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Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent
psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science o ...
. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, visual, as well as auditory, hallucinations. Dilated pupils, increased blood pressure, and increased body temperature are typical. Effects typically begin within half an hour and can last for up to 20 hours. LSD is also capable of causing
mystical experiences Scholarly approaches to mysticism include typologies of mysticism and the explanation of mystical states. Since the 19th century, mystical experience has evolved as a distinctive concept. It is closely related to "mysticism" but lays sole emphasi ...
and
ego dissolution Ego death is a "complete loss of subjective self-identity". The term is used in various intertwined contexts, with related meanings. Jungian psychology uses the synonymous term psychic death, referring to a fundamental transformation of the psych ...
. It is used mainly as a
recreational drug Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...
or for spiritual reasons. LSD is both the prototypical psychedelic and one of the "classical" psychedelics, being the psychedelics with the greatest scientific and cultural significance. LSD is typically either swallowed or held under the tongue. It is most often sold on blotter paper and less commonly as tablets, in a watery solution or in
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
squares called panes. LSD is considered to be non-addictive with low potential for abuse. Frequent use rapidly builds tolerance, requiring exponentially larger doses to feel an effect. Adverse psychological reactions are possible, such as anxiety, paranoia, and
delusions A delusion is a false fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some o ...
. LSD is active in small amounts relative to other psychoactive compounds with doses measured in micrograms. It is possible for LSD to induce either intermittent or chronic visual hallucinations, in spite of no further use. Common effects include visual snow and palinopsia. In cases where this causes distress or impairment it is diagnosed as hallucinogen persisting perception disorder (HPPD). While overdose from LSD is unknown, LSD can cause injury and death as a result of accidents stemming from psychological impairment. The effects of LSD are thought to stem primarily from it being an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
at the 5-HT2A (serotonin) receptor, and while exactly how LSD exerts its effects by agonism at this receptor is still not fully known, corresponding increased glutamatergic neurotransmission and reduced
default mode network In neuroscience, the default mode network (DMN), also known as the default network, default state network, or anatomically the medial frontoparietal network (M-FPN), is a large-scale brain network primarily composed of the dorsal medial prefro ...
activity are thought to be key mechanisms of action. In addition to
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
, LSD also binds to
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
D1 and D2 receptors, which is why LSD tends to be more stimulating than compounds such as psilocybin. In pure form, LSD is clear or white in color, has no smell, and is crystalline. It breaks down with exposure to ultraviolet light. LSD was first synthesized by Swiss chemist Albert Hofmann in 1938 from lysergic acid, a chemical derived from the hydrolysis of ergotamine, an alkaloid found in
ergot Ergot ( ) or ergot fungi refers to a group of fungi of the genus ''Claviceps''. The most prominent member of this group is ''Claviceps purpurea'' ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that ca ...
, a fungus that infects grain. LSD was the 25th of various lysergamides Hofmann synthesized from lysergic acid while trying to develop a new analeptic, hence the alternate name LSD-25. Hofmann discovered its effects in humans in 1943, after unintentionally ingesting an unknown amount, possibly absorbing it through his skin. LSD was subject to exceptional interest within the field of psychiatry in the 1950s and early 1960s, with Sandoz distributing LSD to researchers under the trademark name Delysid in an attempt to find a marketable use for it. LSD-assisted
psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of psychological methods, particularly when based on regular personal interaction, to help a person change behavior, increase happiness, and overcome pro ...
was used in the 1950s and early 1960s by psychiatrists such as Humphry Osmond, who pioneered the application of LSD to the treatment of alcoholism, with promising results. Osmond coined the term "psychedelic" (lit. ''mind manifesting'') as a term for LSD and related hallucinogens, superseding the previously held " psychotomimetic" model in which LSD was believed to mimic schizophrenia. In contrast to schizophrenia, LSD induces transcendental experiences with lasting psychological benefit. During this time, the Central Intelligence Agency (CIA) began using LSD in the research project Project MKUltra, which used
psychoactive substances A psychoactive drug, psychopharmaceutical, psychoactive agent or psychotropic drug is a chemical substance, that changes functions of the nervous system, and results in alterations in perception, mood, consciousness, cognition or behavior. T ...
to aid
interrogation Interrogation (also called questioning) is interviewing as commonly employed by law enforcement officers, military personnel, intelligence agencies, organized crime syndicates, and terrorist organizations with the goal of eliciting useful informa ...
. The CIA administered LSD to unwitting test subjects in order to observe how they would react, and the most well-known example of this is
Operation Midnight Climax Operation Midnight Climax was an operation carried out by the CIA as a sub-project of Project MKUltra, the mind-control research program that began in the 1950s. It was initially established in 1954 by Sidney Gottlieb and placed under the direction ...
. LSD was one of several psychoactive substances evaluated by the
U.S. Army Chemical Corps The Chemical Corps is the branch of the United States Army tasked with defending against chemical, biological, radiological, and nuclear (CBRN) weapons. The Chemical Warfare Service was established on 28 June 1918, combining activities that until ...
as possible non-lethal incapacitants in the Edgewood Arsenal human experiments. In the 1960s, LSD and other psychedelics were adopted by, and became synonymous with, the
counterculture movement The counterculture of the 1960s was an anti-establishment cultural phenomenon that developed throughout much of the Western world in the 1960s and has been ongoing to the present day. The aggregate movement gained momentum as the civil rights mo ...
due to their perceived ability to expand consciousness. This resulted in LSD being viewed as a cultural threat to American values and the Vietnam war effort, and it was designated as a Schedule I (illegal for medical as well as recreational use) substance in 1968. It was listed as a
Schedule 1 controlled substance The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 Februa ...
by the United Nations in 1971 and currently has no approved medical uses. , about 10% of people in the United States have used LSD at some point in their lives, while 0.7% have used it in the last year. It was most popular in the 1960s to 1980s. The use of LSD among US adults increased 56.4% from 2015 to 2018.


