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=== Alteration of gene expression ===
=== Alteration of gene expression ===
Chronic administration of LSD alters [[gene expression]] profiles in the [[medial prefrontal cortex]]. Evidence form studies in rodents demonstrates that chronic LSD affects the expression of [[DRD2]], [[GABRB1]], [[NR2A]], [[Krox20]], [[ATP5D]], [[NADH dehydrogenase (ubiquinone), alpha 1|NDUFA1]], [[Neuropeptide Y|NPY]], and [[BDNF]], among others. Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia.<ref>Martin DA (2014): Neuropharmacology. Epub. PMID 24704148</ref>
Chronic administration of LSD alters [[gene expression]] profiles in the [[medial prefrontal cortex]]. Evidence form studies in rodents demonstrates that chronic LSD affects the expression of [[DRD2]], [[GABRB1]], [[NR2A]], [[Krox20]], [[ATP5D]], [[NADH dehydrogenase (ubiquinone), alpha 1|NDUFA1]], [[Neuropeptide Y|NPY]], and [[BDNF]], among others.<sup style="white-space:nowrap;" class="noprint Inline-Template Template-Fact">&#x5B;<i>[[Wikipedia:Citation needed|<span class="" title="This claim needs references to reliable sources.<nowiki/> (September 2014)">citation needed</span>]]</i>&#x5D;</sup> Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia.<ref>Martin DA (2014): Neuropharmacology. Epub. PMID 24704148</ref>


=== Treatment of intoxication ===
=== Treatment of intoxication ===

Revision as of 15:54, 27 January 2015

"LSD" redirects here. For other uses, see LSD (disambiguation).

LSD
Clinical data
Other namesLSD, LSD-25,
lysergide,
D-lysergic acid diethyl amide,
N,N- diethyl- D- lysergamide
Addiction
liability		None[1]
Routes of
administration		Oral, sublingual, Intravenous, Ocular, Intramuscular
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
Elimination half-life3–5 hours[2][3]
ExcretionRenal
Identifiers
  • (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo-[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.031 Edit this at Wikidata
Chemical and physical data
FormulaC20H25N3O
Molar mass323.43 g/mol g·mol−1
3D model (JSmol)
Melting point80 to 85 °C (176 to 185 °F)
  • CCN(CC)C(=O)[C@H]1CN([C@@H]2Cc3c[nH]c4c3c(ccc4)C2=C1)C
  • 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 checkY
  • Key:VAYOSLLFUXYJDT-RDTXWAMCSA-N checkY
  (verify)
File:Pink Elephants on Parade Blotter LSD Dumbo.jpg
Pink elephant blotters containing LSD

Lysergic acid diethylamide (/daɪ eθəl eɪmaɪd/), abbreviated LSD or LSD-25, also known as lysergide (INN) and colloquially as acid, is a psychedelic drug of the ergoline family, well known for its psychological effects, which can include altered thinking processes, closed- and open-eye visuals, synesthesia, 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.[4] However, acute adverse psychiatric reactions such as anxiety, paranoia, and delusions are possible.[5]

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.[6][7] LSD is sensitive to oxygen, ultraviolet light, and chlorine,[7] 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, tasteless solid.[8] LSD is typically either swallowed (oral) or held under the tongue (sublingual), 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. Interestingly, unlike most other classes of illicit drugs and other groups of psychedelic drugs such as tryptamines and phenethylamines, when LSD is administered via intravenous injection the onset is not immediate, instead taking approximately 30 minutes before the effects are realized. LSD is very potent, with 20–30 µg (micrograms) being the threshold dose.[9]

Hofmann discovered the psychedelic properties of LSD in 1943.[10] It was introduced commercially in 1947 by Sandoz Laboratories under the trade-name Delysid as a drug with various psychiatric uses, and it quickly became a therapeutic agent that appeared to show great promise.[11] 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.[12] 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.[13] New clinical LSD experiments in humans started in 2009 for the first time in 35 years.[14]

Effects

Physical

A chart indicating notable physical effects of LSD and respective locals of occurrence.

