Lysergic Acid Diethylamide and Psilocybin Revisited.

The past decade brought the beginnings of a renaissance in research on psychedelic drugs. Two articles in this issue of Biological Psychiatry signify that the resurrection of this longignored topic has begun to mature and bear at least the promise of fruit. In the early 1970s, the onset of the “War on Drugs” brought with it a near-total hiatus in serious research on psychedelic drugs, especially in the United States. The resumption of credible work in this area has come from Switzerland, where many of the original pioneering studies were initiated in the 1950s and 1960s. The two articles presented here address the phenomenology and underlying mechanisms of action for two classic psychedelic drugs: lysergic acid diethylamide (LSD) and psilocybin. Schmid et al. (1) examined the effects of the most famous psychedelic, LSD, which was discovered in Basel, Switzerland, by Hofmann in 1943 (2). Schmid et al. demonstrated that a robust dose of LSD was feasible for studies in healthy volunteers and that it markedly reduced sensorimotor gating as indexed by prepulse inhibition of the startle response (PPI). This disruption of PPI by LSD mimicked not only the disruption reported in parallel experiments in rodents but also the similar deficit in PPI observed in patients with schizophrenia. Kraehenmann et al. (3) combined state-of-the-art imaging methods with validated clinical rating scales and a well-established affect modulation task to characterize the effects of psilocybin on positive mood and identify circuitry subserving these effects. Hofmann also identified psilocybin as the active principle in Psilocybe mushrooms (“magic mushrooms”) in 1958 (2). Largely as a result of the pioneering work of the Vollenweider group in Zurich, Switzerland, psilocybin became the foremost practical laboratory tool suitable for use in experimental medicine studies in healthy human volunteers. The article by Kraehenmann et al. (3) reflects the maturation of this group’s research by building on their studies addressing the behavioral, emotional, psychophysiologic, electrophysiologic, and brain imaging alterations resulting from administration of psilocybin, ketamine, and other psychoactive drugs in healthy humans. Many of these pharmacologic studies were conducted in parallel with assessments in psychiatric patient populations. Kraehenmann et al. (3) used functional magnetic resonance imaging to confirm that acutely administered psilocybin led to a decrease in right amygdala reactivity to negative stimuli that was associated with a psilocybin-induced reduction in emotional reactivity to negative stimuli. Furthermore, this change in the amygdala response was related to a psilocybin-induced enhancement of positive mood. The demonstration that LSD disrupts PPI in healthy subjects has several implications, as discussed by Kraehenmann et al. (3). As summarized elsewhere (2), the original idea that