The pharmacology of lysergic acid diethylamide: a review

Lysergic acid diethylamide (LSD) is a semisynthetic derivative of lysergic acid originally obtained from the rye fungus Claviceps purpurea. Albert Hofmann synthesised LSD in 1938 and discovered its psychoactive properties in 1943. During the 1950s and 1960s LSD was widely used in psychiatric research both as an experimental tool to model psychotic-like states and as an adjunct in psychotherapeutic approaches described as psycholytic or psychedelic therapy. Recreational and spiritual use expanded in the late 1960s, after which regulatory restrictions and declines in research funding sharply reduced clinical work with the drug. Passie and colleagues set out to review the pharmacology and psychopharmacology of LSD because the experimental literature is extensive, dispersed across many decades and languages, and no comprehensive review had been available since the 1950s. The review aims to collate chemical, pharmacokinetic, pharmacodynamic, toxicological, physiological, and psychiatric data from the experimental literature to provide an updated synthesis useful for researchers and clinicians interested in LSD as a research tool and potential therapeutic agent.

This paper is a narrative review of the experimental literature on LSD. The authors state that they performed a thorough search of the experimental literature and combined older and newer data; however, the extracted text does not present a formal methods section specifying databases searched, date ranges, inclusion or exclusion criteria, or a formal risk-of-bias assessment. The review draws on a large body of predominantly mid-20th century experimental work, including animal studies, human pharmacokinetic and psychopharmacological investigations, and clinical reports from therapeutic use. Where available, quantitative measures (for example doses, plasma levels, animal LD50s, and metabolic identifications) from primary studies are summarised. Because the paper integrates heterogeneous preclinical and clinical sources rather than reporting a systematic meta-analysis, analytical methods are those typical of a narrative synthesis rather than pooled statistical modelling.

