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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.[16] LSD is not considered addictive by the medical community.[7] Tolerance to LSD-25 builds up over consistent use[17] and cross-tolerance has been demonstrated between LSD, mescaline[18] and psilocybin.[19] This tolerance diminishes after a few days after cessation of use and is probably caused by downregulation of 5-HT2A receptors in the brain.[20][21] 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.[medical citation needed] They also vary from one trip to another, and even as time passes during a single trip.[medical citation needed] An LSD trip can have long-term psychoemotional effects; some users[who?] cite the LSD experience as causing significant changes in their personality and life perspective.[22] 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.[citation needed] Long-term adverse effects observed in some users include recurrence of perceptual effects initially experienced while under the acute influence of the drug. These effects have been described as "distressing, spontaneous, recurrent, pervasive" and in some cases irreversible.[23][24] 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.[medical citation needed] Many users experience a dissolution between themselves and the "outside world".[25] 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[weasel words] 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.[26] 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.[25][27] 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[weasel words] 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.[28] 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.[medical citation needed] Research 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.[29] New clinical LSD experiments in humans started in 2009 for the first time in 35 years.[30] Experimental uses of LSD include the treatment of alcoholism,[31] pain and cluster headache relief.[32] It has also been used for spiritual purposes, and for its putative effects in increasing creativity.[33] The United States Drug Enforcement Administration states 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."[34] Therapies Psychedelic therapy In the 1950s and 1960s LSD was used in psychiatry to enhance psychotherapy known as psychedelic therapy. Some psychiatrists[who?] believed LSD was especially useful at helping patients to "unblock" repressed subconscious material through other psychotherapeutic methods,[35] and also for treating alcoholism.[36][37] One study concluded, "The root of the therapeutic value of the LSD experience is its potential for producing self-acceptance and self-surrender,"[38] presumably by forcing the user to face issues and problems in that individual's psyche. Two recent reviews concluded that conclusions drawn from most of these early trials are unreliable due serious methodological flaws. These include the absence of adequate control groups, lack of followup, and vague criteria for therapeutic outcome. In many cases studies failed to convincingly demonstrate whether the drug or the therapeutic interaction was responsible for any beneficial effects.[39][40] 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.[41] Alcoholism treatment 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, but no effect was seen at one year. Adverse events included seizure, moderate confusion and agitation, nausea, vomiting, and acting in a bizarre fashion.[42] 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.[43] Cluster headaches LSD has been used as a treatment for cluster headaches with positive results in some small studies.[32][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[weasel words] 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[weasel words] report using introspection to resolve unresolved or negative feelings towards an individual or incident that occurred in the past. Some users[weasel words] consider LSD a religious sacrament, or a powerful tool for access to the divine. In 1966, Timothy Leary established the League for Spiritual Discovery with LSD as its sacrament.[45][46] 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.[47] 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.[48][49][50][51] Seventy professional artists were asked to draw two pictures of a Hopi Indian kachina doll, one before ingesting LSD and one after.[52] Adverse effects Suicide and acts of violence have been associated with LSD use.[53][54] Long-term effects include "flashbacks" and a syndrome of long-term perceptual changes that are experienced as distressing[23][55] 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. For example, self-inflicted testicular amputation has been noted in medical literature as a result of concurrent LSD and alcohol use.[56][57] It may also cause temporary confusion, difficulty with abstract thinking, or signs of impaired memory and attention span.[58] 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 evidence that people with severe mental illnesses like schizophrenia have a higher likelihood of experiencing adverse effects from taking LSD (see psychosis for further details).[59][unreliable medical source] 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,[60] research from the 1960s suggests there exists evidence that both mentally ill and healthy people are more suggestible while under its influence.[61][62][non-primary source needed] 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.[63] 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.[medical citation needed] 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][non-primary source needed] and Naditch and Fenwick's in 1977,[65][non-primary source needed] which arrived at figures of 20% and 28%, respectively.[66][unreliable medical source] Hallucinogen Persisting Perception Disorder (HPPD) describes a post-LSD exposure syndrome 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 uncommon and affects a distinctly vulnerable subpopulation of users.[68][69] 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.[medical citation needed] Genetic The mutagenic potential of LSD is unclear. Overall, the evidence seems to point to limited or no effect at commonly used doses.[70] 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.[71] 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.[medical citation needed] 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.[10] 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[72] and peptide coupling reagents.[73] 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.[74] Lysergic acid can also be produced synthetically, eliminating the need for ergotamines.[75][76] 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."[10] 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.[10] 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.[10] A controlled study was undertaken to determine the stability of LSD in pooled urine samples.[77] 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.[12][78] 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.[9] In the mid-1960s, the most important black market LSD manufacturer (Owsley Stanley) distributed acid at a standard concentration of 270 µg.[79] 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,[80] and even more in the 2000s (decade).[79] [81] Pharmacokinetics LSD's effects normally last from 6–12 hours depending on dosage, tolerance, body weight and age.[10] The Sandoz prospectus for "Delysid" warned: "intermittent disturbances of affect may occasionally persist for several days."[9] 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.[82] 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.[83][84] 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.[85] 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][86] 5-HT5B receptors, which are not present in humans, also have a high affinity for LSD.[87] The psychedelic effects of LSD are attributed to cross-activation of 5-HT2A receptor heteromers.[88] 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.[89] Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex[85] and therefore excitation in this area, specifically in layers IV and V.[90] LSD, like many other drugs, has been shown to activate DARPP-32-related pathways.[91] LSD enhances dopamine D2R protomer recognition and signaling of D2–5-HT2A receptor complexes. This mechanism may contribute to the psychotic actions of LSD.[92] Lysergic acid diethylamide (/daɪ eθəl ˈæmaɪd/ or /æmɪd/ or /eɪmaɪd/),[4][5][6] 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 and recreational drug. LSD is non-addictive, and is not known to cause brain damage.[7] However, acute adverse psychiatric reactions such as anxiety, paranoia, and delusions are possible.[8] 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.[9][10] LSD is sensitive to oxygen, ultraviolet light, and chlorine,[10] 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.[11] 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.[12] Hofmann discovered the psychedelic properties of LSD in 1943.[13] It was introduced commercially in 1947 by Sandoz Laboratories under the trade-name Delysid as a drug with various psychiatric uses.[14] 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.[15] |
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