Lysergic acid diethylamide

Systematic (IUPAC) name
(6aR,9R)- N,N- diethyl- 7-methyl- 4,6,6a,7,8,9- hexahydroindolo- [4,3-fg] quinoline- 9-carboxamide
Clinical data
Pregnancy cat.	C (US)
Legal status	Prohibited (S9) (AU) Schedule III (CA) CD (UK) Schedule I (US)
Routes	Oral, Intravenous, Ocular, Intramuscular
Pharmacokinetic data
Metabolism	Hepatic
Half-life	3–5 hours[1][2]
Excretion	Renal
Identifiers
CAS number	50-37-3 Y
ATC code	?
PubChem	CID 5761
IUPHAR ligand	17
DrugBank	DB04829
ChemSpider	5558 Y
UNII	8NA5SWF92O Y
ChEBI	CHEBI:6605 N
ChEMBL	CHEMBL263881 Y
Synonyms	LSD, LSD-25, lysergide, D-lysergic acid diethyl amide, N,N- diethyl- D- lysergamide
Chemical data
Formula	C20H25N3O
Mol. mass	323.43 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C20H25N3O/c1-4-23(5-2)20(24)14-9-16-15-7-6-8-17-19(15)13(11-21-17)10-18(16)22(3)12-14/h6-9,11,14,18,21H,4-5,10,12H2,1-3H3/t14-,18-/m1/s1 Y Key:VAYOSLLFUXYJDT-RDTXWAMCSA-N Y
Physical data
Melt. point	80–85 °C (176–185 °F)
N (what is this?)  (verify)

Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an altered sense of time and spiritual experiences, as well as for its key role in 1960s counterculture. It is used mainly as an entheogen, recreational drug, and as an agent in psychedelic therapy. LSD is non-addictive, is not known to cause brain damage, and has extremely low toxicity relative to dose, although in rare cases adverse psychiatric reactions such as anxiety or delusions are possible.^[3]

LSD was first synthesized by Albert Hofmann in 1938 from ergotamine, a chemical derived by Arthur Stoll from ergot, a grain fungus that typically grows on rye. 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.^[4][5] 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 a colorless, odorless, and mildly bitter solid.^[6] 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 also be administered by intramuscular or intravenous injection. LSD is very potent, with 20–30 µg (micrograms) being the threshold dose. New experiments with LSD have started in 2009 for the first time in 40 years. ^[7]

Introduced by Sandoz Laboratories, with trade-name Delysid, as a drug with various psychiatric uses in 1947, LSD quickly became a therapeutic agent that appeared to show great promise.^[8] In the 1950s, officials at the U.S. Central Intelligence Agency (CIA) thought the drug might be applicable to mind control and chemical warfare; the agency's MKULTRA research program propagated the drug among young servicemen and students. The subsequent recreational use of the drug by youth culture in the Western world during the 1960s led to a political firestorm that resulted in its prohibition.^[9] Currently, 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 the medicinal and spiritual uses of LSD and related psychedelics.^[10]

Effects[link]

Physical[link]

LSD can cause pupil dilation, reduced appetite (for some, it increases), and wakefulness. Other physical reactions to LSD are highly variable and nonspecific, and some of these reactions may be secondary to the psychological effects of LSD. The following symptoms have been reported: numbness, weakness, nausea, hypothermia or hyperthermia (decreased or increased body temperature), elevated blood sugar, goose bumps, increase in heart rate, jaw clenching, perspiration, saliva production, mucus production, sleeplessness, hyperreflexia, and tremors. Some users, including Albert Hofmann, report a strong metallic taste for the duration of the effects.^[11]

LSD is not considered addictive by the medical community.^[12] Rapid tolerance build-up prevents regular use, and there is cross-tolerance shown between LSD, mescaline^[13] and psilocybin.^[14] This tolerance diminishes after a few days without use and is probably caused by downregulation of 5-HT_2A receptors in the brain^[15][16]

Psychological[link]

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 Timothy Leary 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.