Chemistry and stereochemistry: LSD is an indole-containing tetracyclic molecule (molar mass 323.42 g/mol) that exists as four optically active isomers; only the d-LSD isomer possesses psychoactive properties. LSD is usually stabilised as its tartrate salt for solution storage. Numerous homologues and analogues have been synthesised, but none match LSD's potency except some derivatives substituted at the N-6 position. Acute psychological and cognitive effects: A moderate oral dose for humans is cited as 75–150 μg, with the minimal recognisable dose around 25 μg and an ‘‘optimum’’ full reaction estimated at 100–200 μg. Acute psychological effects typically last 6–10 hours. Subjective effects include stimulation of affect (often euphoria), enhanced introspection, alterations in perception (illusions, pseudohallucinations, synaesthesia), distortions of time and body image, and changes in ego function. Psychomotor coordination and reaction time are frequently impaired; attention and memory tasks show dose-dependent deficits in many studies, although some lower-dose studies reported preserved learning. The extracted text reports that chronic exposure has not been shown to produce lasting neurocognitive impairments in retrospective reviews. Toxicology and somatic effects: LD50 values vary widely by species (rabbit LD50 0.3 mg/kg i.v.; rat 16.5 mg/kg i.v.; mouse 46–60 mg/kg i.v.). No documented human deaths from LSD overdose are reported in the extracted text, and several cases of extremely high accidental ingestion were survivable with hospital care. Reports of chromosomal damage were not upheld by subsequent studies. Teratogenic effects in animals occurred only at extraordinarily high doses, and there is no evidence of carcinogenicity. Somatic autonomic effects in humans include pupillary dilatation, modest increases in heart rate and blood pressure in most subjects, diaphoresis, salivation, nausea, and occasional changes in body temperature; respiratory function is generally unchanged. Neurologically, hyperreflexia and mild ataxia are commonly described; EEG studies show modest activation changes, commonly an increase in alpha mean frequency and occasional desynchronisation. Biochemical and endocrine changes: LSD has been associated with reduced urinary inorganic phosphate excretion in humans, interpreted as an unclear biochemical correlate possibly related to stress. A small study reported reduced urinary dopamine excretion after LSD (200–300 μg p.o.), while many other monoamine metabolites were unchanged. In humans LSD increases serum growth hormone with a peak around 120 minutes; rat studies showed lowered resting prolactin. Routine liver and renal biochemical tests were generally unchanged in reported studies. Sleep and dreaming: Low doses (reported n = 12, 6–40 μg p.o.) given at or shortly after sleep onset prolonged early REM periods substantially (30–240%) and altered subsequent REM architecture, increasing total REM sleep in these paradigms. Pharmacokinetics and distribution: Oral administration leads to essentially complete absorption; onset of subjective and sympathomimetic effects is within 30–45 minutes with peak effects at about 1.5–2.5 hours. Upshall and Wailling found that a large meal halved plasma concentrations relative to fasting, indicating food and gastric pH affect absorption. In animals, radiolabel studies show rapid clearance from blood and substantial early accumulation in the digestive tract and liver, consistent with enterohepatic circulation; brain concentrations in rodents fall more rapidly than plasma. In monkeys the CSF concentration reached a maximum within 10 minutes and paralleled unbound plasma levels, supporting ready blood–brain barrier passage. Human plasma half-life is reported as circa 175 minutes in one study; species half-lives vary (mice 7 min, cats 130 min, monkeys 100 min in quoted animal studies). Metabolism and detection: LSD is almost completely metabolised, with only trace unchanged drug excreted. Identified human urinary metabolites include nor-LSD, lysergic acid ethylamide (LAE), 2-oxo-LSD, 2-oxy-3-hydroxy-LSD (reported as a major urinary metabolite), and glucuronide conjugates of 13- and 14-hydroxy-LSD among others. Routine forensic detection methods include HPTLC and GC–MS with detection limits around 0.4 μg/L, while immunoassays and ELISAs can detect much lower concentrations; practical forensic detection limits of 0.1–0.25 ng/mL for LSD and N-desmethyl-LSD are cited. LSD and some metabolites can be detected in blood, urine and hair with varying windows. Pharmacodynamics and receptor interactions: The review emphasises complex interactions with serotonergic systems. LSD acts as an agonist at several 5-HT receptor subtypes and is characterised as a partial agonist at 5-HT2A receptors, which are strongly implicated in hallucinogenic effects. It also has activity at 5-HT1A autoreceptors, inhibiting serotonergic cell firing, and binds to other 5-HT subtypes (1B, 1D, 2C, 5A, 6, 7) with uncertain significance. Activation of cortical 5-HT2A receptors may increase cortical glutamate release and alter corticocortical and corticosubcortical transmission. LSD also interacts with dopaminergic D1 and D2 receptors; some animal data suggest time-dependent shifts in receptor mediation (early 5-HT2A, later D2 involvement), which might help explain temporal variations in effects. Regional brain distribution and functional studies: Autoradiographic and tissue studies in animals show uneven brain distribution, with relatively high concentrations in limbic structures, pituitary and pineal glands, and sensory cortices compared with other areas. Human cerebral blood flow and global measures (n = 13 at 120 μg i.v.) did not show significant changes in total cerebral blood flow, oxygen consumption or glucose utilisation, although the authors note that regionally specific effects could be obscured by whole-brain measures. Neurometabolic data for hallucinogens more broadly suggest increased activity in paralimbic and frontal regions and some right-hemisphere activation, but results across studies are inconsistent and may reflect stress-related as well as substance-related effects. Tolerance and drug interactions: Rapid tolerance to LSD develops after a few days of repeated dosing in humans and animals. Drug interactions reported include incomplete antagonism by chlorpromazine at higher doses, attenuation of LSD effects after chronic SSRI or MAOI treatment (possibly via downregulation of 5-HT2 receptors), and potentiation by lithium and some tricyclics, with anecdotal reports linking lithium co-administration to markedly exaggerated or dangerous reactions. Psychiatric complications: The most common acute adverse psychological reaction is severe anxiety or panic (‘‘bad trip’’). Temporary paranoid ideation, transient depressive after-effects, and rare persistent phenomena such as hallucinogen persisting perception disorder (HPPD or ‘‘flashbacks’’) are described; a review of studies concluded HPPD is rare and, when present, usually limited to months up to a year but occasionally persistent for years. Historical clinical series reported relatively low complication rates when LSD was administered in supervised therapeutic contexts.

Passie and colleagues conclude that LSD has a complex pharmacology that helps explain why its precise mechanisms of action remain incompletely understood. The drug is, within the reviewed literature, physiologically well tolerated and there is no convincing evidence for long-lasting somatic or brain damage from controlled use. The authors situate the bulk of the experimental data in the mid-20th century, noting that earlier LSD research contributed substantially to the discovery of serotonin systems and to methodological advances in psychopharmacology. They also observe that regulatory restrictions and lack of funding curtailed research after the 1960s, but renewed interest is emerging for specific clinical and research applications, such as treating cluster headache and supporting psychotherapy for terminally ill patients and for post-traumatic stress disorder. The paper is presented as a roadmap to identify gaps and to support further targeted research into the pharmacology of LSD.