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Psychedelics Alcohol and Drug Foundation

Shaw and Woolley later modified their hypothesis to include the possibility that LSD might mimic the actions of serotonin. Numerous studies in the subsequent decade examined the possibility that LSD blocked the actions of serotonin, but it was a concept that proved untenable. It was clear, however, that LSD did have a potent effect on brain serotonin systems, elevating whole brain serotonin content and reducing brain levels of the major metabolite of serotonin, 5-hydroxyindole acetic acid (Rosecrans et al., 1967). By way of illustration, in 1952, there were only 10 publications in the National Library of Medicine concerning serotonin, nearly all of them dealing with some aspect of its ability to constrict blood vessels. Only 8 years later, in 1960, there were 300 publications on serotonin, 35 of which were now focused on studies of serotonin in the brain.

Borderline personality disorder is a high-risk model for studying suicidal behavior and is a contributing factor in more than one-third of completed suicides (Soloff et al., 2007, and references therein); indeed, BPD is one of the most lethal psychiatric disorders. Soloff et al. used altanserin, a high-affinity 5-HT2A antagonist, to conduct PET imaging studies of 5-HT2A receptor binding in 14 female impulsive BPD subjects with recurrent suicidal or self-injurious behaviors who were considered at high risk for future suicide. Significantly increased 5-HT2A binding was found for BPD patients in the hippocampus, medial temporal cortex, and occipital cortex compared with healthy controls.

Although LSD was most widely used and therefore has led to the greatest number of HPPD cases, it is clear that other hallucinogens also can evoke the syndrome. For example, Espiard et al. reported HPPD in an 18-year-old man after mixed intoxication with psilocybin and cannabis. Ikeda et al. reported flashbacks after use of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) by a 35-year-old man without a previous psychiatric history. He had used the substance six or seven times over 5 months but discontinued it after he had a bad trip, with anxiety, palpitations, auditory oversensitiveness, and visual distortions.

They recovered 11 functional brain networks, 7 of which showed postpsilocybin infusion decreases in oscillatory power in the frequency bands from which they were derived. A further four networks were identified that did not pass the significance criterion, but activity in these networks was consistently decreased by psilocybin. Wood et al. compared the effect of DOI with amphetamine and MK-801 on PFC neuronal activity in freely moving rats. They implanted microelectrode arrays in male rats and measured neuronal activity in the OFC and ACC. Their study was the first to investigate the effects of a psychedelic on cortical neurophysiology in awake animals. They analyzed neuronal population activity, LFP power, and correlations between spike-discharge power and LFP power.

The most significant limiting factor for survival after liver surgery and transplantation of a partial graft is the ability of the remnant liver to regenerate (Furrer et al., 2011, and references therein). Serotonin, derived from platelets, is thought to be involved in liver regeneration after major tissue loss. Platelets are major carriers of serotonin in the blood, and 5-HT2A/2C serotonin agonist DOI completely restored liver proliferation in thrombocytopenic mice (Lesurtel et al., 2006). Partial (70%) hepatectomy was performed in mice, in which platelet function was inhibited pharmacologically or platelets were depleted.

The caveat here, which drove much of the more recent drug development efforts, was to identify potent agonists that would not penetrate the CNS and thus would lack psychedelic activity. Clearly, highly 5-HT2A receptor–specific agonists would be most desirable, but thus far no such ligand has been identified. A very similar study was also just completed at NYU under the direction of Dr. Stephen Ross (S. Ross, personal Psychedelics communication), in which 29 participants with significant distress due to a cancer diagnosis were enrolled and randomized. The therapeutic approach and clinical setting were very similar to the one employed in the JHU study, the chief difference being the use of niacin as the placebo control in the NYU study, contrasted with the use of low-dose psilocybin, versus high-dose psilocybin in the JHU study.

In the study by Gouzoulis-Mayfrank et al. , psilocybin increased regional cerebral glucose metabolism in distinct right hemispheric frontotemporal cortical regions, particularly in the ACC, consistent with the findings of Vollenweider et al. . It remains to be determined whether the effects of R-DOI on these immune cells, and on its ability to prevent the development of asthma, involves blockade of TNF-α signaling. Together, each of these studies indicates that agonism of 5-HT2A receptors may be a novel small molecule steroid-sparing therapeutic strategy to treat inflammatory diseases that include asthma, atherosclerosis, and inflammatory bowel disease. Importantly, the doses of R-DOI necessary to produce these therapeutic effects are orders of magnitude lower than those necessary to influence behaviors.

In stage 1 (the initial double-blind group), the clinical response was 83.3% in the MDMA group versus 25% in the placebo group. Likewise, 10 participants in the MDMA group no longer met DSM-IV criteria for PTSD compared with only 2 in the placebo group. In stage 2 (a second open-label administration that was offered to the initial placebo group), the clinical response rate was 100% in the seven subjects, six of whom had failed to respond to placebo and one of whom had relapsed after an initial placebo response. A decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the MDMA group than for the placebo group. The rate of clinical response in the active treatment groups was 85% compared with 25% in the placebo group.

The authors suggest that their findings have implications not only for the pathophysiology of dysfunctional emotional biases, but they may also provide a framework to delineate the mechanisms underlying psilocybin’s putative antidepressant effects. Studerus et al. analyzed acute, short-, and long-term subjective effects of psilocybin in healthy humans. Again, using pooled raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008, their analysis included 110 healthy subjects who had received between one and four oral doses of psilocybin (45–315 μg/kg body weight). Psilocybin dose-dependently induced profound changes in mood, perception, thought, and self-experience, but most subjects described the experience as pleasurable, enriching, and nonthreatening.