Uses


Recreational

LSD is commonly used as a recreational drug in the company of friends, in large crowds, or by oneself.


Spiritual

LSD can catalyze intense spiritual experiences and is thus considered an entheogen. Some users have reported
out of body An out-of-body experience (OBE or sometimes OOBE) is a phenomenon in which a person perceives the world from a location outside their physical body. An OBE is a form of autoscopy (literally "seeing self"), although this term is more commonly us ...
experiences. In 1966, Timothy Leary established the League for Spiritual Discovery with LSD as its
sacrament A sacrament is a Christianity, Christian Rite (Christianity), rite that is recognized as being particularly important and significant. There are various views on the existence and meaning of such rites. Many Christians consider the sacraments ...
.
Stanislav Grof Stanislav "Stan" Grof is a Czech-born psychiatrist who has been living in the United States since the 1960s. Grof is one of the principal developers of transpersonal psychology and research into the use of non-ordinary states of consciousness ...
has written that religious and mystical experiences observed during LSD sessions appear to be phenomenologically indistinguishable from similar descriptions in the
sacred scriptures Religious texts, including scripture, are texts which various religions consider to be of central importance to their religious tradition. They differ from literature by being a compilation or discussion of beliefs, mythologies, ritual pra ...
of the great religions of the world and the texts of ancient civilizations.


Medical

LSD currently has no approved uses in medicine. A meta analysis concluded that a single dose was effective at reducing alcohol consumption in alcoholism. LSD has also been studied in depression, anxiety, and drug dependence, with positive preliminary results.


Effects

LSD is exceptionally potent, with as little as 20 μg capable of producing a noticeable effect.


Physical

LSD can cause
pupil dilation Pupillary response is a physiological response that varies the size of the pupil, via the optic and oculomotor cranial nerve. A constriction response (miosis), is the narrowing of the pupil, which may be caused by scleral buckles or drugs such a ...
, reduced
appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...
, profuse sweating, 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 elevated body temperature, blood sugar, and heart rate, alongside goose bumps, jaw clenching, mouth dryness, and hyperreflexia. In negative experiences, numbness, weakness, nausea, and tremors have also been exhibited.


Psychological

The most common immediate psychological effects of LSD are visual hallucinations and illusions (colloquially known as " trips"), which vary depending on how much is used and how the dosage interacts with the brain. Trips usually start within 20–30 minutes of taking LSD orally (less if snorted or taken intravenously), peak three to four hours after ingestion, and can last up to 20 hours in high doses. Users may also experience an " afterglow" of improved mood or perceived mental state for days or even weeks after ingestion in some experiences. Good trips are reportedly deeply stimulating and pleasurable, and typically involve intense joy or euphoria, a greater appreciation for life, reduced anxiety, a sense of spiritual enlightenment, and a sense of belonging or interconnectedness with the universe. Negative experiences, colloquially known as "bad trips," evoke an array of dark emotions, such as irrational fear, anxiety, panic, paranoia, dread, distrustfulness, hopelessness, and even
suicidal ideation Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
. While it is impossible to predict when a bad trip will occur, one's mood, surroundings, sleep, hydration, social setting, and other factors can be controlled (colloquially referred to as " set and setting") to minimize the risk of a bad trip.


