LSD

Lysergic acid diethylamide, commonly known as LSD (from German ) and by the nicknames acid and Lucy, is a semisynthetic hallucinogenic drug derived from ergot, known for its potent psychological effects and serotonergic activity.

LSD taken orally has an onset of action of 0.4 to 1.0hours and a duration of 7 to 12hours. LSD is extremely potent, with noticeable effects at doses as low as 20micrograms and is sometimes taken in even smaller amounts for microdosing. Despite widespread use, no fatal human overdoses have been documented. LSD is mainly used recreationally or for spiritual purposes. LSD can cause mystical experiences. LSD exerts its effects primarily through high-affinity binding to several serotonin receptors, especially the serotonin 5-HT_2A receptor, and to a lesser extent dopamine and adrenergic receptors. Neuroimaging studies indicate that LSD reduces the efficacy of thalmo-cortical information filtering, decreases oscillatory power within the default mode network, and flattens hierarchical organization of large-brain activity. At higher doses, it can induce visual and auditory hallucinations, ego dissolution, and anxiety. LSD use can cause adverse psychological effects such as paranoia and delusions and may lead to persistent visual disturbances known as hallucinogen persisting perception disorder (HPPD).

Swiss chemist Albert Hofmann first synthesized LSD in 1938 and discovered its potent psychedelic effects in 1943 after accidental ingestion. It became widely studied in the 1950s and 1960s. The drug was initially explored for psychiatric use due to its structural similarity to serotonin and safety profile. It was used experimentally in psychiatry for treating alcoholism and schizophrenia. By the mid-1960s, LSD became central to the youth counterculture in places like San Francisco and London, influencing art, music, and social movements through events like Acid Tests and figures such as Owsley Stanley and Michael Hollingshead. Its psychedelic effects inspired distinct visual art styles and musical innovations, and caused a lasting cultural impact. However, its association with the counterculture movement of the 1960s led to its classification as a Schedule I drug in the United States in 1970. It was also listed as a Schedule I controlled substance by the United Nations in 1971 and remains without approved medical uses. As of 2017, about 10% of people in the United States had used LSD at some point, with 0.7% having used it in the past year. Usage rates have risen, with a 56.4% increase in adult use in the United States from 2015 to 2018.

Uses

Recreational

LSD is commonly used as a recreational drug for its psychedelic effects.

Spiritual

LSD can catalyze intense spiritual experiences and is thus considered an entheogen. Some users have reported out of body experiences. In 1966, Timothy Leary established the League for Spiritual Discovery with LSD as its sacrament. Stanislav Grof has written that religious and mystical experiences observed during LSD sessions appear similar to descriptions in sacred scriptures of great religions of the world and the texts of ancient civilizations.

Medical

LSD currently has no formally approved medical use anywhere in the world.

In Switzerland, a special authorization program allows limited medical use of substances like LSD for patients with serious, treatment-resistant conditions, with patients treated under physician supervision.

Dosing

thumb|A "five strip" of LSD blotters.

LSD is an extraordinarily potent substance, A dose range as wide as 10 to 450μg has been reported. LSD may also be used in microdosing. In this context, it may be used at subthreshold or microdoses of less than 10μg. while street samples of the 1970s contained 30 to 300μg. By the 1980s, the amount had reduced to between 100 and 125μg, dropping more in the 1990s to the 20 to 80μg range, and even further in the 2000s.

Effects

LSD produces a variety of physical, psychological, and sensory effects. LSD is not considered addictive. An "afterglow" effect, characterized by an improved mood or perceived mental state, may persist for days or weeks following ingestion. Positive experiences, or "good trips", are described as intensely pleasurable and can include feelings of joy, euphoria, an increased appreciation for life, decreased anxiety, a sense of spiritual enlightenment, and a feeling of interconnectedness with the universe.

Negative experiences, commonly known as "bad trips", can induce feelings of fear, agitation, anxiety, panic, and paranoia. While the occurrence of a bad trip is unpredictable, factors such as mood, surroundings, sleep, hydration, and social setting, collectively referred to as "set and setting", can influence the risk and are considered important in minimizing the likelihood of a negative experience.

