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Microscopy reveals how psychedelics light up brains neuropathways Cornell Chronicle

With a legacy of putting patients first, Weill Cornell Medicine is committed to providing exemplary and individualized clinical care, making groundbreaking biomedical discoveries, and educating generations of exceptional doctors and scientists. “Serotonin 2a receptors have a spatial distribution in the brain that appears to be optimized for lowering these state transition energies,” Singleton said. The new proposal excludes synthetic psychedelics including LSD and MDMA, known commonly as ecstasy, which were included in the previous iteration. For LSD to become an accepted microdose treatment, pharmaceutical companies must develop a standard formulation whose dosage can be individualized and that doesn’t degrade over time, as LSD is known to do, Hanka says.

Ensuring widespread availability means understanding that each patient comes to these drugs with a story. No matter their background, respecting a patient’s individual experience during any such therapy session is paramount. Amanda Kim, a psychiatry resident at Brigham and Women’s Hospital, runs an affinity group through the Boston Psychedelic Research Group that serves as a community for clinical trainees to share their perspectives on psychedelics and brainstorm ways to pursue their interest in this area.

Similarly, in situ hybridization has demonstrated that most nuclei of the amygdala have moderate levels of 5-HT2A receptor mRNA, with higher levels in the cortical nucleus and dorsolateral subdivision of the lateral nucleus (Wright et al., 1995). Ettrup et al. evaluated CIMBI-5 [N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine] (25I-NBOMe) as an agonist radioligand for PET imaging of 5-HT2A receptors. CIMBI-5 and the 5-HT2A antagonist PET ligand altanserin showed similar cortex-to-cerebellum uptake and had similar target-to-background ratios.

They suggest that some of the cortical actions of 5-HT may be constantly exerted, with more or less efficacy at the various 5-HT receptors, thus providing widespread global and/or sustained influence in the neocortex. A later study of 5-HT2A receptor localization in the rat cortex by Miner et al. employed immunoperoxidase labeling to determine the localization of 5-HT2A receptors in the middle layers of the rat PFC. Using a polyclonal antibody, they found most 5-HT2A receptors to be expressed on postsynaptic structures, predominantly on proximal and distal dendritic shafts, apparently on both pyramidal and local circuit neurons. Most often, Miner et al. observed that 5-HT2A receptors were restricted to a particular area of the dendrite, usually extrasynaptic regions apposed to unlabeled dendrites. They reported that 73% of the immunopositive sites were postsynaptic, and 58% of those were on dendritic shafts, with 42% expressed in dendritic spines. A postsynaptic localization is also consistent with the reports by Xia et al. , who demonstrated that 5-HT2A receptors interact with PSD-95, the major protein of postsynaptic densities in asymmetric synapses.

Jenna Lombardo-Grosso, a former Marine relaxes after drinking psilocybin mushroom tea with others at a Missions Within, a psychedelic therapy retreat on the outskirts of Tijuana, Mexico, March 19, 2022. A growing body of research into the therapeutic benefits of psychedelic compounds has generated enthusiasm among some psychiatrists and venture capitalists, and is drawing veterans of America's latest conflicts to treatment sessions. Small studies like Johnson’s have confirmed the power of Psychedelics to treat certain types of mental illness but have also raised concerns about side effects. That has spurred biotech and pharmaceutical companies, drawn to the tremendous potential, to try to design new psychedelic compounds without the downsides—including, perhaps, the long-and-winding trip for which they are famous.

Moreover, animals typically engage in self-medicative and drug instrumentalization behaviors to solve adaptive problems directly related to their way of life (Forbey et al., 2009; Müller, 2020). Therefore, the answer to this question also resides in the specifics of the human lifeway, which placed a premium on social tolerance and cognitive flexibility (both regulated by 5-HT; Tricklebank and Daly, 2019) making the ingestion of 5-HT-mimicking psychedelics potentially beneficial and adaptive. Concomitantly, mythological narratives and religious beliefs were elaborated that enabled individual integration and collective accommodation (McKay, 2018; Sterelny, 2018) of the profound, and often unsettling, visionary experiences encountered in ASC. We think this niche-construction dynamic, which involves a combination of cultural and biological selection, helps explain why psychedelic use is not ubiquitous while institutionalized ASC , music (Mehr et al., 2019), and religion are cross-cultural universals. Rituals are socially stipulated, conventional behaviors that are critical for group social interaction; they also drive cultural transmission within and between generations . Rituals are very diverse and complex, but often involve synchronic movement, causally opaque action, and both euphoric and dysphoric arousal (Whitehouse and Lanman, 2014; Boyer and Liénard, 2020).

Kwan’s research primarily focuses on psilocybin, the active ingredient in so-called magic mushrooms. As psilocybin is already being tested in Phase II clinical trials, it is the most promising candidate for pharmaceutical development. Kwan’s lab is also looking at other compounds, such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), which is exuded by the glands of the Sonoran Desert Toad as a defense mechanism.

Psychedelics cause specific psychological, visual, and auditory changes, and often a substantially altered state of consciousness. Psychedelic states are often compared to meditative, psychodynamic or transcendental types of alterations of mind. The "classical" psychedelics, the psychedelics with the largest scientific and cultural influence, are mescaline, LSD, psilocybin, and DMT. Drugs that induce mental changes similar to psychotic states are called hallucinogens or ‘psychedelic’ drugs. In 1938, the Swiss chemist Albert Hofmann synthesized the compound lysergic acid diethylamide , and a few years after its synthesis accidentally ingested some powder, subsequently experiencing the ‘mind-expanding’ properties of this compound.

This was the first systematic controlled study of the use of a psychedelic to give insights and produce well-being in normal volunteers, and served as the basis on which subsequent patient studies were conducted. Psilocybin (2 mg/kg, i.v.) administered to rats evoked phMRI signal increases in a number of regions, including olfactory and limbic areas and elements of the visual system (Spain et al., 2015). LFP amplitude in response to sensory stimuli was decreased by psilocin administration, concurrently with enhanced CBF. These results suggest that the hemodynamic signal changes underlying phMRI responses reflect changes in both neuronal activity and neurovascular coupling. A further potential confound in BOLD signal interpretation in the case of psilocin results from its combined neuronal and vascular effects. Both the 5-HT2A and 5-HT1A receptors can mediate vasoconstriction, and negative BOLD signals may occur in the presence of increased neuronal signaling (Angenstein et al., 2009).

Respiratory and cardiovascular support, mechanical ventilation, continuous venovenous hemodialysis, and corticosteroid treatment led to improvement and the patient recovered completely over several months. These substances do not lead to addiction or dependence and are not considered to be reinforcing (O'Brien, 2001). This is understandable when one realizes that the serotonergic hallucinogens do not have direct effects on brain dopaminergic systems, a pharmacology that appears essential for nearly all drugs that can engender dependence. Attempts to train animals to self-administer hallucinogens, an animal model that can predict abuse liability, have generally been unsuccessful. These findings of Kometer et al. provide further evidence that decreased ongoing oscillations below 20 Hz, particularly θ/α oscillations, may be a common mechanism of action of psychedelics.