Sensory

LSD causes an animated sensory experience of senses, emotions, memories, time, and awareness for 6 to 20 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 shift A cognitive shift or shift in cognitive focus is triggered by the brain's response and change due to some external force. General cause A cognitive shift can occur when a person undergoes a new experience, such as astronauts experiencing the ove ...
s. Changes in auditory and visual perception are also typical. Some sensory effects may include an experience of radiant or more vibrant colors, objects and surfaces appearing to ripple, "breathe," or otherwise move, spinning fractals superimposed on one's vision, colored patterns behind closed eyelids, an altered sense of time, geometric patterns emerging on walls and other textured objects, and morphing objects. Some users also report a strong metallic taste for the duration of the effects. Food's texture or taste may be different, and users may also have an aversion to foods that they would normally enjoy. Similar effects have also been found in rats. Some 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. Many of the basic visual effects resemble the phosphenes seen after applying pressure to the eye and have also been studied as
form constant A form constant is one of several geometric patterns which are recurringly observed during hypnagogia, hallucinations and altered states of consciousness. History In 1926, Heinrich Klüver systematically studied the effects of mescaline (peyote ...
s. Sometimes these effects and patterns can be changed when concentrated on, or can change based on thoughts, emotions or music. The auditory effects of LSD may include echo-like distortions of sounds, changes in ability to discern concurrent auditory and visual stimuli, and a general intensification of the experience of music. Higher doses often cause intense and fundamental distortions of sensory perception such as
synesthesia Synesthesia (American English) or synaesthesia (British English) is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to involuntary experiences in a second sensory or cognitive pathway. People who re ...
, the experience of additional spatial or temporal dimensions, and temporary dissociation.


Adverse effects

Out of the 20 drugs ranked in order of individual and societal harm by David Nutt, LSD was third to last, or approximately 1/10th as harmful as alcohol. The most significant adverse effect of LSD was impairment of mental functioning while intoxicated.


Mental disorders

LSD may trigger panic attacks or feelings of extreme anxiety, known colloquially as a "
bad trip A bad trip (also known as challenging experiences, acute intoxication from hallucinogens, psychedelic crisis, or emergence phenomenon) is an acute adverse psychological reaction to classic hallucinogens. With proper screening, preparation, and su ...
". LSD is capable of exacerbating mental illnesses and precipitating the early onset of schizophrenia in vulnerable individuals. Although population studies have not found an increased incidence of mental illness in psychedelic drug users overall, with psychedelic users actually having lower rates of depression and substance abuse than the control group, there is evidence that people with severe mental illnesses like schizophrenia have a higher likelihood of experiencing adverse effects from taking LSD.


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, research from the 1960s suggests that both mentally ill and healthy people are more suggestible while under its influence.


Flashbacks

" Flashbacks" are a reported psychological phenomenon in which an individual experiences an episode of some of LSD's subjective effects after the drug has worn off, persisting for days or months after hallucinogen use. Individuals with hallucinogen persisting perception disorder experience intermittent or chronic flashbacks that cause distress or impairment in life and work. The
etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
of the "flashback" phenomenon appears to be varied. Some researchers such as Krebs and Johansen (2015) attribute at least some of the cases to be related to somatic symptom disorder, when people fixate on normal
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
experiences and perceptions that they weren't aware of before consuming the drug. Other researchers relate it to an associative reaction to a contextual cue akin to what people that have faced trauma or strongly emotional experiences face when receiving a triggering stimulus (Holland and Passie 2011). There is no consensus on what are the risk factors but some researchers
theorize A theory is a rational type of abstract thinking about a phenomenon, or the results of such thinking. The process of contemplative and rational thinking is often associated with such processes as observational study or research. Theories may be s ...
that pre-existing
psychopathologies Psychopathology is the study of Abnormal psychology, abnormal cognition, behaviour, and experiences which differs according to social norms and rests upon a number of constructs that are deemed to be the social norm at any particular era. Biol ...
may be a significant contributor (Abraham and Duffy 1996) The prevalence of HPPD is difficult to estimate but appears to be very rare (Halpern et al 2016), with estimates ranging from 1 in 20 users for the transitory and less serious type 1 HPPD, to 1 in 50,000 users for the more concerning type 2 HPPD. Contrary to rumors circulating the internet that LSD is stored in the spinal cord or other parts of your body long-term, the pharmacological evidence (Passie et all 2008) shows LSD has a short half-life of 175 minutes, undergoing enzymatic metabolism into more polar and therefore water-soluble compounds such as 2-oxo-3-hydroxy-LSD that are eliminated through the urine. No evidence of long term storage of LSD in the body exists.


