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Altering Perceptions on Psychedelics Harvard Medicine magazine

While it is typical to have anxiety about the traumatic event weeks or months after it happens, people with PTSD find it difficult to perform daily functions for an extended period of time. The new techniques at Kwan’s disposal include two-photon microscopy, viral tracing and optogenetic manipulations, in which the activity of neurons can be controlled with light – all of which can be used to target functional neurons in the cortical and subcortical regions of a living mouse’s brain. It was the development of these tools at Cornell that brought Kwan back to his alma mater in 2021 after spending the last nine years in the Yale School of Medicine. Dr. Kuceyeski and Singleton and their colleagues now plan to use their approach to study the longer-term brain-dynamics effects of LSD and psilocybin—effects that would be more relevant in a clinical setting—as well as the connections between psychedelic-altered brain dynamics and users’ subjective experiences. Working with the University of Auckland, MindBio recently completed the first-ever phase-one clinical trial of microdosed LSD, in which 80 healthy participants took either an oral version of the drug or a placebo every three days for six weeks.

Learning what these are is the next big challenge, a process that promises to completely revolutionize the way we approach discovering better treatments for a host of human psychiatric disorders. The fMRI studies and their various analyses and reanalyses by Carhart-Harris and colleagues are at odds with the earlier SPECT and PET imaging studies and may reflect different methodologies. In particular, psilocybin is not typically administered to humans by injection, nor are Psilocybe mushrooms generally taken in routes other than by mouth. In the Hermle et al. , Vollenweider et al. , and Gouzoulis-Mayfrank et al. studies cited earlier, the drug was administered orally, but psilocybin was administered intravenously in the studies by Carhart-Harris et al. Subjective reports from the two different routes of administration indicate profound differences in the speed of onset, as well as the intensity of the subjective effects. Psilocybin given orally generally takes about 40 minutes to begin to manifest its effect, with a duration of action lasting 4–6 hours.

Although serotonin itself has long been established to be involved in inflammation and inflammatory processes, the role of psychedelics and their primary target, the serotonin 5-HT2A receptor, in these processes was unknown until recently. In 2008, Charles Nichols discovered that psychedelics produced powerful anti-inflammatory effects against tumor necrosis factor -α–mediated inflammatory processes in several cell types, including primary aortic smooth muscle cells, through activation of 5-HT2A receptors (Yu et al., 2008). Whereas several psychedelic drugs, including LSD, demonstrated potent anti-inflammatory effects, the drug R-DOI was extraordinarily potent at blocking inflammation.

The mechanisms of long-term effects of one or several psychedelic experiences are even less well understood. The initial agonist action on serotonin receptors does not explain the long-term effects seen 14 months after these experiences with “positive changes in attitudes, mood, life satisfaction, behavior, and altruism/social effects” (Griffiths et al., 2011). After this “sense of self,” reassembles at the end of the psilocybin experience, there appears to be a chance of abandoning habits and repetitive thoughts that no longer serve a useful purpose for the person. One open study found that long-term positive effects may persist for decades and it seems possible that long-term adaptation through changes in gene expression also may occur that can be therapeutic (e.g., see Nichols and Sanders-Bush, 2002). Evidence from animal studies suggests that some psychedelics may alleviate anxiety, in particular DOI, a nonselective 5-HT2A/2C agonist, which has been perhaps the most widely studied drug in this class.

Although lacking detailed specifics as well as a follow-up, this early report does suggest that Psychedelics might acutely improve creativity. Nair and Gudelsky , using in vivo microdialysis experiments in rats, reported that DOI significantly increased extracellular ACh in both the PFC and dorsal hippocampus. Although the 5-HT2C–selective agonist MK-212 [6-chloro-2-(1-piperazinyl)pyrazine] significantly enhanced release of ACh in both brain areas, the 5-HT2A/2C agonist mescaline produced a 2-fold ACh increase only in the PFC.

They note that when KO mice were trained to discriminate a visual stimulus, 85% of the mice exhibited operant behavior, whereas 100% of the WT mice reached criterion. Elevated synaptic levels of serotonin occur in the SERT KO mice, which would be expected to lead to receptor downregulation. Indeed, Li et al. showed that SERT KO mice have reduced densities of 5-HT1A receptors, and Rioux et al. demonstrated reduced 5-HT2A receptors in SERT KO mice.