LSD can cause pupil dilation, reduced appetite, and wakefulness. Other physical reactions to LSD are highly variable and nonspecific, some of which may be secondary to the psychological effects of LSD. Among the reported symptoms are numbness, weakness, nausea, hypothermia or hyperthermia, elevated blood sugar, goose bumps, heart rate increase, 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.[15]

LSD is not considered addictive by the medical community.[4] Tolerance to LSD-25 builds up over consistent use[16] and cross-tolerance has been demonstrated between LSD, mescaline[17] and psilocybin.[18] This tolerance diminishes after a few days after cessation of use and is probably caused by downregulation of 5-HT2A receptors in the brain.[19][20]

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.[21] 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.[22] Many users experience a dissolution between themselves and the "outside world".[23] 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.

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.[24]

Sensory

LSD causes an animated sensory experience of senses, emotions, memories, time, and awareness for 6 to 14 hours, depending on dosage and tolerance. Generally beginning within 30 to 90 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.[23][25] 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 inexplicable way; for instance, objects that are static in three dimensions can seem to be moving relative to one or more additional spatial dimensions.[26] 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

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."[27]

Therapies

Psychedelic therapy

In the 1950s and 1960s LSD was used in psychiatry to enhance psychotherapy known as psychedelic therapy. Some psychiatrists believed LSD was especially useful at helping patients to "unblock" repressed subconscious material through other psychotherapeutic methods,[28] and also for treating alcoholism.[29][30] One study concluded, "The root of the therapeutic value of the LSD experience is its potential for producing self-acceptance and self-surrender,"[31] 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. The majority of UK doctors with clinical experience with LSD felt that LSD was effective and had acceptable safety:

  • 56% (41) continued with clinical use of LSD
  • 15% (11) had stopped because of retirement or other extraneous reasons
  • 12% (9) had stopped because they found LSD ineffective
  • 10% (7) had stopped for unspecified reasons
  • 7% (5) had stopped because they felt LSD was too dangerous[32]
End-of-life anxiety

Since 2008 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.[33][34][35]

Alcoholism treatment

Some studies in the 1960s that used LSD to treat alcoholism reduced levels of alcohol misuse in almost 60% of those treated, an effect which lasted six months but disappeared after a year.[36][37] A 1998 review was inconclusive.[38] However, a 2012 meta-analysis of six randomized controlled trials found evidence that a single dose of LSD in conjunction with various alcoholism treatment programs was associated with a decrease in alcohol abuse, lasting for several months.[39]

Pain management

LSD was studied in the 1960s by Eric Kast for pain management as an analgesic for serious and chronic suffer caused by cancer or other major trauma.[40] 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 that patients were not experiencing less pain, but rather were less distressed by the pain they experienced. This reported effect is being tested (though not using LSD) in an ongoing (as of 2006) study of the effects of psilocybin on anxiety in terminal cancer patients.

Cluster headaches

LSD has been used as a treatment for cluster headaches, an uncommon but extremely painful disorder which researcher Peter Goadsby describes as "worse than natural childbirth or even amputation without anesthetic."[41] 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.[42] Unlike use of LSD or MDMA in psychotherapy, this research involves non-psychological effects and often sub-psychedelic dosages.[43][44]

Entheogen

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.[45]

Creativity

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.[46][47][48][49] Seventy professional artists were asked to draw two pictures of a Hopi Indian kachina doll, one before ingesting LSD and one after.[50]

Potential adverse effects

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

There are no human deaths documented from an LSD overdose.[51] 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.[52]

LSD can temporarily impair the ability to fully understand common dangers and therefore lack awareness to make appropriate judgments -thus making the user more susceptible to personal injury and accidents. It may cause temporary confusion, difficulty with abstract thinking, or signs of impaired memory and attention span.[53] For example, self-inflicted testicular amputation has been noted in medical literature as a result of concurrent LSD and alcohol use.[54][55]

Adverse drug interactions

Mental disorders

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, there is some evidence that people with such conditions as schizophrenia can worsen with LSD.[56]

Suggestibility

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,[57] research from the 1960s suggests there exists evidence that both mentally ill and healthy people are more suggestible while under its influence.[58][59]

Psychosis

Historical data suggests that there has been the occasional incidence of LSD induced psychosis in people who appeared to be healthy prior to taking the drug.[60]

Estimates of the prevalence of LSD-induced psychosis diagnosed by surveying researchers and therapists who had administered LSD are given in two early papers.

