LSD, for example, can produce subtle intensifications in perception-or it can completely dissolve all sense of space, time, and self. The first gap is that we do not have an account of how psychedelic drugs can produce such a broad diversity of subjective effects. A ‘third wave’ of psychedelic science has recently emerged with its own set of sleuths on the trail, sleuths who now wield an arsenal of 21st-century scientific methodologies and are uncovering new sets of clues.Įxisting theoretical hurdles span five major gaps in understanding. “Meanwhile the clue is being systematically followed, the sleuths-biochemists, psychiatrists, psychologists-are on the trail” ( Huxley, 1991, p. 12) commented that our understanding circa 1954 was “absurdly inadequate” and amounted to a mere “clue” that he hoped would soon develop into a more robust understanding. Because of their dramatic effect on the character and contents of subjective awareness, psychedelic drugs magnified the gaps in our scientific understanding of how brain chemistry relates to subjective experience (see Evarts, 1957 Purpura, 1968). By the 1950s, rising interest in mescaline research was expanded to include drugs like DMT, LSD, and psilocybin in a ‘second wave’ of psychedelic science. How do they do this? Western science began its ‘first wave’ of systematic investigations into the unique effects of mescaline 125 years ago. Lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and mescaline-the ‘classic’ psychedelic drugs-can produce a broad range of effects in perception, emotion, cognition, and sense of self.
I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks- entropic brain theory, integrated information theory, and predictive processing-and point out key shared features that link back to earlier theories. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Next, I review late 19th-century and early 20th-century theories- model psychoses theory, filtration theory, and psychoanalytic theory-and highlight their shared features. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science.
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