LSD

LSD (lysergic acid diethylamide) is a semi-synthetic classic psychedelic, derived from lysergic acid found in the ergot alkaloids of rye (Claviceps purpurea). It is distinguished by a highly polypharmacological profile, a prolonged duration, and a strong biographical depth. It was synthesised by Albert Hofmann in 1938, and its psychedelic properties were discovered in 1943 (Bicycle Day).

Pharmacology

LSD acts as a polypharmacological partial agonist. Its affinity is high for the 5-HT2A receptor, which forms the core of the psychedelic effect, but also for 5-HT2B, 5-HT2C, 5-HT1A, 5-HT6 and 5-HT7, as well as for the dopaminergic D1 and D2 receptors and the alpha-adrenergic receptors.

Each target contributes to one aspect of the profile: 5-HT1A modulates the anxious and affective component, D1/D2 dopaminergic activity underlies a later component, and the alpha-adrenergic action explains moderate vasoconstriction and tachycardia.

A structural feature accounts for the unusual duration of the effect: LSD remains trapped within the receptor through closure of the extracellular loop EL2 (a mechanism shown on 5-HT2B by Wacker et al., 2017, and confirmed on 5-HT2A by Kim et al., 2020). This phenomenon explains 8 to 12 hours of effect despite a plasma half-life of only about 3 hours.

Mechanisms

At the level of brain networks, LSD reduces the coherence of the default mode network (DMN) and increases global connectivity as well as brain entropy. Filtering decreases in favour of integration: the brain becomes more flexible, more associative and more unpredictable.

This profile is interpreted within the theoretical framework REBUS / Anarchic Brain (Carhart-Harris and Friston, 2019). DMN disintegration correlates with the subjective intensity of ego dissolution. The work of Lebedev (2015, on psilocybin) and Tagliazucchi (2016, on LSD) documented this correlation between network disintegration and subjective ego dissolution. More recent data place LSD among the psychoplastogens, via the TrkB, BDNF and mTOR pathways.

Phenomenology

Reported subjective effects include vivid sensory alterations and synaesthesias, very rich mental imagery and complex visions, deep ideas and new perspectives, as well as marked access to biographical material (memories, relational patterns, traumas). Thought becomes non-linear and associative.

Ego dissolution and the sense of unity are possible, but they remain dose-dependent and appear mainly at strong or heroic doses. Alteration of time (dilation, distortion) is common, as are cognitive plasticity and a possible narrative restructuring.

LSD occupies a singular position, combining polypharmacology, prolonged duration and a unique kinetics. Beyond about 200 µg, the experience often becomes qualitatively other, and not merely more intense. At heroic doses (500 to 1000 µg and above), narrative dissolution, ontological shock and phenomenological structures absent at lower doses may appear. It is also one of the most demanding tools of classic psychedelic psychotherapy.

Duration and tolerance

The effect begins within 30 to 90 minutes, peaks between 2 and 6 hours, with a total duration of 8 to 12 hours (sometimes up to 14 hours). Tolerance sets in rapidly, through desensitisation of 5-HT2A receptors within hours, with cross-tolerance with psilocybin, mescaline, the 2C-x compounds and partially DMT. A return close to baseline takes about two weeks. Microdosing (5 to 20 µg) is a widespread practice, but controlled data remain mixed.

Harm reduction

LSD shows no documented addictive potential, but the experience is powerful, long, and highly dependent on context. A personal or family history of schizophrenia or bipolar I disorder is a contraindication. Several interactions are documented: convulsive risk with lithium and tramadol, unpredictable potentiation with MAOIs, possible attenuation of effects with SSRIs and antipsychotics. HPPD (persistent perception disorder) is rare but real, and moderate hypertension or tachycardia are possible. Given the duration of 8 to 12 hours or more, set and setting are non-negotiable.

Sources

• Wacker et al. (2017), crystal structure of the LSD / 5-HT2B complex (a receptor related to 5-HT2A) and closure of the EL2 loop; the first LSD / 5-HT2A structure is Kim et al. (2020)
• Carhart-Harris and Friston (2019), REBUS / Anarchic Brain model
• Lebedev et al. (2015), network disintegration and ego dissolution (study on psilocybin)
• Tagliazucchi et al. (2016), brain connectivity under LSD
• Work on psychedelic psychoplastogenesis (TrkB / BDNF / mTOR pathways)
• Albert Hofmann, discovery of LSD (1938 and 1943)