  • Cohen (1960) analysed data from 44 practitioners who had administered LSD and estimated 0.8 per 1,000 volunteers (a single case out of 1,250, where the volunteer was the identical twin of a person with schizophrenia) and 1.8 per 1,000 psychiatric patients (7 cases among approximately 3850 patients).[61]
  • Malleson (1971) reported no cases of psychosis among experimental subjects (170 volunteers) and estimated 9 per 1,000 among psychiatric patients (37 cases among 4300 patients).[32]

This data comes with several limitations, the first being that many of the psychiatric patients who were given LSD had severe mental health issues (inpatients) so the results cannot be used to make conclusions about the general population. Secondly, it was not possible to verify whether the psychosis was in fact due to LSD administration, external variables or a combination of both and this is further confounded by the lack of control groups (no LSD) from which to make a comparison. Cohen (1960) noted that many subsequent disturbances had been attributed to LSD without any further justification and individuals would tend to focus on their LSD experience to explain any subsequent illness including migraines and attacks of influenza that occurred up to a year later.[61] He concluded that

This inquiry into the adverse effects of the hallucinogenic drugs indicates that with proper precautions they are safe when given to a selected healthy group. Their use in patients [psychiatric inpatients] has been associated with an occasional complication.

The most recent data collected by the National Survey on Drug Use and Health (conducted by the National Institute on Drug Abuse), summarized results, comparing those who used psychedelic drugs to a population who had not, from 130,152 respondents (of the psychedelic drug users, 17,486 of 21,967 respondents accounting for 80% of the cohort had used LSD). They found that there was no association between psychedelic drug use and mental health problems in later life and if anything there was a trend suggesting that psychedelic drug users had a lower risk of a mental health problems than the control group.[62]

Flashbacks and HPPD

See also: Flashback (psychology)

"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.[63] 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[64] and Naditch and Fenwick's in 1977,[65] which arrived at figures of 20% and 28%, respectively. Interestingly, the experiments by Sidney Cohen in 1960 did not report a single "flashback" phenomenon.[66]

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.[67]

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.[68] 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.[69]

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.[70] 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.[63] 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.[63]

Uterine contractions

Early pharmacological testing by Sandoz in laboratory animals 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.[6] However, the relevance of these animal studies to humans is unclear, and a 2008 medical reference guide to drugs in pregnancy and lactation stated, "It appears unlikely that pure LSD administered in a controlled condition is an abortifacient."[71]

Genetic

In 1967, a report concluded that the addition of LSD to human leukocytes caused an increase in chromosomal damage.[72] This report did not however, withstand the test of time and this was disproved in later studies.[73] In 1969 Moseley, working under Edward Pauling showed that therapeutically high doses of LSD actually reduced chromosomal breakage."[71] Further research using empirical evidence also found that there was no evidence of chromosomal abnormalities with LSD use.[74] In 1980 a study of the existing literature concluded that there was no evidence of chromosomal damage, no mutagenic effects, no teratogenic effects and that LSD has no carcinogenic potential, and this is still the scientific consensus today.[75]

Alteration of gene expression

Chronic administration of LSD alters gene expression profiles in the medial prefrontal cortex. Evidence form studies in rodents demonstrates that chronic LSD affects the expression of DRD2, GABRB1, NR2A, Krox20, ATP5D, NDUFA1, NPY, and BDNF, among others.[citation needed] Many processes identified as altered by chronic LSD are also implicated in the pathogenesis of schizophrenia.[76]

Treatment of intoxication

Reassurance in a calm, safe environment is beneficial. Agitation can be safely addressed with benzodiazepines such as diazepam. Neuroleptics such as haloperidol reduce hallucinations and paranoid delusions and can be used to terminate the effects of LSD. LSD is rapidly absorbed, so activated charcoal and emptying of the stomach will be of little benefit. Sedation or physical restraint is rarely required, and excessive restraint may cause complications such as hyperthermia (over-heating) or rhabdomyolysis.[77]

Massive doses require supportive care,[citation needed] which may include endotracheal intubation or respiratory support. High blood pressure, tachycardia (rapid heart-beat) and hyperthermia, if present, should be treated symptomatically. Treat low blood pressure initially with fluids and then with pressors if necessary. Intravenous administration of anticoagulants, vasodilators, and sympatholytics may be useful with massive doses.

Chemistry and structure

The four possible stereoisomers of LSD. Only (+)-LSD is psychoactive.

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. Retrosynthetically, the C-5 stereocenter could be analysed as having the same configuration of the alpha carbon of the naturally occurring amino acid L-tryptophan, the precursor to all biosynthetic ergoline compounds.

