Background
Lysergic acid diethylamide (LSD), a hallucinogen that is also known as an entactogen (“to touch within” [1] ), is one of the most potent psychoactive compounds known (said to be more than 3000 times more potent than mescaline). Doses as small as 1-1.5 mcg/kg can produce psychoactive effects; an oral dose of 25 mcg is capable of producing potential deleterious psychedelic effects. [2, 3, 4]
The drug is odorless, colorless, and slightly bitter tasting. It is usually taken by mouth and is rapidly absorbed by the gastrointestinal (GI) tract. The image below depicts LSD in several different pill forms.
While LSD usage reached epidemic proportions in the 1960s, subsequent constraints on the manufacture and distribution of the drug have led to a reduction in rates of abuse. LSD is classified as a schedule I drug by the US Food and Drug Administration, meaning it is considered a narcotic drug with no known acceptable medical use that has a high potential for abuse; the possession of any amount of LSD is illegal.
There has also been a concerted effort to educate the public that the psychedelic experiences are a potential health hazard. Nevertheless, LSD continues to be used. Pockets of continued abuse have been documented across the country.
Pathophysiology and Etiology
Most hallucinogens belong to one of the following two structurally distinct classes:
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Indoles and tryptamines - Eg, LSD, psilocybin, and N,N-dimethyltryptamine (DMT)
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Phenylethylamines - Mescaline and MDMA
The most common route of exposure to LSD is oral; the drug is absorbed rapidly from the GI tract. Dermal absorption has not been well documented. LSD can be aerosolized and is absorbed by the lungs if the particle diameter is 5 micrometers or less.
Disruption of the serotonin system
Hallucinogens have a high affinity for serotonin (5-hydroxytryptamine [5-HT]) receptors, at which LSD exhibits agonist and antagonist properties. [19]
Hallucinogenic substances primarily exert their effect on the central nervous system (CNS) by way of neurotransmitter level manipulation. Stimulating secretion, inhibiting reuptake, delaying enzymatic breakdown, or directly stimulating or inhibiting neurotransmitter receptors are mechanisms by which hallucinogens can increase the synaptic concentration of the major neurotransmitters (ie, norepinephrine, serotonin, dopamine). Small differences in structure affect neurotransmitter levels differently, which leads to the wildly varied clinical effects.
MDMA (ecstasy) enhances presynaptic release and reuptake of serotonin and norepinephrine. [20] JWH-018 and other synthetic cannabinoids are cannabinoid receptor (CB1 and CB2) agonists that can exert a secondary effect on the balance of circulating catecholamines. [21]
Although these small differences help to explain the varied hallucinogenic experiences, they can also predict the spectrum of deleterious effects. Serotonin syndrome (serotonin toxicity) can occur with any agent that increases concentrations of serotonin, including LSD, psilocybin, and mescaline. [22] The neurotransmitter dopamine is associated with the reward system of the brain. Substances that stimulate release or inhibit reuptake of dopamine typically exhibit a strong addictiveness, as seen with cathinones (bath salts) and methamphetamines.
The 5-HT2A receptor plays a major role in the modulation of sensory signals and is predominantly found in pyramidal neurons of the prefrontal cerebral cortex, where hallucinogens have effects on cognition, mood, and perception and on emotions ranging from fear to euphoria. These receptors are also thought to be responsible for the pathology and therapy of schizophrenia. Serotonin receptors found in the locus coeruleus are important for sensory modulation and are responsible for the sympathomimetic effects of the drug (hypertension, tachycardia, dizziness, loss of appetite, dry mouth, sweating, nausea, numbness, tremor).
Affinities to other serotonin receptors differ between the two hallucinogen classes, which makes attributing specific effects to a single 5-HT receptor subtype impossible. LSD also stimulates dopamine D2 receptors. [23] This leads to a biphasic pharmacologic pattern of early serotoninlike effects (15-30 min after administration) and late mediated dopaminelike effects (60-90 min after administration). The relationship between the dopaminergic and serotonergic systems is not fully understood. [24, 25]
After oral administration, the early drug effects of LSD appear after 30-60 minutes. More profound psychoactive effects peak at 2-4 hours, and some effects may last as long as 12 hours. [2] A typical dose to obtain the desired effects ranges from 50-200 mcg. LSD is rapidly metabolized in the liver by N-demethylation, N-deethylation, and aromatic hydroxylation after oral ingestion. The LSD metabolites N-demethyl-LSD (nor-LSD), lysergic acid ethylamide (LAE), iso-LAE, mono-oxylated LSD, and hydroxylated LSD are excreted in the urine. The elimination half-life of LSD is 3-5 hours.
