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The UC Berkeley Center for the Science of Psychedelics BCSP

Programs Training in psychedelic facilitation BCSP is training the next generation of psychedelic guides in a new program focused on interdisciplinary training for religious, spiritual-care, and health-care professionals. Programs Learn more about BCSP psychedelic research We bring together researchers from across disciplines, including neuroscience, molecular biology, psychology, chemistry, and genetics, and experts in public policy, law, health economics, and religion. Hallucinogens work by stimulating, suppressing, or modulating the activity of the various neurotransmitters in the brain. The specific neurotransmitter systems they influence are related to their particular chemical structures. Hosted by Editor-in-Chief and therapist Amy Morin, LCSW, this episode of The Verywell Mind Podcast, featuring psychologist Brian Pilecki, shares how psychedelics can be used to treat emotional pain. The person spends a significant amount of time using, trying to obtain, or recovering from use of the drug.

After additional experiments, it was ultimately discovered that suppression of raphe cell firing by psychedelic tryptamines resulted from stimulation of 5-HT1A somatodendritic autoreceptors, and nonhallucinogenic 5-HT1A agonists were identified that also suppressed raphe firing . Phenethylamine-type psychedelics such as mescaline lack 5-HT1A agonist activity, so this hypothesis for the mechanism of action of psychedelics was, therefore, not tenable. Nevertheless, phenethylamine-type psychedelics do suppress firing of a subset of raphe cells when given systemically but not when administered directly into the raphe (Aghajanian et al., 1970; Haigler and Aghajanian, 1973). This suppressant effect by phenethylamine psychedelics is thought to occur through an indirect GABA-mediated mechanism (Liu et al., 2000; Martín-Ruiz et al., 2001). Thus, an increased GABA release onto raphe cells may explain the previous observation of an indirect suppression of 5-HT cells in the dorsal raphe induced by phenethylamine psychedelics in vivo. Although the focus of most research on amino acid neurotransmitters in the frontal cortex has been on glutamate, GABA interneurons play an important role.

Milardi et al. used constrained spherical deconvolution tractography to elucidate the complex relationships between the fiber systems in the claustrum. They detected four groups of white matter fibers connecting the claustrum to the cortex and provided a detailed representation of brain areas connected to the claustrum. One very important scientific consequence of the discovery of LSD also is often overlooked. The powerful psychologic effect of LSD was accidently discovered in 1943 , followed only a decade later in 1953 by the detection of serotonin in the mammalian brain .

Furthermore, the fly has glutamate and GABA systems that are known to be indirectly modulated by psychedelics in mammals that are important for the behavioral effects. In the initial study reporting on the behavioral effects of LSD in the fly, Nichols et al. examined the effect of acute LSD on general activity, and the effects of LSD on the ability of the fly to follow a moving object . In that study, feeding was accomplished by starving the fly for 15–18 hours and then placing it on blotting paper saturated with a solution of LSD spiked with glucose so as to be able to measure the amount of drug consumed after the experiments. With this method, a single bolus dose ranging from 200 to 1200 ng/fly was ingested within 1 to 2 minutes. Keller and Umbreit administered LSD intravenously to mice and reported “…a rapid and violent head shaking” that did not occur in normal mice. They indicated that it was easily observed, that independent observers could reliably detect the behavior, and that this HTR in mice “provided a suitable tool for the behavioral studies” .

In one experiment, they transfected cortical pyramidal cells with a construct coding for the C-terminal portion of PLCβ1, which acts as a dominant negative to suppress Gαq/11 signaling. The 5-HT2A agonist AMS induced a small inward current in nontransfected cells, but not in neighboring neurons transfected with PLCβ-ct. The investigators reasoned that if postsynaptic 5-HT2A receptor signaling induces glutamate release from presynaptic terminals, then inhibition of postsynaptic 5-HT2A signaling should also inhibit the ability of the cells to increase sEPSCs. They found, however, that the ability of AMS to increase frequency of sEPSCs was no different between control cells and those transfected with PLCβ-ct.

The lack of psychedelic activity for BOL-148 clearly indicates that therapeutic efficacy in cluster headaches cannot be related to psychoactive effects, which presumably are manifested through the 5-HT2A receptor, but the mechanism of action remains unknown. Early reports examined the pharmacology of BOL compared with LSD, although not much conclusive was found; however, it does appear that there must be some overlap between the pharmacology of BOL and LSD. For example, when 1 mg BOL was given three times a day for 5 days to 10 human volunteers, the effect of 1 μg/kg LSD was significantly attenuated (Isbell et al., 1959). If a single dose of 2–4 mg BOL was given along with LSD, there was no effect on the LSD response. When 3 mg/d BOL was given for 2 days prior to LSD, a trend was observed but not a significant block of the LSD effect. Early in vitro studies showed that the “antiserotonin” effect of BOL was at least comparable to that of LSD , so downregulation of the 5-HT2A receptor by BOL might be expected to block the effects of LSD.

Furrer et al. conclude that liver regeneration is impaired in old mice due to a deficiency in the fenestration of hepatic sinusoids. Administering DOI ameliorates this defect through a pathway that involves VEGF, which regulates opening of endothelial fenestrae, improving microcirculation and enabling normal regenerative response after liver injury. Canadian psychiatrists Humphrey Osmond and Abram Hoffer considered LSD for the treatment of alcoholism to be especially promising. Indeed, there were a number of publications suggesting that psychedelics could be useful in treating substance abuse (Chwelos et al., 1959; Smart et al., 1966; Hollister et al., 1969; Savage and McCabe, 1973). Unfortunately, early investigators did not employ rigorous clinical methods such as randomized controlled trials, outcome measures, and treatment settings, and thus those studies did not provide definitive results.

Recent evidence, however, has indicated that psychedelics may be more effective therapies for aborting acute attacks than conventional treatments. Online interviews of 53 cluster headache patients who had used either psilocybin or LSD to treat their condition found that 22 of 26 psilocybin users reported that psilocybin aborted attacks, and 25 of 48 psilocybin users and 7 of 8 LSD users reported cluster period termination. Extension of the remission period for attacks was reported by 18 of 19 psilocybin users and 4 of 5 LSD users (Sewell et al., 2006). Expectancy is likely to be significantly operative in a standard drug versus placebo design when the drug being evaluated produces highly discriminable effects and participants and staff know the specific drug conditions to be tested. Therefore, a low dose of psilocybin was compared with a high dose of psilocybin and participants and guides were given instructions that obscured the range of possible drug conditions to be tested.

Other studies examined the use of Psychedelics to treat anxiety and depression, schizophrenia, and even autism (e.g., Bender, 1966). Historically, Hirschhorn and Winter published the first report of a psychedelic producing a discriminative stimulus in rats. Using a 1-minute VI schedule of reinforcement with diluted sweetened condensed milk as the reinforcer, intraperitoneal injections of both LSD and mescaline were shown to produce discriminative stimuli in female rats.

Typically, at least two successful Phase III trials are required in order to provide sufficient evidence of efficacy. Given the large number of participants required, Phase III trials are most often multi-centre, international trials. A particularly relevant clinical study examining the ability of psilocybin-assisted therapy to treat MDD was released in 2020 by the Center for Psychedelic and Consciousness Research at Johns Hopkins (Davis et al., 2020). MDD is one of the most common mental health disorders in the United States, and across the world. Affecting over 165 million people annually, MDD is onset by a combination of genetic, environmental, and physiological factors. They contain a lower dose of psilocybin than magic mushrooms, resulting in a short, yet impactful trip.