However, LSD and iso-LSD, the two C-8 isomers, rapidly interconvert in the presence of bases, as the alpha proton is acidic and can be deprotonated and reprotonated. Non-psychoactive iso-LSD which has formed during the synthesis can be separated by chromatography and can be isomerized to LSD.

Pure salts of LSD are triboluminescent, emitting small flashes of white light when shaken in the dark.[7] LSD is strongly fluorescent and will glow bluish-white under UV light.

Synthesis

LSD is an ergoline derivative. It is commonly synthesised by reacting diethylamine with an activated form of lysergic acid. Activating reagents include phosphoryl chloride[78] and peptide coupling reagents.[79] Lysergic acid is made by alkaline hydrolysis of lysergamides like ergotamine, a substance usually derived from the ergot fungus on agar plate, or theoretically possible, but impractical and uncommon from ergine (lysergic acid amide, LSA) extracted from morning glory seeds.[80] Lysergic acid can also be produced synthetically, eliminating the need for ergotamines.[81][82]

Reactivity and degradation

"LSD," writes the chemist Alexander Shulgin, "is an unusually fragile molecule...As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely."[7]

LSD has two labile protons at the tertiary stereogenic C5 and C8 positions, rendering these centres prone to epimerisation. The C8 proton is more labile due to the electron-withdrawing carboxamide attachment, but removal of the chiral proton at the C5 position (which was once also an alpha proton of the parent molecule tryptophan) is assisted by the inductively withdrawing nitrogen and pi electron delocalisation with the indole ring.[citation needed]

LSD also has enamine-type reactivity because of the electron-donating effects of the indole ring. Because of this, chlorine destroys LSD molecules on contact; even though chlorinated tap water contains only a slight amount of chlorine, the small quantity of compound typical to an LSD solution will likely be eliminated when dissolved in tap water.[7] The double bond between the 8-position and the aromatic ring, being conjugated with the indole ring, is susceptible to nucleophilic attacks by water or alcohol, especially in the presence of light. LSD often converts to "lumi-LSD", which is inactive in human beings.[7]

A controlled study was undertaken to determine the stability of LSD in pooled urine samples.[83] The concentrations of LSD in urine samples were followed over time at various temperatures, in different types of storage containers, at various exposures to different wavelengths of light, and at varying pH values. These studies demonstrated no significant loss in LSD concentration at 25 °C for up to four weeks. After four weeks of incubation, a 30% loss in LSD concentration at 37 °C and up to a 40% at 45 °C were observed. Urine fortified with LSD and stored in amber glass or nontransparent polyethylene containers showed no change in concentration under any light conditions. Stability of LSD in transparent containers under light was dependent on the distance between the light source and the samples, the wavelength of light, exposure time, and the intensity of light. After prolonged exposure to heat in alkaline pH conditions, 10 to 15% of the parent LSD epimerized to iso-LSD. Under acidic conditions, less than 5% of the LSD was converted to iso-LSD. It was also demonstrated that trace amounts of metal ions in buffer or urine could catalyze the decomposition of LSD and that this process can be avoided by the addition of EDTA.

Dosage

White on White blotters (WoW)
Bottle of liquid LSD

A single dose of LSD may be between 40 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 of LSD.[9][84] Dosages of LSD are measured in micrograms (µg), or millionths of a gram. By comparison, dosages of most drugs, both recreational and medicinal, are measured in milligrams (mg), or thousandths of a gram. For example, an active dose of mescaline, roughly 0.2 to 0.5 g, has effects comparable to 100 µg or less of LSD.[6]

In the mid-1960s, the most important black market LSD manufacturer (Owsley Stanley) distributed acid at a standard concentration of 270 µg.[85] While street samples of the 1970s contained 30 to 300 µg. By the 1980s, the amount had reduced to between 100 and 125 µg, lowering more in the 1990s to the 20–80 µg range,[86] and even more in the 2000s (decade).[85] [87]

Estimates for the median lethal dose (LD50) of LSD range from 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. (This is a very extraordinary amount, equivalent to over 3,000 times the average LSD dosage of ~100 µg).[88][89] Experiments with LSD have also been done on animals; in 1962, an elephant named Tusko died shortly after being injected with 297 mg, but whether the LSD was the cause of his death is controversial (due, in part, to a plethora of other chemical substances administered simultaneously).[90]