Uniquely among psychedelics, LSD appears to have two temporally and qualitatively distinct phases of psychoactive effects. These include an initial psychedelic phase associated with serotonin 5-HT_2A receptor agonism and a subsequent paranoia- and psychosis-like phase associated with dopamine D₂-like receptor agonism.

Users may experience enhanced visual phenomena, such as vibrant colors, objects appearing to morph, ripple, or move, and geometric patterns on various surfaces. Changes in the perception of food's texture and taste are also noted, sometimes leading to aversion towards certain foods.

There are reports of inanimate objects appearing animated, with static objects seeming to move in additional spatial dimensions. The auditory effects of LSD may include echo-like distortions of sounds, and an intensified experience of music. Basic visual effects often resemble phosphenes and can be influenced by concentration, thoughts, emotions, or music. Higher doses can lead to more intense sensory perception alterations, including synesthesia, perception of additional dimensions, and temporary dissociation.

Physical

thumb|upright=1|Some symptoms reported for LSD.

alt=Patient with Mydriasis due to usage of LSD|thumb|upright=1|left|Patient with [[mydriasis (pupil dilation) due to usage of LSD.]]

LSD can induce physical effects such as pupil dilation, decreased appetite, increased sweating, and wakefulness. The physical reactions to LSD vary greatly, and some may be a result of its psychological effects. Commonly observed symptoms include increased body temperature, blood sugar, and heart rate, as well as goose bumps, jaw clenching, dry mouth, and hyperreflexia. In cases of adverse reactions, users may experience numbness, weakness, nausea, and tremors. In a clinical trial, ketanserin given 1hour after LSD shortened its duration from 8.5hours to 3.5hours or by about 60%.]]

thumb|upright=1.35|class=skin-invert-image|Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in [[Delphi method|delphic analysis regarding 20 popular recreational drugs. LSD was ranked 14th in dependence, 15th in physical harm, and 13th in social harm.]]

LSD, a classical psychedelic, is deemed physiologically safe at standard doses (50–200 μg), and its primary risks lie in psychological effects rather than physiological harm. A 2010 study by David Nutt ranked LSD as significantly less harmful than alcohol, placing it near the bottom of a list assessing the harm of 20 drugs.

Psychological effects

Mental disorders

LSD can induce panic attacks or extreme anxiety, colloquially termed a "bad trip". Despite lower rates of depression and substance abuse found in psychedelic drug users compared to controls, LSD presents heightened risks for individuals with severe mental illnesses like schizophrenia. These hallucinogens can catalyze psychiatric disorders in predisposed individuals, although they do not tend to induce illness in emotionally healthy people.

Flashbacks

Flashbacks are psychological episodes where individuals re-experience some of LSD's subjective effects after the drug has worn off, persisting for days or months post-hallucinogen use. These experiences are associated with hallucinogen persisting perception disorder (HPPD), where flashbacks occur intermittently or chronically, causing distress or functional impairment.

The etiology of flashbacks is varied. Some cases are attributed to somatic symptom disorder, where individuals fixate on normal somatic experiences previously unnoticed before drug consumption. Other instances are linked to associative reactions to contextual cues, similar to responses observed in individuals with past trauma or emotional experiences. The risk factors for flashbacks remain unclear, but pre-existing psychopathologies may be significant contributors.

Estimating the prevalence of HPPD is challenging. It is considered rare, with occurrences ranging from 1 in 20 users experiencing the transient and less severe type 1 HPPD, to 1 in 50,000 for the more concerning type 2 HPPD.

Tolerance

LSD shows significant tachyphylaxis, with tolerance developing 24 hours after administration. The progression of tolerance at intervals shorter than 24 hours remains largely unknown. Tolerance typically resets to baseline after 3–4 days of abstinence. Significant cross-tolerance occurs between LSD, mescaline and psilocybin. A slight cross-tolerance to DMT is observed in humans highly tolerant to LSD. Tolerance to LSD also builds up with consistent use, and is believed to result from serotonin 5-HT_2A receptor downregulation.