Some psychological effects may include an experience of radiant colors, objects and surfaces appearing to ripple or "breathe", colored patterns behind the closed eyelids (eidetic imagery), an altered sense of time (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 other powerful psycho-physical reactions.^[17] Many users experience a dissolution between themselves and the "outside world".^[18] 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.^{[citation needed]}

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.^[19]

Sensory[link]

LSD causes an altered sensory 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.^[18][20] 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 unexplainable way; for instance, objects that are static in three dimensions can seem to be moving relative to one or more additional spatial dimensions.^[21] 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.

Potential uses[link]

Bottle of LSD from a Swiss clinical trial of LSD for anxiety in cancer patients, c. 2007.

LSD has been used in psychiatry for its perceived therapeutic value, in the treatment of alcoholism, pain and cluster headache relief, for spiritual purposes, and to enhance creativity. However, government organizations like the United States Drug Enforcement Administration maintain that LSD "produces no aphrodisiac effects, does not increase creativity, has no lasting positive effect in treating alcoholics or criminals, does not produce a 'model psychosis', and does not generate immediate personality change."^[22]

Psychotherapy[link]

In the 1950s and 1960s LSD was used in psychiatry to enhance psychotherapy. Some psychiatrists believed LSD was especially useful at helping patients to "unblock" repressed subconscious material through other psychotherapeutic methods,^[23] and also for treating alcoholism.^[24][25] One study concluded, "The root of the therapeutic value of the LSD experience is its potential for producing self-acceptance and self-surrender,"^[26] presumably by forcing the user to face issues and problems in that individual's psyche.

In December 1968, a survey was made of all 74 UK doctors who had used LSD in humans; 73 replied, 1 had moved overseas and was unavailable. Of the 73 replies, the majority of UK doctors with clinical experience with LSD felt that LSD was effective and had acceptable safety: 41 (56%) continued with clinical use of LSD, 11 (15%) had stopped because of retirement or other extraneous reasons, 9 (12%) had stopped because they found LSD ineffective, and 5 (7%) had stopped because they felt LSD was too dangerous.^[27]

End-of-life anxiety[link]

From 2008-2011 there has been ongoing research in Switzerland into using LSD to alleviate anxiety for terminally ill cancer patients coping with their impending deaths. Preliminary results from the study are promising, and no negative effects have been reported.^[28][29][30]

Alcoholism[link]

Some studies in the 1950s that used LSD to treat alcoholism professed a 50% success rate,^[31][32] five times higher than estimates near 10% for Alcoholics Anonymous.^[33] A 1998 review was inconclusive.^[34] However, a 2012 meta-analysis of 6 randomized controlled trials found evidence that a single dose of LSD was associated with a decrease in alcohol abuse, lasting for several months.^[35]

Pain[link]

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 in pain reduction (lasting as long as a week after peak effects had subsided). Kast attributed this effect to a decrease in anxiety; that is to say they were not experiencing less pain, but rather being less distressed by pain. 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.

Cluster headaches[link]

LSD has been 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 was planned at McLean Hospital, although the current status of this project is unclear. 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 use of LSD or MDMA in psychotherapy, this research involves non-psychological effects and often sub-psychedelic dosages.^[39][40]

Spiritual[link]

LSD 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. Users claim to experience lucid sensations where they have "out of body" experiences. Some users report insights into the way the mind works, and some experience permanent shifts in their life perspective. LSD also allows users to view their life from an introspective point of view. Some users report using introspection to resolve unresolved or negative feelings towards an individual or incident that occurred in the past. Some users consider LSD a religious sacrament, or a powerful tool for access to the divine. 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.^[41]

Creativity[link]

In the 1950s and 1960s, psychiatrists like Oscar Janiger explored the potential effect of LSD on creativity. Experimental studies attempted to measure the effect of LSD on creative activity and aesthetic appreciation.^{[42][43][44][45]} Seventy professional artists were asked to draw two pictures of a Hopi Indian kachina doll, one before ingesting LSD and one after.^[46]

Potential adverse effects[link]

Chart of dependence potential and effective dose/lethal dose of some psychoactive drugs.

