What is the physiology behind the lack of effect of LSD (lysergic acid diethylamide) or psilocybin in specific populations?

Physiological Mechanisms Behind Non-Response to LSD and Psilocybin

The primary physiological explanation for lack of effect from LSD or psilocybin is highly variable individual threshold doses for acute effects on conscious state, with approximately 20% of individuals requiring substantially higher doses to experience any subjective effects. 1

Individual Dose-Response Variability

The most critical factor determining non-response is inter-individual variation in pharmacodynamic sensitivity:

• Laboratory research demonstrates that threshold doses for acute effects on conscious state vary widely across individuals, with some people requiring substantially higher doses than others to experience any subjective changes 1
• Studies show that approximately 20% of participants taking what are considered standard microdoses report no discernible acute drug effects whatsoever 1
• The dose-response relationship for various psychedelic outcomes varies dramatically between individuals, suggesting fundamental differences in receptor sensitivity or drug metabolism 1

Receptor-Level Mechanisms

The underlying physiology involves serotonergic receptor sensitivity and expression:

• LSD and psilocybin exert their effects primarily through 5-HT2A receptors, with additional activity at 5-HT1A receptors and indirect effects on dopaminergic (D2) and glutamatergic (NMDA) systems 2
• Individual differences in receptor density, affinity, or downstream signaling cascades likely account for variable responses 2
• Genetic polymorphisms affecting serotonin receptor expression or function may explain why some individuals are pharmacologically "non-responders"

Population-Specific Differences

Certain clinical populations show differential sensitivity:

• Headache patients demonstrate considerably higher likelihood of acute psychological, affective, and perceptual alterations following microdoses of both psilocybin and LSD compared to healthy controls 1
• This suggests that baseline neurobiological state and existing pathophysiology can modulate psychedelic sensitivity 1

Pharmacokinetic Factors

Drug metabolism and bioavailability contribute to apparent non-response:

• Both LSD and psilocybin demonstrate dose-proportional pharmacokinetics with first-order elimination, but individual metabolic rates vary 3
• Differences in hepatic enzyme activity (particularly cytochrome P450 enzymes) can lead to variable plasma concentrations even with identical doses
• Poor absorption or rapid metabolism may result in subtherapeutic drug levels despite adequate dosing 3

Bidirectional Effects Masking Response

An important caveat is that some individuals may experience effects in opposite directions, which can appear as non-response in group analyses:

• Microdosing may affect subgroups of individuals in opposite ways on particular variables (some increase while others decrease on the same measure) 1
• When aggregated at the group level, these bidirectional effects can cancel out, making it appear that no effect occurred when in fact the drug produced variable but real effects 1

Clinical Implications

When encountering apparent non-responders:

• Consider that the intensity of acute subjective effects may serve as a proxy indicator of an individual's sensitivity to other psychedelic outcomes 1
• Individuals reporting no subjective effects likely did not receive an effective dose for their particular physiology 1
• Dose escalation may be necessary, though this must be balanced against safety concerns including hyperthermia, seizures, and cardiovascular effects 4
• The 100 µg and 200 µg doses of LSD and 30 mg dose of psilocybin produce comparable subjective effects in most individuals, providing guidance for dose equivalence 3