Lysergic acid diethylamide, LSD, LSD-25, or acid, is a semisynthetic 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.^[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 Foundatio exist to fund, encourage and coordinate research into its medicinal uses.^[4]

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]

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,^[27] 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.^[28] 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.^[29] 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.^[29] 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.^[30] 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.^[31].Affinity of LSD for various receptors, averaged from data from the K_i Database

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.^[33] 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".^[34] 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. Niacin is used in Orthomolecular psychiatry to treat schizophrenia successfully; however, this kind of treatment is considered Alternative Medicine as it is not accepted by the American Psychiatric Association.

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.^[35] LSD was studied in the 1960s by Eric Kast as an analgesic for serious and chronic pain caused by cancer or other major trauma.^[36] 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."^[37] 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.^[38] 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.^[39]

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 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 described by users as reliving their own birth.

Many users experience a dissolution between themselves and the "outside world".^[40] 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,^[41] 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,"^[42] 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,^[43] five times higher than estimates near 10% for Alcoholics Anonymous.^[44]

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.^[40][46] 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.^[47] 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.

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.^[50] SSRIs are believed to interact more benignly, with a tendency to noticeably reduce LSD's subjective effects.^[51] Similar and perhaps greater reductions have also been reported with MAOIs.^[50]

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.^[52] 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.^[52]

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.^[53]

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 been established; and third, a higher proportion of psychiatric patients report flashbacks than "normal" users.^[54] 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^[55] and Naditch and Fenwick's in 1977,^[56] 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.^[57] 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.^[54] 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.^[54]

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.^[58] 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 0 in 1,000 individuals (0 in 1,000 volunteers and 0 in 1,000 psychotherapy patients in Cohen 1960;^[59] 9 per 1,000 psychotherapy patients in Melleson 1971).^[60]

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^[61] and peptide coupling reagents.^[62] 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.^[63] LSD is strongly fluorescent and will glow bluish-white under UV light.

References