Lysergic acid diethylamide: a drug of ‘use’?

Das and colleagues situate lysergic acid diethylamide (LSD) as a classical hallucinogen with a complex history: synthesized in the late 1930s, it became both a focus of mid-20th century clinical experimentation and a widely used recreational drug. Earlier work explored LSD's psychotomimetic properties and its potential as an adjunct to psychotherapy, but many of those studies predate current methodological standards. The authors note renewed recent interest in psychedelic research and frame LSD as a drug whose therapeutic potential and safety profile remain incompletely characterised. This review article aims to describe LSD's receptor pharmacology and presumed mechanisms of action, to summarise its acute and long-term effects on the body and mind, and to collate historical and contemporary evidence for therapeutic applications. The paper addresses areas including addiction treatment, anxiety in terminal illness, creativity and suggestibility enhancement, and safety issues, and concludes by considering whether LSD might be used therapeutically in specific, controlled settings.

The extracted text does not provide a formal Methods section or a clear description of search strategy, inclusion/exclusion criteria, databases searched, or quality-assessment procedures. The paper is presented as a narrative review that integrates historical reports, clinical case series, controlled trials where available, and prior meta-analytic findings. From the content, the authors appear to draw on diverse sources — early clinical reports from the 1950s–1970s, selected experimental human studies (for example, crossover trials and challenge studies), and at least one quantitative meta-analysis of alcoholism trials — but the extraction does not report how studies were identified, selected, or synthesised. Because no explicit systematic review methods are described in the extracted text, the review should be regarded as a synthesis of illustrative and historically important studies rather than the product of a reproducible systematic search.

Acute and general effects: The review summarises LSD's acute psychological effects as highly variable and dose-dependent, typically beginning 30–60 minutes after ingestion and lasting up to about 12 hours. Reported mental effects include visual hallucinations, synesthesia, distortion of time and identity, emotional lability ranging from euphoria to intense fear, and the phenomenon of 'bad trips' that can precipitate panic or lasting psychiatric disturbance in vulnerable individuals. Common physiological responses include mydriasis, sweating or chills, tachycardia, blood pressure elevation, tremor, and autonomic changes; a typical moderate dose is cited as 1–3 µg/kg. Flashbacks or persistent perceptual disturbances are described as rare but clinically important adverse effects. Pharmacology and mechanism: LSD acts on multiple neurotransmitter systems, but its characteristic psychosensory effects are primarily linked to agonism at 5-HT2A receptors, with modulation by 5-HT2C and 5-HT1A receptors. The authors describe intracellular signalling pathways (for example Gq-mediated inositol triphosphate–diacylglycerol and Gi/o-mediated pathways) and note interactions between 5-HT2A and metabotropic glutamate receptor 2. Binding affinities (Ki values) across several serotonergic receptor subtypes are reported in the extracted text, indicating high affinity at 5-HT2A among others. Tolerance and dependence: Repeated LSD use produces rapid tolerance that dissipates after a few days of abstinence; the review reports that LSD does not typically cause physical dependence or compulsive drug-seeking but can lead to psychological dependence. Flashbacks and, in some cases, long-lasting psychoses or severe depression are noted as risks associated with chronic or poorly supervised use. Historical and contemporary research context: The paper recounts mid-20th century clinical interest in LSD for psychotherapeutic purposes, including psycholytic and psychedelic models, and notes that research largely ceased in many countries amid recreational use and regulation. A limited resurgence of clinical research is described, with modern investigators reassessing LSD for conditions such as cluster headache, Alzheimer's disease, addiction, and anxiety in terminal illness. Evidence in addiction and alcohol dependence: The authors cite historical reports of LSD-assisted treatment for addiction and refer to a quantitative meta-analysis (Krebs and Johansen) of six trials with a combined 536 participants. In that meta-analysis, 59% of subjects receiving LSD (210–800 µg) reportedly showed lower levels of alcohol misuse, compared with 38% receiving placebo. The review also discusses proposed mechanisms for therapeutic effects in addiction, including 5-HT2A-mediated receptor downregulation, neuroplastic changes involving BDNF and GDNF, and enduring psychological changes following mystical-type experiences. Anxiety in life‑threatening illness and palliative care: Older studies and more recent pilot work are summarised. An early report cited 100 of 150 patients with nonpsychotic functional psychiatric disorders benefiting from LSD (doses reported across a very wide range). A contemporary double-blind, randomized, active placebo‑controlled crossover pilot study of 12 patients (LSD 20 and 200 µg) is reported to have produced reductions in trait anxiety on the State‑Trait Anxiety Inventory that persisted to 12 months, with no treatment‑related serious adverse events persisting beyond one day. Prepulse inhibition and experimental models: A double‑blind, randomized, placebo‑controlled crossover challenge in 16 healthy subjects (200 µg LSD) produced pronounced alterations of waking consciousness, visual hallucinations and synesthesia, and reductions in prepulse inhibition (PPI) of the acoustic startle response. Physiological and endocrine changes included increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin and epinephrine. The authors link PPI disruption to sensorimotor deficits reminiscent of psychosis and discuss genetic influences on 5-HT2A that may modulate PPI. Creativity and suggestibility: The review summarises anecdotal and small experimental studies suggesting that LSD can enhance aspects of creativity and suggestibility. Examples include long‑term case series of artists reporting subjective and stylistic changes in artwork, and controlled small studies (for example, 19 graduate students in one experiment) showing improvements on creativity tests. Intravenous LSD in 10 volunteers (40–80 µg) increased scores on a suggestibility scale (Creative Imagination Scale), and other small studies reported enhanced suggestibility in healthy participants and in some patient groups. The authors caution that increased suggestibility carries risks such as false memories or adoption of maladaptive beliefs. Safety profile and contraindications: The authors contend that classical hallucinogens have low physiological toxicity and do not typically produce organ damage or neuropsychological deficits in controlled settings. Nevertheless, nonmedical use can precipitate prolonged psychiatric reactions in rare cases. Absolute contraindications listed include significant cardiovascular disease, pregnancy, epilepsy, overt psychosis or paranoid personality, and organic cerebral disorders. The extracted text notes that teratogenic findings in animal studies are inconsistent.

Das and colleagues interpret the assembled evidence as indicating that LSD has a set of identifiable pharmacological actions and a long history of both problematic recreational use and experimental therapeutic application. They emphasise that many early clinical reports suggested benefits in areas such as alcoholism, other addictions, and anxiety in terminal illness, and that more recent controlled studies and translational research provide renewed, if still limited, support for therapeutic exploration. The authors highlight mechanisms plausibly linking 5-HT2A agonism and downstream neuroplastic effects to enduring psychological change, and they point to observed endocrine and psychosocial effects (for example, increased oxytocin and prosocial feelings) that could contribute to therapeutic processes. At the same time, the paper stresses important limitations: much of the historical literature predates modern trial methodology, many studies were uncontrolled or underpowered, and standardised pharmacological or clinical research on LSD has been sparse over the last several decades. Safety concerns are underscored, particularly the risk of acute adverse psychological reactions, rare prolonged perceptual disturbances, and exacerbation of pre-existing psychiatric vulnerability. The authors therefore argue for cautious, supervised use only within controlled clinical settings, with well‑trained therapists and adherence to ethical and regulatory safeguards. In terms of implications, the review suggests that LSD might be reconsidered as a therapeutic adjunct in specific conditions under strict controls, and that further rigorous clinical research is warranted. They recommend careful patient selection, structured therapeutic support, and avoidance of nontherapeutic or unsupervised use, but refrain from asserting definitive clinical recommendations given the current state of the evidence.