Addiction and dependence liability

LSD is widely considered to be non-addictive, despite its potential for abuse. A report examining substance use disorder for DSM-IV noted that almost no hallucinogens produced dependence, unlike psychoactive drugs of other classes such as stimulants and depressants.

Cancer and pregnancy

The mutagenic potential of LSD is unclear. Overall, the evidence points to limited or no effect at commonly used doses. Studies showed no evidence of teratogenic or mutagenic effects. This may also be the case with microdosing. Research appears to be mixed on whether LSD is a potent serotonin 5-HT_2B receptor agonist or not, with some studies finding it to be essentially inactive.

Interactions

Some psychedelics, including LSD, are metabolized by the cytochrome P450 enzyme CYP2D6. Concurrent use of selective serotonin reuptake inhibitors (SSRIs), some of which are potent inhibitors of CYP2D6, with LSD may heighten the risk of serotonin syndrome. Similarly, a clinical study with LSD found that LSD levels were 75% higher in people with non-functional CYP2D6 (poor metabolizers) compared to those with functional CYP2D6. In contrast to certain other psychedelics, MAOIs do not inhibit the metabolism of or potentiate the effects of LSD and instead reduce its effects. Lithium notably intensifies LSD reactions, potentially leading to acute comatose states when combined. The exact doses of LSD were unknown, but were considered to be massive. The individuals reported to the hospital within 10 to 15minutes, with five of them comatose, three requiring intubation and mechanical ventilation, and the conscious individuals experiencing severe hallucinogenic effects, among other toxic symptoms. In other reports, a 5mg overdose of LSD produced severe nausea and vomiting along with severe behavioral disturbances, while a 10mg overdose was also non-fatal.

Despite acting as non-selective serotonin receptor agonists, major psychedelics like LSD and psilocybin do not cause serotonin syndrome even with extreme overdose. This is thought to be because they act as partial agonists of serotonin receptors like the serotonin 5-HT_2A receptor relative to serotonin itself. Common adverse effects (2.4–42%) included agitation or irritability, tachycardia, hallucinations or delusions, confusion, pupil dilation, hypertension, drowsiness or lethargy, elevated creatine phosphokinase (CPK), nausea and vomiting, and others. In general, psychedelics like LSD may rarely cause seizures in some individuals.

The median lethal dose (LD₅₀) of LSD in animals varies and is 50 to 60mg/kg in mice, 16.5mg/kg in rats, and 0.3mg/kg in rabbits all given by injection. These findings suggest that elephants may be much more sensitive to LSD in overdose than humans and other species.

Massive doses of LSD are largely managed by symptomatic treatments, and agitation can be addressed with benzodiazepines. Antipsychotics such as haloperidol are not recommended as they may have adverse effects. Owing to their high potency analogous to LSD, these drugs are also regularly sold as "LSD" in blotter papers. Fatalities involved in NBOMe intoxication suggest that a significant number of individuals ingested the substance which they believed was LSD, and researchers report that "users familiar with LSD may have a false sense of security when ingesting NBOMe inadvertently". Researchers state that the alleged physiological toxicity of LSD is likely due to psychoactive substances other than LSD. Researches hypothesize the low oral metabolic stability of N-benzylphenethylamines is likely causing the low bioavailability on the oral route, although the metabolic profile of this compounds remains unpredictable; therefore researches state that the fatalities linked to these substances may partly be explained by differences in the metabolism between individuals. When NBOMes are administered sublingually, numbness of the tongue and mouth followed by a metallic chemical taste was observed, and researchers describe this physical side effect as one of the main discriminants between NBOMe compounds and LSD. Despite its high potency, recreational doses of LSD have only produced low incidents of acute toxicity, but NBOMe compounds have extremely different safety profiles. Testing with Ehrlich's reagent gives a positive result for LSD and a negative result for NBOMe compounds.