Cancer and pregnancy

The mutagenic potential of LSD is unclear. Overall, the evidence seems to point to limited or no effect at commonly used doses. Studies showed no evidence of teratogenic or mutagenic effects.


Addiction and tolerance

Tolerance to LSD builds up with consistent use and cross-tolerance has been demonstrated between LSD,
mescaline Mescaline or mescalin (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class, known for its hallucinogenic effects comparable to those of LSD and psilocybin. Biological sou ...
, and psilocybin. Researchers believe that tolerance returns to baseline after two weeks of not using psychedelics. The NIH states that LSD is addictive, while most other sources state it is not. A 2009 textbook states that it "rarely produce compulsive use." A 2006 review states it is readily abused, but does not result in addiction. There are no recorded successful attempts to train animals to self-administer LSD in laboratory settings.


Overdose

A report in 2008 stated that, though there was no "comprehensive review since the 1950s" and "almost no legal clinical research" since the 1970s, there had been "no documented human deaths from an LSD overdose". Eight individuals who accidentally consumed very high amounts by mistaking LSD for cocaine developed comatose states, hyperthermia, vomiting, gastric bleeding, and respiratory problems—all survived, however, with hospital treatment and without residual effects. According to more recent reports, several behavioral-related fatalities and suicides have occurred due to LSD. Reassurance in a calm, safe environment is beneficial. Agitation can be safely addressed with
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s such as lorazepam or diazepam. Neuroleptics such as haloperidol are not recommended because they may have adverse effects. LSD is rapidly absorbed, so
activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an interv ...
and emptying of the stomach is of little benefit, unless done within 30–60 minutes of ingesting an overdose of LSD. Sedation or physical restraint is rarely required, and excessive restraint may cause complications such as hyperthermia (over-heating) or
rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...
. Massive doses "should be treated with supportive care, including respiratory support and endotracheal intubation if needed.
Hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
igh blood pressure tachycardia
apid heart-beat Apidae is the largest family within the superfamily Apoidea, containing at least 5700 species of bees. The family includes some of the most commonly seen bees, including bumblebees and honey bees, but also includes stingless bees (also used for ...
and hyperthermia should be treated symptomatically. Hypotension ow blood pressureshould be treated initially with fluids and subsequently with pressors if required." "Intravenous administration of anticoagulants, vasodilators, and
sympatholytics A sympatholytic (or sympathoplegic) drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS). They are indicated for various functions; for example, ...
may be useful" when treating
ergotism Ergotism (pron. ) is the effect of long-term ergot poisoning, traditionally due to the ingestion of the alkaloids produced by the ''Claviceps purpurea'' fungus—from the Latin "club" or clavus "nail" and for "head", i.e. the purple club-head ...
.