Although LSD does not cause physical or psychological addiction, users quickly develop a high degree of short-lived tolerance (tachyphylaxis), which is due to down-regulation of 5-HT2A receptors. Long-term effects of chronic use can result in persistent psychosis and hallucinogen persisting perception disorder (HPPD), so called “flashbacks." LSD remains one of the most potent mood-altering and perception-altering drugs. [16]
Epidemiology
In 2021, the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS) reported 491 single exposures to LSD, with 67 major outcomes and four deaths. [26] In contrast, the 2023 AAPCC-NPDS reported 247 single exposures, nine major outcomes, and no deaths. [27]
A review of data from the National Survey on Drug Use and Health indicated that LSD use in the US increased 200% from 2002-2018, with higher likelihood of use noted in four groups: those with higher levels of education, those who were not married or had never been married, those with severe comorbid mental health disorders, and those with criminal justice involvement. [28]
The overall prevalence of LSD use among adolescents and young adults aged 15-34 years in Europe is estimated to be 1.0% or less, although higher prevalence has been reported in Finland (2.0%) and Estonia (1.7%). [29]
While LSD is included in national drug trending reports, the accuracy of these for actual LSD use is complicated by novel non-lysergamide hallucinogenic compounds being marketed as LSD. For example, a class of designer research chemicals includes highly potent hallucinogenic serotonin agonists. Of these, 25I-NBOMe and 25C-NBOMe are the most common type; called "Bomb" or "N-Bomb," they are sold on blotter paper and, like LSD, are taken via the buccal or sublingual route. NBOMes are commonly misrepresented as LSD because of their similar routes of administration and effects. [30]
A survey of 682 adults (aged 18-25 years) in 2015 entering electronic dance music (EDM) events at nightclubs and festivals in New York City found that 2.9% of respondents reported lifetime use of LSD. In addition, LSD use significantly increased the risk of novel psychoactive substance (NPS) use (adjusted odds ratio = 4.64, P = 0.004). [30] Another study of self-reported NPS use in a nationally representative US sample found that 73.7% of NPS users reported lifetime LSD use. [31]
In the United States, LSD is used predominantly by Whites. [32] While use by Blacks and Hispanics is less common, it has been reported in surveys of urban populations, being especially used in clubs and raves. [30]
Males use LSD more frequently than do females. The typical LSD user is a risk-taking, White male in high school or college. However, a survey of women attending university-based ambulatory reproductive health clinics revealed that 13% had used LSD in the past. [33] There was also an association between LSD and high-risk sexual behavior.
According to the 2023 AAPCC-NPDS, 71% of reported single exposures to LSD were in adolescents aged 13-19 years. [26] According to the Monitoring the Future study, in 2022, 0.6% of US 8th graders, 1.3% of 10th graders, and 2.5% of 12th graders reported using LSD during the past year. [34]
Prognosis
The long-term prognosis for persons who use LSD is good provided that they stop using it, and most users voluntarily decrease or stop the use of the drug over time. LSD is not considered an addictive drug, because it does not produce compulsive drug-seeking behavior; however, LSD does produce a physiologic tolerance, requiring that subsequent doses be increased to achieve the same effect.
A study by Vizeli et al indicated that, with regard to the effects of LSD, the size of the dose is the most important factor. However, the investigators also found that prior to taking the drug, non-pharmacologic factors, such as feelings of well-being, extraversion, and levels of emotional excitability and anxiety, affect the subjective response to LSD, with factors such as emotional excitability and anxiety also predicting heart rate, and emotional excitability predicting body temperature. Sex and body weight were determined not to significantly influence the drug experience. [35]
For those who use LSD chronically, there is the enhanced risk for schizophreniform psychosis and derangements in memory function, problem solving, and abstract thinking. Long-term complications from LSD use may include prolonged psychotic reactions, severe depression, or an exacerbation/unmasking of a preexisting psychiatric illness. LSD potentially may exacerbate comorbid conditions in elderly patients.
Because of its large index of toxicity, patients must have access to unusually concentrated forms of LSD if they are to overdose. The lethal dose of LSD has been estimated to be 14,000 mcg. However, only a few cases of massive ingestions have been reported. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD. Their plasma LSD levels were reported as between 1000 and 7000 mcg/100 mL. These individuals all became comatose, with hyperthermia, vomiting, light gastric bleeding, and respiratory problems. With hospital treatment, however, all were reported to have survived without apparent residual effects. [36]
The patient's altered perceptions can lead to behavioral toxicity, in which the patient does not appreciate the dangers in the environment and may be injured. Users may believe that they are invincible or possess superpowers and may do things they would not normally consider, such as believing they can fly, jumping from buildings, or incurring severe ocular damage by prolonged staring at the sun. [36] Extreme agitation brought on by disturbing hallucinations has been known to lead to suicide or to unintentional death, as users have tried to flee from these drug-induced illusions.
Despite early reports of LSD-related fetal malformations, inadequate evidence exists to establish causality.
Hallucinogen persisting perception disorder (HPPD) has an estimated prevalence of 4.2%. With HPPD, individuals who are not intoxicated experience symptoms (flashbacks) that initially arose during the use of LSD. Flashbacks tend to occur during times of psychological stress and can last for minutes to hours. HPPD may last several months; however, some patients report these experiences for as long as 5 years, with many of these individuals having an underlying psychiatric illness. [37]
Patient Education
Counsel patients on the potential dangers of LSD use, including driving automobiles while intoxicated or combining LSD ingestion with ethanol, marijuana, or other illicit drugs. Because the metabolism of LSD is not fully understood, human immunodeficiency virus (HIV)–positive patients on highly active antiretroviral therapy should be counseled to not use LSD, due to the possibility of adverse drug-drug interactions. "Mind Matters," an educational tool, is designed to encourage young people in grades 5-9 to learn about the effects of drug abuse on the body and brain (see National Institute on Drug Abuse, Mind Matters Series).
For patient education information, see Substance Abuse.
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Assorted lysergic acid diethylamide (LSD) blotter papers.
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Lysergic acid diethylamide (LSD) in assorted pill forms.
