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. As the effect of the drug is psychological as well as physical, any treatment should focus on calming the patient. Limiting stimuli such as bright light and loud sounds can help in the event of an abreaction
PsychologicalLSD'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 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 spiraling 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 to other drugs (such as alcohol, heroin, and cocaine) which are used to escape from reality, LSD produces a more introspective experience.Some 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.

These studies were criticized for methodological flaws, and different groups had inconsistent results. Mangini's 1998 paper reviewed this history. She concluded that the efficacy of LSD in treating alcoholism remains an open question.

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 / perceptionLSD causes expansion and an 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. 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 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

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 may include echo-like distortions of sounds, changes in ability to discern concurrent auditory stimuli, and a general intensification of the experience of music.

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.

SpiritualLSD is considered an entheogen because it can catalyze intense spiritual experiences, during which users may 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.

Potential risks of LSD useLSD is generally considered nontoxic, although 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 effects 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 1970s raised concerns that LSD might produce genetic damageor 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 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 this 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 versus HPPD"Flashbacks" are a reported psychological phenomenon in which an individual experiences an episode of some of LSD's subjective effects long after the drug has worn off — usually in the days after typical doses. In some rarer cases, flashbacks have lasted longer, but are generally short-lived and mild compared to the actual LSD "trip." Flashbacks can incorporate both positive and negative aspects of LSD trips.

Flashbacks have proven difficult to study and are no longer officially recognized as a psychiatric syndrome. However, colloquial usage of the term persists and usually refers to any drug-free experience reminiscent of psychedelic drug effects, with the typical connotation that the episodes are of short duration.

No definitive explanation is currently available for these experiences. 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 other users.

Several studies have tried to determine how likely a user of LSD, not suffering from known psychiatric conditions, 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.

Although flashbacks themselves are not recognized as a medical syndrome, there is a recognized syndrome called Hallucinogen Persisting Perception Disorder (HPPD) in which LSD-like visual changes are not temporary and brief, as they are in flash-backs, but instead are persistent, and cause clinically significant impairment or distress.

This syndrome can occur in people who have never taken hallucinogenic drugs. The syndrome is a DSM-IV diagnosis. Several scientific journal articles have described the disorder.

HPPD differs from flashbacks in that it is persistent and apparently entirely visual (although mood and anxiety disorders are sometimes diagnosed in the same individuals). A recent review suggests that HPPD (as defined in the DSM-IV) is rare and affects only a distinctly vulnerable subpopulation of users. However, it is possible that the prevalence of HPPD is underestimated because most of the diagnoses are applied to people who are willing to admit to their health care practitioner that they have previously used psychotropics, and presumably many people are reluctant to admit this.There is no consensus regarding the nature and causes of HPPD (or flashbacks).

Given that some symptoms have environmental triggers, it may represent a failure to adjust visual processing to changing environmental conditions. There are no explanations for why only some individuals develop HPPD. 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 HPPD appear to describe an anxious hyper-vigilant state reminiscent of post-traumatic stress disorder. Instead, some cases appear to involve only visual symptoms.

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.[65] In most cases, the psychosis-like reaction is of short duration, but in other cases it may be chronic. It is difficult to determine whether 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; 9 per 1,000 psychotherapy patients in Melleson 1971).

Source : Wikipediahttp://en.wikipedia.org/wiki/LSD