There have been no documented human deaths from an LSD overdose.^[47] It is physiologically well tolerated and there is no evidence for long-lasting physiological effects on the brain or other parts of the human organism.^[48]

LSD may temporarily impair the ability to make sensible judgments and understand common dangers, thus making the user more susceptible to accidents and personal injury. It may cause temporary confusion, difficulty with abstract thinking, or signs of impaired memory and attention span similar to brain damage.^[49]

Adverse drug interactions[link]

There is 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. Anonymous anecdotal reports have attributed seizures and one death to the combination of LSD with lithium.^[50] SSRIs noticeably reduce LSD's subjective effects.^[51] MAOIs are also reported to reduce the effects of LSD.^[50]

Mental disorders[link]

LSD may trigger panic attacks or feelings of extreme anxiety, colloquially referred to as a "bad trip". No real prolonged effects have been proven, however people with such conditions as schizophrenia and depression can worsen with LSD.^[52]

Suggestibility[link]

While publicly available documents indicate that the CIA and Department Of Defense have discontinued research into the use of LSD as a means of mind control,^[53] research from the 1960s suggests there exists evidence that both mentally ill and healthy people are more suggestible while under its influence.^[54][55]

Psychosis[link]

There are some cases of LSD inducing a psychosis in people who appeared to be healthy before taking LSD.^[56] 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 suggest that the two types of syndromes are not different and that LSD may have been a nonspecific trigger.^{[citation needed]}

Estimates of the prevalence of LSD-induced prolonged psychosis lasting over 48 hours have been made by surveying researchers and therapists who had administered LSD:

• Cohen (1960) estimated 0.8 per 1,000 volunteers (the single case among approximately 1250 study volunteers was the identical twin of a schizophrenic and he recovered within 5 days) and 1.8 per 1,000 psychiatric patients (7 cases among approximately 3850 patients, of which 2 cases were "preschizophrenic" or had previous hallucinatory experience, 1 case had unknown outcome, 1 case had incomplete recovery, and 5 cases recovered within up to 6 months).^[57]
• Malleson (1971) reported no cases of psychosis among experimental subjects (170 volunteers who received a total of 450 LSD sessions) and estimated 9 per 1,000 among psychiatric patients (37 cases among 4300 patients, of which 8 details are unknown, 10 appeared chronic, and 19 recovered completely within up to 3 months).^[27]

However, in neither survey study was it possible to compare the rate of lasting psychosis in these volunteers and patients receiving LSD with the rate of psychosis found in other groups of research volunteers or in other methods of psychiatric treatment (for example, those receiving placebo).

Cohen (1960) noted:^[57]

"The hallucinogenic experience is so striking that many subsequent disturbances may be attributed to it without further justification. The highly suggestible or hysterical individual would tend to focus on his LSD experience to explain subsequent illness. Patients have complained to Abramson that their LSD exposure produced migraine headaches and attacks of influenza up to a year later. One Chinese girl became paraplegic and ascribed that catastrophe to LSD. It so happened that these people were all in the control group and had received nothing but tap water."

Flashbacks and HPPD[link]

"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, and are typically elicited by triggers such as alcohol or cannabis use, stress, caffeine, or sleepiness. 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.^[58] 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^[59] and Naditch and Fenwick's in 1977,^[60] 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 flashbacks, but instead are persistent, and cause clinically significant impairment or distress. The syndrome is a DSM-IV diagnosis. Several scientific journal articles have described the disorder.^[61]

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.^[62] 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.^[63]

There is no consensus regarding the nature and causes of HPPD (or flashbacks). A study of 44 HPPD subjects who had previously ingested LSD showed EEG abnormalities.^[64] 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.^[58] 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.^[58]

Uterine contractions[link]