Toxicity, Hallucinogens - LSD 

Lysergsãurediethylamid (LSD), or lysergic acid diethylamide, is the prototype of the hallucinogen class. It was first synthesized as LSD-25 from lysergic acid in 1938 by the Swiss biochemist Albert Hofmann while researching the medical effects of ergot-derived synthetic molecules. The hallucinogenic properties of LSD were not discovered until 1943, when Hofmann unintentionally ingested the substance and experienced an “extremely stimulated experience." Hailed as a wonder drug in the field of psychoanalysis during the 1950s and 1960s, LSD was used as an experimental drug in schizophrenia research to produce “experimental psychosis” by altering neurotransmitter systems and was used in so-called “psycholytic” or “psychedelic” therapy.^[1]

The American psychologist, writer, and futurist Timothy Leary popularized LSD and other hallucinogens in the 1960s based on their alleged therapeutic and spiritual benefits; this led to a psychedelic revolution, with large numbers of people using LSD as part of a counterculture movement. As a result of public health concerns, the drug was banned for recreational purposes by federal law in 1966.^[2] Currently, LSD is known for its use as a “club drug” together with gamma-hydroxybutyric acid (GHB); 3,4 methylenedioxymethamphetamine (MDMA), also referred to as ecstasy; and ketamine. Other hallucinogens include mescaline, psilocybin, and ibogaine, which all possess a structural similarity to serotonin.

LSD causes changes in thought, mood, and perception, with minimal effects on memory and orientation. LSD primarily produces so-called pseudohallucinations, which are illusions derived from the misinterpretation of actual experiences. One form of such illusions are synesthesias (the transposition of certain sensory modes), which create an experience known as sensory crossover . Examples include the perception of a sound evoked by a visual image or the impression of hearing colors or feeling sounds. True hallucinations occur as well; visual hallucinations are the most common.

Exposure to LSD causes pleasant and unpleasant emotions, but the overall effects are unpredictable and vary with the ingested amount, the user’s personality and mood, individual expectations, and surroundings. Users are typically aware that visual, auditory, and olfactorial perceptions are distorted and unreal (“good trip”); however, acute adverse drug effects can include panic reactions, psychoses, and major depression (“bad trip”).^[3]

LSD can be synthesized from easily obtainable chemicals or from naturally occurring substances. Ergotamine alkaloids produced from a fungus that grows on rye and other grains contain lysergic acid. Lysergic acid amide (LSA) is found in the seeds of Morning Glories and Hawaiian Baby Woodrose. LSD is one of the most potent psychoactive drugs. It is 3000 times more potent than mescaline, and doses as small as 1-1.5 mcg/kg can produce psychoactive effects; the minimum effective dose is approximately 25 mcg. The drug is odorless, colorless, and slightly bitter tasting. It is usually taken by mouth and rapidly absorbed by the GI tract.

LSD is produced as a crystalline powder and then mixed with various binding agents. It is sold in the streets as tablets (“microdots”), capsules, or in liquid form; often, it is applied to absorbent materials such as blotter paper (“blotter acid”) or gelatin (“window panes”). These are divided into small, decorated squares, with each square representing one dose.

According to the US Drug Enforcement Administration (DEA), the strength of samples obtained from illicit sources ranges from 20-80 mcg of LSD per dose. Although LSD possesses a wide margin of safety, single doses obtained over recent years were significantly less potent than those available during the 1960s and 1970s, when a dose contained 100-200 mcg or more of LSD. LSD has no known medical use. Most LSD manufactured in the United States is intended for illegal use, with small amounts used for research purposes. Most illegal laboratories are found in the West Coast, and the possession of any amount of LSD is illegal in the United States. LSD is a Schedule I substance under the Controlled Substances Act because of its high potential for abuse without any legitimate medical purpose. LSA is a Schedule III substance.^[4]

LSD is sold under more than 80 street names, including "A", acid, Adams, back breaker, battery acid, beast, blotter, blue chairs, blue cheers, blue mist, brown dot, buttons, California triple dip, cube, dose, dot, Elvis, flat blues, gelatin, green wedge, hawk, looney toons, Lucy in the sky with diamonds, M and Ms, mellow yellow, mescal, microdot, mighty Quinn, mind detergent, Owsley acid, Owsley blue dot, pane, pearly gates, pink wedge, pink Owsley, purple Owsley, Sandoz's, strawberries, sugar cube, sunshine, Superman, uncle, vacation, wedding bells, window pane, and zen.

Most hallucinogens belong to two structurally distinct classes: indoles and tryptamines (eg, LSD, N,N-dimethyltryptamine [DMT], psilocybin) or phenylethylamines (mescaline, MDMA). The structural similarity to serotonin and the intrinsic potency allow hallucinogens to disrupt the balanced functioning of the serotonin system.

Hallucinogens have a high affinity for serotonin (5-HT) receptors where LSD exhibits both agonist and antagonist properties. The 5-HT_2A 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, perception, and 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 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.^[5] This leads to a biphasic pharmacological 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.^{[6, 7]}

LSD is absorbed rapidly after oral administration, and early drug effects appear after 30-60 minutes. More profound psychoactive effects peak at 2-4 hours and some effects may last as long as 12 hours. 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. Its metabolites N-demethyl-LSD (nor-LSD), lysergic acid ethylamide (LAE), iso-LAE, monooxylated 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-HT_2A receptors. Long-term effects of chronic use can result in persistent psychosis and hallucinogenic persisting perception disorder (HPPD), so called “flashbacks." LSD remains one of the most potent mood-altering and perception-altering drugs.^[3]

Frequency

United States

Emergency department (ED) visits from patients with adverse reactions to hallucinogens are relatively uncommon. In 2006, the Drug Abuse Warning Network (DAWN) estimated 4,002 LSD related ED visits out of a total of 958,164 ED visits involving illicit drugs (approximately 1.3 ED visits per 100,000 population).^[8] However, this is a 2-fold increase in LSD-related ED visits compared with 2005. Given its popularity as a club drug, LSD-related ED visits often involve multidrug use, including MDMA and others. According to DAWN data, LSD users in the United States tend to be white males aged 12-24 years and of lower socioeconomic backgrounds.

Mortality/Morbidity

Deaths caused by primary LSD effects have not been well documented. The lethal dose of LSD has been estimated to be 14,000 mcg. Few cases of massive ingestions have been reported; because of its large index of toxicity, patients must have access to unusually concentrated forms of LSD if they are to overdose. Massive overdoses can lead to respiratory arrest, coma, emesis, hyperthermia, autonomic instability, and bleeding disorders. No suicide attempts using LSD intoxication have been reported.

Age

In general, adolescents and young adults are now the most frequent LSD users after it regained popularity since the 1990s. Low cost (prices ranging from $2-5 per single dose or hit, with prices of $1 or less at wholesale lots), easy availability, alleged mind-expanding properties, and attractive paper designs make LSD especially intriguing to junior-high and high-school students.^[9]

In 2002, 13% of young American aged 16-23 years used LSD according to a report on age-related drug use based on the National Survey on Drug Use and Health (NSDUH).^[10] LSD was the second most frequent used drug after MDMA in this age group.

In 2006, the National Institutes of Health (NIH) reported that 9.5% of Americans aged 12 years and older have used LSD at least once in their lifetime, and 0.3% had used it in the year prior to the survey.^[11]