Pharmacology

Pharmacodynamics

{| class="wikitable floatright" style="font-size:small;"

|+

|-

! Target !! Affinity (K_i, nM)

|-

| 5-HT_1A || 0.64–7.3 (K_i)<br />6.4 ()<br />110% ()

|-

| 5-HT_1B || 3.9

|-

| 5-HT_1D || 3.9–14

|-

| 5-HT_1E || 93

|-

| 5-HT_1F ||

|-

| 5-HT_2A || 0.47–21 (K_i)<br />0.24–538 ()<br />23–88% ()

|-

| 5-HT_2B || 0.98–30 (K_i)<br />0.68–12,000 ()<br />13–73% ()

|-

| 5-HT_2C || 1.1–48 (K_i)<br />0.85–1,590 ()<br />26–79% ()

|-

| 5-HT₃ || >10,000

|-

| 5-HT₄ || 1,000 (rat)

|-

| 5-HT_5A || 9.0

|-

| 5-HT_5B || 3.2 (rat)

|-

| 5-HT₆ || 2.3–6.9

|-

| 5-HT₇ || 6.3–6.6

|-

| α_1A || 670–1,128

|-

| α_1B || 8,677

|-

| α_1D ||

|-

| α_2A || 12–46

|-

| α_2B, α_2C ||

|-

| β₁ || 140–1,601

|-

| β₂ || 740–3,461

|-

| β₃ ||

|-

| D₁ || 155–340 (K_i)<br />35–63 ()<br />35–44% ()

|-

| D₂ || 61–126

|-

| D₃ || 27–60

|-

| D₄ || 26–158

|-

| D₅ || 75–344

|-

| H₁ || 1,100–1,540

|-

| H₂–H₄ ||

|-

| M₁–M₅ ||

|-

| I₁ ||

|-

| σ₁, σ₂ ||

|-

| TAAR1 || 450 (K_i) (rat)<br />10,000 (K_i) (mouse)<br />1,400 () (rat)<br />9,700 () (mouse)<br />>20,000 () (human)

|-

| || >30,000 (K_i)<br />>100,000 ()

|-

| || 5,600–>30,000 (K_i)<br />>100,000 ()

|-

| || >30,000 (K_i)<br />>100,000 ()

|- class="sortbottom"

| colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise noted. Refs: <br />

|}

LSD is a serotonergic psychedelic and acts as a non-selective serotonin receptor modulator. Uniquely among serotonergic psychedelics, LSD also shows potentially significant affinity for the dopamine receptors, albeit much lower than for most of the serotonin receptors.

LSD binds to most serotonin receptor subtypes except for the serotonin 5-HT₃ and 5-HT₄ receptors. The psychedelic effects of LSD are attributed to activation of 5-HT_2A receptors. Many but not all serotonin 5-HT_2A receptor agonists are psychedelics, and serotonin 5-HT_2A receptor antagonists block the psychedelic effects of LSD. The drug exhibits pronounced functional selectivity or biased agonism at the serotonin 5-HT_2A and 5-HT_2C receptors in that it activates the signal transduction enzyme phospholipase A2 (PLA2) instead of activating the enzyme phospholipase C (PLC) as the endogenous ligand serotonin does, among other differences.

Exactly how LSD produces its effects is unknown, but it is thought that it may work in part by increasing glutamate release in the cerebral cortex LSD, like many other drugs of recreational use, has been shown to activate DARPP-32-related pathways. The drug enhances dopamine D₂ receptor protomer recognition and signaling of D₂–5-HT_2A heteromeric receptor complexes, which may contribute to its psychotropic effects.

LSD is a biased agonist that induces a conformation in serotonin 5-HT₂ receptors that preferentially recruits β-arrestin over activating G proteins. It 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. In rodents, LSD levels are undetectable by 8hours post-dosing, yet LSD continues to produce partial interoceptive effects (54% responding) at this time point. The related lysergamide lysergic acid amide (LSA) that lacks the diethylamide moiety is far less potent in comparison. It is unclear why LSD is so potent. The affinity and activational potency of LSD at the human serotonin 5-HT_2A receptor in vitro is unremarkable compared to other psychedelics such as DOI and DOB. This appears to be mediated by serotonin 5-HT_2A receptor agonism. However, subsequent studies failed to reproduce these findings and instead found no interaction of LSD with TrkB.

There appears to be no significant acute tolerance to the subjective effects of LSD. Hence, its duration appears to be dictated by pharmacokinetics rather than by pharmacodynamics.

Mechanisms of action