Pharmacokinetics

LSD's effects normally last from 6–12 hours depending on dosage, tolerance, body weight and age.[7] The Sandoz prospectus for "Delysid" warned: "intermittent disturbances of affect may occasionally persist for several days."[6] 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 (1964) found LSD had an elimination half-life of only 175 minutes.[2] However, using more accurate techniques, Papac and Foltz (1990) 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.[3]

Detection in biological fluids

LSD may be quantified in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Both the parent drug and its major metabolite are unstable in biofluids when exposed to light, heat or alkaline conditions and therefore specimens are protected from light, stored at the lowest possible temperature and analyzed quickly to minimize losses.[91]

Pharmacodynamics

Binding affinities of LSD for various receptors. The lower the dissociation constant (Ki), the more strongly LSD binds to that receptor (i.e. with higher affinity). The horizontal line represents an approximate value for human plasma concentrations of LSD, and hence, receptor affinities that are above the line are unlikely to be involved in LSD's effect. Data averaged from data from the Ki Database

LSD affects a large number of the G protein-coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others.[citation needed] Most serotonergic psychedelics are not significantly dopaminergic, and LSD is therefore rather unique in this regard. LSD's agonism of D2 receptors contributes to its psychoactive effects.[92][93] 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 sufficiently activated by the brain concentration of approximately 10–20 nM.[94] In humans, recreational doses of LSD can affect 5-HT1A (Ki=1.1nM), 5-HT2A (Ki=2.9nM), 5-HT2B (Ki=4.9nM), 5-HT2C (Ki=23nM), 5-HT5A (Ki=9nM [in cloned rat tissues]), and 5-HT6 receptors (Ki=2.3nM).[2][95] 5-HT5B receptors, which are not present in humans, also have a high affinity for LSD.[96] The psychedelic effects of LSD are attributed to cross-activation of 5-HT2A receptor heteromers.[97] Many but not all 5-HT2A agonists are psychedelics and 5-HT2A antagonists block the psychedelic activity of LSD. LSD exhibits functional selectivity at the 5-HT2A and 5HT2C receptors in that it activates the signal transduction enzyme phospholipase A2 instead of activating the enzyme phospholipase C as the endogenous ligand serotonin does.[98] Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex[94] and therefore excitation in this area, specifically in layers IV and V.[99] LSD, like many other drugs, has been shown to activate DARPP-32-related pathways.[100]

LSD enhances dopamine D2R protomer recognition and signaling of D2–5-HT2A receptor complexes. This mechanism may contribute to the psychotic actions of LSD.[101]

History

"... affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away."

Albert Hofmann, on his first experience with LSD[102]

Main article: History of lysergic acid diethylamide

LSD was first synthesized on November 16, 1938[103] 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. LSD's psychedelic properties were discovered 5 years later when Hofmann himself accidentally ingested an unknown quantity of the chemical.[104] The first intentional ingestion of LSD occurred on April 19, 1943,[105] when Hofmann ingested 250 µg of LSD. He said this would be a threshold dose based on the dosages of other ergot alkaloids. Hofmann found the effects to be much stronger than he anticipated.[106] Sandoz Laboratories introduced LSD as a psychiatric drug in 1947.[107]

Albert Hofmann in 2006

Beginning in the 1950s the US Central Intelligence Agency began a research program code named Project MKULTRA. Experiments included administering LSD to CIA employees, military personnel, doctors, other government agents, prostitutes, mentally ill patients, and members of the general public in order to study their reactions, usually without the subject's knowledge. The project was revealed in the US congressional Rockefeller Commission report in 1975.

In 1963 the Sandoz patents expired on LSD.[86] Also in 1963, the US Food and Drug Administration classified LSD as an Investigational New Drug, which meant new restrictions on medical and scientific use.[86] Several figures, including Aldous Huxley, Timothy Leary, and Al Hubbard, began to advocate the consumption of LSD. LSD became central to the counterculture of the 1960s.[108] On October 24, 1968, possession of LSD was made illegal in the United States.[109] The last FDA approved study of LSD in patients ended in 1980, while a study in healthy volunteers was made in the late 1980s. Legally approved and regulated psychiatric use of LSD continued in Switzerland until 1993.[110] Today, medical research is resuming around the world.[14]