Pharmacology


Pharmacodynamics

Most serotonergic psychedelics are not significantly
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
, and LSD is therefore atypical in this regard. The agonism of the D2 receptor by LSD may contribute to its psychoactive effects in humans. LSD binds to most serotonin receptor subtypes except for the 5-HT3 and 5-HT4 receptors. However, most of these receptors are affected at too low affinity to be sufficiently activated by the brain concentration of approximately 10–20  nM. 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
n cloned rat tissues N, or n, is the fourteenth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''en'' (pronounced ), plural ''ens''. History ...
, and 5-HT6 receptors (Ki=2.3nM). Although not present in humans, 5-HT5B receptors found in rodents also have a high affinity for LSD. The psychedelic effects of LSD are attributed to cross-activation of 5-HT2A receptor heteromers. Many but not all 5-HT2A
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s 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 Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
enzyme
phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glyce ...
instead of activating the enzyme
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
as the endogenous ligand serotonin does. Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
release in the cerebral cortex and therefore
excitation Excitation, excite, exciting, or excitement may refer to: * Excitation (magnetic), provided with an electrical generator or alternator * Excite Ballpark, located in San Jose, California * Excite (web portal), web portal owned by IAC * Electron exc ...
in this area, specifically in layers IV and V. LSD, like many other drugs of recreational use, has been shown to activate
DARPP-32 Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the ''PPP1R1B'' gene. Function Midbrain dopaminergic neurons play a ...
-related pathways. The drug enhances dopamine D2 receptor protomer recognition and
signaling In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The ''IEEE Transactions on Signal Processing'' ...
of D2–5-HT2A receptor complexes, which may contribute to its psychotropic effects. LSD has been shown to have low affinity for
H1 receptors The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the h ...
, displaying antihistamine effects. LSD is a biased agonist that induces a conformation in serotonin receptors that preferentially recruits
β-arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of ...
over activating G proteins. LSD also has an exceptionally long residence time when bound to serotonin receptors lasting hours, consistent with the long lasting effects of LSD despite its relatively rapid clearance. A crystal structure of 5-HT2B bound to LSD reveals an extracellular loop that forms a lid over the diethylamide end of the binding cavity which explains the slow rate of LSD unbinding from serotonin receptors. The related lysergamide lysergic acid amide (LSA) that lacks the diethylamide moiety is far less hallucinogenic in comparison.


Pharmacokinetics

The effects of LSD normally last between 6 and 12 hours depending on dosage, tolerance, and age. The Sandoz prospectus for "Delysid" warned: "intermittent disturbances of affect may occasionally persist for several days.". Aghajanian and Bing (1964) found LSD had an elimination half-life of only 175 minutes (about 3 hours). 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. The
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
of LSD were not properly determined until 2015, which is not surprising for a drug with the kind of low-μg potency that LSD possesses. In a sample of 16 healthy subjects, a single mid-range 200 μg oral dose of LSD was found to produce mean maximal concentrations of 4.5 ng/mL at a median of 1.5 hours (range 0.5–4 hours) post-administration. Concentrations of LSD decreased following first-order kinetics with a half-life of 3.6±0.9 hours and a terminal half-life of 8.9±5.9 hours. The effects of the dose of LSD given lasted for up to 12 hours and were closely correlated with the concentrations of LSD present in circulation over time, with no acute
tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...
observed. Only 1% of the drug was eliminated in urine unchanged, whereas 13% was eliminated as the major
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
2-oxo-3-hydroxy-LSD (O-H-LSD) within 24 hours. O-H-LSD is formed by
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzymes, although the specific enzymes involved are unknown, and it does not appear to be known whether O-H-LSD is pharmacologically active or not. The oral bioavailability of LSD was crudely estimated as approximately 71% using previous data on
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
administration of LSD. The sample was equally divided between male and female subjects and there were no significant sex differences observed in the pharmacokinetics of LSD.


Chemistry

LSD is a chiral compound with two stereocenters at the carbon atoms C-5 and C-8, so that theoretically four different
optical isomers In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...
of LSD could exist. LSD, also called (+)-D-LSD, has the absolute configuration (5''R'',8''R''). The C-5
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...
s 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. LSD is strongly fluorescent and will glow bluish-white under UV light.


Synthesis

LSD is an ergoline derivative. It is commonly synthesized by reacting diethylamine with an activated form of lysergic acid. Activating reagents include phosphoryl chloride and
peptide coupling reagent In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl ...
s. Lysergic acid is made by alkaline hydrolysis of lysergamides like ergotamine, a substance usually derived from the
ergot Ergot ( ) or ergot fungi refers to a group of fungi of the genus ''Claviceps''. The most prominent member of this group is ''Claviceps purpurea'' ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that ca ...
fungus on agar plate; or, theoretically possible, but impractical and uncommon, from ergine (lysergic acid amide, LSA) extracted from morning glory seeds. Lysergic acid can also be produced synthetically, although these processes are not used in clandestine manufacture due to their low yields and high complexity.


Research

The precursor for LSD, lysergic acid, has been produced by
GMO A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and what constitutes genetic engineering varies, with ...
baker's yeast.