Production

Glassware seized by the DEA

An active dose of LSD is very minute, allowing a large number of doses to be synthesized from a comparatively small amount of raw material. Twenty five kilograms of precursor ergotamine tartrate can produce 5–6 kg of pure crystalline LSD; this corresponds to 100 million doses. Because the masses involved are so small, concealing and transporting illicit LSD is much easier than smuggling other illegal drugs like cocaine or cannabis.[111]

Manufacturing LSD requires laboratory equipment and experience in the field of organic chemistry. It takes two to three days to produce 30 to 100 grams of pure compound. It is believed that LSD is not usually produced in large quantities, but rather in a series of small batches. This technique minimizes the loss of precursor chemicals in case a step does not work as expected.[111]

Forms

Five doses of LSD, often called a "five strip"

LSD is produced in crystalline form and then mixed with excipients or redissolved for production in ingestible forms. Liquid solution is either distributed 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. Appearing in 1968 as an orange tablet measuring about 6 mm across, "Orange Sunshine" acid was the first largely available form of LSD after its possession was made illegal. Tim Scully, a prominent chemist, made some of it, but said that most "Sunshine" in the USA came by way of Ronald Stark, who imported approximately thirty-five million doses from Europe.[112]

Over a period of time, tablet dimensions, weight, shape and concentration of LSD evolved from large (4.5–8.1 mm diameter), heavyweight (≥150 mg), round, high concentration (90–350 µg/tab) dosage units to small (2.0–3.5 mm diameter) lightweight (as low as 4.7 mg/tab), variously shaped, lower concentration (12–85 µg/tab, average range 30–40 µg/tab) dosage units. LSD tablet shapes have included cylinders, cones, stars, spacecraft, and heart shapes. The smallest tablets became known as "Microdots".[113]

After tablets came "computer acid" or "blotter paper LSD", typically made by dipping a preprinted sheet of blotting paper into an LSD/water/alcohol solution.[112][113] More than 200 types of LSD tablets have been encountered since 1969 and more than 350 blotter paper designs have been observed since 1975.[113] About the same time as blotter paper LSD came "Windowpane" (AKA "Clearlight"), which contained LSD inside a thin gelatin square a quarter of an inch (6 mm) across.[112] LSD has been sold under a wide variety of often short-lived and regionally restricted street names including Acid, Trips, Uncle Sid, Blotter, Lucy, Alice and doses, as well as names that reflect the designs on the sheets of blotter paper.[114][115] Authorities have encountered the drug in other forms—including powder or crystal, and capsule.[116]

Modern distribution

LSD manufacturers and traffickers in the United States can be categorized into two groups: A few large-scale producers, and an equally limited number of small, clandestine chemists, consisting of independent producers who, operating on a comparatively limited scale, can be found throughout the country.[117] As a group, independent producers are of less concern to the Drug Enforcement Administration than the larger groups, as their product reaches only local markets.[118]

Mimics

LSD blotter acid mimic actually containing DOC
Different blotters which could possibly be mimics

Since 2005, law enforcement in the United States and elsewhere has seized several chemicals and combinations of chemicals in blotter paper which were sold as LSD mimics, including DOB,[119][120] a mixture of DOC and DOI,[121] 25I-NBOMe,[122] and a mixture of DOC and DOB.[123] Street users of LSD are often under the impression that blotter paper which is actively hallucinogenic can only be LSD because that is the only chemical with low enough doses to fit on a small square of blotter paper. While it is true that LSD requires lower doses than most other hallucinogens, blotter paper is capable of absorbing a much larger amount of material. The DEA performed a chromatographic analysis of blotter paper containing 2C-C which showed that the paper contained a much greater concentration of the active chemical than typical LSD doses, although the exact quantity was not determined.[124] Blotter LSD mimics can have relatively small dose squares; a sample of blotter paper containing DOC seized by Concord, California police had dose markings approximately 6 mm apart.[125]

Legal status

Template:Globalize/Eng The United Nations Convention on Psychotropic Substances (adopted in 1971) requires its parties to prohibit LSD. Hence, it is illegal in all parties to the convention, which includes the United States, Australia, New Zealand, and most of Europe. However, enforcement of extant laws varies from country to country. Medical and scientific research with LSD in humans is permitted under the 1971 UN Convention.[126]

Canada

In Canada, LSD is a controlled substance under Schedule III of the Controlled Drugs and Substances Act.[127] Every person who seeks to obtain the substance, without disclosing authorization to obtain such substances 30 days before obtaining another prescription from a practitioner, is guilty of an indictable offense and liable to imprisonment for a term not exceeding 3 years. Possession for purpose of trafficking is an indictable offense punishable by imprisonment for 10 years.