Dosage

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. The practice of using sub-threshold doses is called microdosing. 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 Mescaline or mescalin (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class, known for its hallucinogenic effects comparable to those of LSD and psilocybin. Biological sou ...
, roughly , has effects comparable to 100 µg (0.0001 g) or less of LSD. In the mid-1960s, the most important
black market A black market, underground economy, or shadow economy is a clandestine market or series of transactions that has some aspect of illegality or is characterized by noncompliance with an institutional set of rules. If the rule defines the se ...
LSD manufacturer ( Owsley Stanley) distributed LSD at a standard concentration of 270 µg, while street samples of the 1970s contained 30 to 300 µg. By the 1980s, the amount had reduced to between 100 and 125 µg, dropping more in the 1990s to the 20–80 µg range, and even more in the 2000s (decade).


Reactivity and degradation

"LSD," writes the chemist
Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American medicinal chemist, biochemist, organic chemist, pharmacologist, psychopharmacologist, and author. He is credited with introducing 3,4-methylenedioxymethamph ...
, "is an unusually fragile molecule ... As a salt, in water, cold, and free from air and light exposure, it is stable indefinitely." LSD has two labile protons at the tertiary stereogenic C5 and C8 positions, rendering these centers prone to
epimerisation In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite absolute configuration, configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in ...
. The C8 proton is more labile due to the electron-withdrawing
carboxamide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
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. 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. 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 Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
, especially in the presence of UV or other kinds of light. LSD often converts to "lumi-LSD," which is inactive in human beings. A controlled study was undertaken to determine the stability of LSD in pooled urine samples. 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.


Detection

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. Maximum plasma concentrations were found to be 1.4 and 1.5 hours after oral administration of 100µg and 200µg respectively with a plasma half-life of 2.6 hours (ranging from 2.2–3.4 hours among 40 human test subjects). LSD can be detected using an
Ehrlich's reagent Ehrlich's reagent or Ehrlich reagent is a reagent containing ''p''-dimethylaminobenzaldehyde (DMAB) and thus can act as an indicator to presumptively identify indoles and urobilinogen. Several Ehrlich tests use the reagent in a medical test; som ...
and a Hofmann's reagent.


History

LSD was first synthesized on November 16, 1938 by Swiss chemist Albert Hofmann at the Sandoz Laboratories in Basel, Switzerland as part of a large research program searching for medically useful ergot alkaloid derivatives. The abbreviation "LSD" is from the German "Lysergsäurediethylamid". LSD's
psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...
properties were discovered 5 years later when Hofmann himself accidentally ingested an unknown quantity of the chemical. The first intentional ingestion of LSD occurred on April 19, 1943, 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. Sandoz Laboratories introduced LSD as a psychiatric drug in 1947 and marketed LSD as a psychiatric panacea, hailing it "as a cure for everything from schizophrenia to criminal behavior, 'sexual perversions', and alcoholism." Sandoz would send the drug for free to researchers investigating its effects. Beginning in the 1950s, the US Central Intelligence Agency (CIA) began a research program code named Project MKUltra. The CIA introduced LSD to the United States, purchasing the entire world's supply for $240,000 and propagating the LSD through CIA front organizations to American hospitals, clinics, prisons and research centers. 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 subjects' knowledge. The project was revealed in the US congressional Rockefeller Commission report in 1975. In 1963, the Sandoz patents on LSD expired and the Czech company Spofa began to produce the substance. Sandoz stopped the production and distribution in 1965. Several figures, including Aldous Huxley, Timothy Leary, and Al Hubbard, had begun to advocate the consumption of LSD. LSD became central to the counterculture of the 1960s. In the early 1960s the use of LSD and other hallucinogens was advocated by new proponents of consciousness expansion such as Leary, Huxley, Alan Watts and Arthur Koestler, and according to L. R. Veysey they profoundly influenced the thinking of the new generation of youth. On October 24, 1968, possession of LSD was made illegal in the United States. 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. In November 2020, Oregon became the first US state to decriminalize possession of small amounts of LSD after voters approved Ballot Measure 110.