United Kingdom

In the United Kingdom, LSD is a Schedule 1 Class 'A' drug. This means it has no recognised legitimate uses and possession of the drug without a license is punishable with 7 years imprisonment and/or an unlimited fine, and trafficking is punishable with life imprisonment and an unlimited fine (see main article on drug punishments Misuse of Drugs Act 1971).

In 2000, after consultation with members of the Royal College of Psychiatrists' Faculty of Substance Misuse, the UK Police Foundation issued the Runciman Report which recommended "the transfer of LSD from Class A to Class B".[128]

In November 2009, the UK Transform Drug Policy Foundation released in the House of Commons a guidebooks to the legal regulation of drugs, After the War on Drugs: Blueprint for Regulation, which details options for regulated distribution and sale of LSD and other psychedelics.[129]

United States

LSD is Schedule I in the United States, according to the Controlled Substances Act of 1970.[130] This means LSD is illegal to manufacture, buy, possess, process, or distribute without a DEA license. By classifying LSD as a Schedule I substance, the Drug Enforcement Administration holds that LSD meets the following three criteria: it is deemed to have a high potential for abuse; it has no legitimate medical use in treatment; and there is a lack of accepted safety for its use under medical supervision. There are no documented deaths from chemical toxicity; most LSD deaths are a result of behavioral toxicity.[131]

There can also be substantial discrepancies between the amount of chemical LSD that one possesses and the amount of possession with which one can be charged in the U.S. This is because LSD is almost always present in a medium (e.g. blotter or neutral liquid), and the amount that can be considered with respect to sentencing is the total mass of the drug and its medium. This discrepancy was the subject of 1995 United States Supreme Court case, Neal v. U.S.[132]

Lysergic acid and lysergic acid amide, LSD precursors, are both classified in Schedule III of the Controlled Substances Act. Ergotamine tartrate, a precursor to lysergic acid, is regulated under the Chemical Diversion and Trafficking Act.

See also

References

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Further reading

  • Marks, John. The Search for the Manchurian Candidate: The CIA and Mind Control (1979), ISBN 0-8129-0773-6
  • Hofmann, Albert. LSD My Problem Child: Reflections on Sacred Drugs, Mysticism and Science (1983) ISBN 978-0-9660019-8-3
  • Lee, Martin A. and Bruce Shlain. Acid Dreams: The Complete Social History of LSD: The CIA, the Sixties, and Beyond (1992) ISBN 978-0-8021-3062-4
  • Henderson, Leigh A. and William J. Glass. LSD: Still With Us After All These Years: Based on the National Institute of Drug Abuse Studies on the Resurgence of Contemporary LSD Use (1st edition 1994, 2nd edition 1998) ISBN 978-0-7879-4379-0
  • Stevens, Jay. Storming Heaven: LSD And The American Dream (1998) ISBN 978-0-8021-3587-2
  • Grof, Stanislav. LSD Psychotherapy. (April 10, 2001)
  • de Rios, Marlene Dobkin and Oscar Janiger. LSD, spirituality, and the creative process (2003, Inner Traditions) ISBN 978-0-89281-973-7 – "An exploration of how LSD influences imagination and the creative process. Based on the results of one of the longest clinical studies of LSD that took place between 1954 and 1962, before LSD was illegal. Includes personal reports, artwork, and poetry from the original sessions as testimony of the impact of LSD on the creative process."
  • Roberts, Andy. Albion Dreaming: A Popular History of LSD in Britain (2008), Marshall Cavendish, U.K, ISBN 1-905736-27-4
  • Bebergal, Peter, "Will Harvard drop acid again? Psychedelic research returns to Crimsonland", The Phoenix (Boston), June 2, 2008
  • Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008). "The pharmacology of lysergic acid diethylamide: a review". CNS Neuroscience & Therapeutics. 14 (4): 295–314. doi:10.1111/j.1755-5949.2008.00059.x. PMID 19040555.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • BBC News: Pont-Saint-Esprit poisoning: Did the CIA spread LSD? (2010)
  • Dale Bewan. Dropping Acid: A Beginner's Guide to the Responsible Use of LSD for Self-Discovery (1st edition 2013) ISBN 1492318191

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