Society and culture


Counterculture

By the mid-1960s, the youth countercultures in California, particularly in San Francisco, had adopted the use of hallucinogenic drugs, with the first major underground LSD factory established by Owsley Stanley. From 1964, the Merry Pranksters, a loose group that developed around novelist Ken Kesey, sponsored the Acid Tests, a series of events primarily staged in or near San Francisco, involving the taking of LSD (supplied by Stanley), accompanied by light shows, film projection and discordant, improvised music known as the ''psychedelic symphony''. The Pranksters helped popularize LSD use, through their road trips across America in a psychedelically decorated converted school bus, which involved distributing the drug and meeting with major figures of the beat movement, and through publications about their activities such as Tom Wolfe's '' The Electric Kool-Aid Acid Test'' (1968). In San Francisco's Haight-Ashbury neighborhood, brothers Ron and Jay Thelin opened the Psychedelic Shop in January 1966. The Thelins opened the store to promote safe use of LSD, which was then still legal in California. The Psychedelic Shop helped to further popularize LSD in the Haight and to make the neighborhood the unofficial capital of the hippie counterculture in the United States. Ron Thelin was also involved in organizing the Love Pageant rally, a protest held in Golden Gate park to protest California's newly adopted ban on LSD in October 1966. At the rally, hundreds of attendees took acid in unison. Although the Psychedelic Shop closed after barely a year-and-a-half in business, its role in popularizing LSD was considerable. A similar and connected nexus of LSD use in the creative arts developed around the same time in London. A key figure in this phenomenon in the UK was British academic Michael Hollingshead, who first tried LSD in America in 1961 while he was the Executive Secretary for the Institute of British-American Cultural Exchange. After being given a large quantity of pure Sandoz LSD (which was still legal at the time) and experiencing his first "trip," Hollingshead contacted Aldous Huxley, who suggested that he get in touch with Harvard academic Timothy Leary, and over the next few years, in concert with Leary and Richard Alpert, Hollingshead played a major role in their famous LSD research at Millbrook before moving to New York City, where he conducted his own LSD experiments. In 1965 Hollingshead returned to the UK and founded the World Psychedelic Center in Chelsea, London.


Music and art

In both music and art, the influence of LSD was soon being more widely seen and heard thanks to the bands that participated in the Acid Tests and related events, including the Grateful Dead,
Jefferson Airplane Jefferson Airplane was an American rock band based in San Francisco, California, that became one of the pioneering bands of psychedelic rock. Formed in 1965, the group defined the San Francisco Sound and was the first from the Bay Area to ac ...
and Big Brother and the Holding Company, and through the inventive poster and album art of San Francisco-based artists like Rick Griffin, Victor Moscoso,
Bonnie MacLean Bonnie MacLean (December 28, 1939  – February 4, 2020), also known as Bonnie MacLean Graham, was an American artist known for her classic rock posters. In the 1960s and 1970s she created posters and other art for the promotion of rock and ...
, Stanley Mouse & Alton Kelley, and Wes Wilson, meant to evoke the visual experience of an LSD trip. LSD had a strong influence on the Grateful Dead and the culture of " Deadheads." Among the many famous people in the UK that Michael Hollingshead is reputed to have introduced to LSD are artist and Hipgnosis founder Storm Thorgerson, and musicians
Donovan Donovan Phillips Leitch (born 10 May 1946), known mononymously as Donovan, is a Scottish musician, songwriter, and record producer. He developed an eclectic and distinctive style that blended folk, jazz, pop, psychedelic rock and world mus ...
, Keith Richards, Paul McCartney, John Lennon, and
George Harrison George Harrison (25 February 1943 – 29 November 2001) was an English musician and singer-songwriter who achieved international fame as the lead guitarist of the Beatles. Sometimes called "the quiet Beatle", Harrison embraced Indian c ...
. Although establishment concern about the new drug led to it being declared an illegal drug by the Home Secretary in 1966, LSD was soon being used widely in the upper echelons of the British art and music scene, including members of the Beatles, the Rolling Stones, the Moody Blues, the Small Faces,
Syd Barrett Roger Keith "Syd" Barrett (6 January 1946 – 7 July 2006) was an English singer, songwriter, and musician who co-founded the rock band Pink Floyd in 1965. Barrett was their original frontman and primary songwriter, becoming known for his ...
,
Jimi Hendrix James Marshall "Jimi" Hendrix (born Johnny Allen Hendrix; November 27, 1942September 18, 1970) was an American guitarist, singer and songwriter. Although his mainstream career spanned only four years, he is widely regarded as one of the most ...
and others, and the products of these experiences were soon being both heard and seen by the public with singles like the Small Faces' " Itchycoo Park" and LPs like the Beatles' ''
Sgt. Pepper's Lonely Hearts Club Band ''Sgt. Pepper's Lonely Hearts Club Band'' is the eighth studio album by the English rock band the Beatles. Released on 26May 1967, ''Sgt. Pepper'' is regarded by musicologists as an early concept album that advanced the roles of sound composi ...
'' and Cream's '' Disraeli Gears'', which featured music that showed the obvious influence of the musicians' recent psychedelic excursions, and which were packaged in elaborately-designed album covers that featured vividly-coloured psychedelic artwork by artists like Peter Blake, Martin Sharp, Hapshash and the Coloured Coat ( Nigel Waymouth and Michael English) and art/music collective The Fool. In the 1960s, musicians from
psychedelic music Psychedelic music (sometimes called psychedelia) is a wide range of popular music styles and genres influenced by 1960s psychedelia, a subculture of people who used psychedelic drugs such as LSD, psilocybin mushrooms, mescaline, and cannabis to ...
and
psychedelic rock Psychedelic rock is a rock music Music genre, genre that is inspired, influenced, or representative of psychedelia, psychedelic culture, which is centered on perception-altering hallucinogenic drugs. The music incorporated new electronic sound ...
bands began to refer (at first indirectly, and later explicitly) to the drug and attempted to recreate or reflect the experience of taking LSD in their music. A number of features are often included in psychedelic music. Exotic instrumentation, with a particular fondness for the sitar and tabla are common. Electric guitars are used to create
feedback Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled ...
, and are played through wah wah and fuzzbox effect pedals. Elaborate studio effects are often used, such as backwards tapes, panning, phasing, long delay loops, and extreme reverb. In the 1960s there was a use of primitive electronic instruments such as early synthesizers and the theremin. Later forms of electronic psychedelia also employed repetitive computer-generated beats. Songs allegedly referring to LSD include John Prine's "Illegal Smile" and the Beatles' song " Lucy in the Sky with Diamonds," although the authors of the latter song repeatedly denied this claim. In modern times, LSD has had a prominent influence on artists such as Keith Haring, electronic dance music, and the jam band
Phish Phish is an American rock band formed in Burlington, Vermont, in 1983. The band is known for musical improvisation, extended jams, blending of genres, and a dedicated fan base. The band consists of guitarist Trey Anastasio, bassist Mike Gordon ...
.


Legal status

The United Nations
Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as #Amphetamine-type stimulants, amphetamine-type stimulants, barbiturates, benzodiazepines, and Psychedelic drug, psychede ...
(adopted in 1971) requires the signing parties to prohibit LSD. Hence, it is illegal in all countries that were parties to the convention, including the United States, Australia, New Zealand, and most of Europe. However, enforcement of those laws varies from country to country. Medical and scientific research with LSD in humans is permitted under the 1971 UN Convention.


Australia

LSD is a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2017). A Schedule 9 substance is defined as a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities. In Western Australia section 9 of the
Misuse of Drugs Act 1981 Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
provides for summary trial before a magistrate for possession of less than 0.004g; section 11 provides rebuttable presumptions of intent to sell or supply if the quantity is 0.002g or more, or of possession for the purpose of trafficking if 0.01g.


Canada

In Canada, LSD is a controlled substance under Schedule III of the Controlled Drugs and Substances Act. 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 offence In many common law jurisdictions (e.g. England and Wales, Ireland, Canada, Hong Kong, India, Australia, New Zealand, Malaysia, Singapore), an indictable offence is an offence which can only be tried on an indictment after a preliminary hearing ...
and liable to
imprisonment Imprisonment is the restraint of a person's liberty, for any cause whatsoever, whether by authority of the government, or by a person acting without such authority. In the latter case it is "false imprisonment". Imprisonment does not necessari ...
for a term not exceeding 3 years. Possession for purpose of trafficking is an indictable offence 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 recognized legitimate uses and possession of the drug without a licence 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 The Misuse of Drugs Act 1971 is an Act of the Parliament of the United Kingdom. It represents action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nation ...
).'' In 2000, after consultation with members of the
Royal College of Psychiatrists The Royal College of Psychiatrists is the main professional organisation of psychiatrists in the United Kingdom, and is responsible for representing psychiatrists, for psychiatric research and for providing public information about mental health ...
' Faculty of Substance Misuse, the UK Police Foundation issued the
Runciman Report The Runciman Report
was published by in 2000 by the UK policing think tank the