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Altering Perceptions on Psychedelics Harvard Medicine magazine

Wittmann et al. carried out a study to elucidate the role of the serotonin system in time perception and temporal behavior. Theirs was the first study to systematically assess the effect of psilocybin on timing performance on standardized measures of temporal processing. They used a placebo-controlled, double-blind design in 12 healthy volunteers, administering placebo, a medium psilocybin dose of 115 μg/kg, or a high psilocybin dose of 250 μg/kg. The standardized measures of temporal processing included the temporal reproduction, sensorimotor synchronization, and tapping speed . Using double in situ hybridization, Santana et al. performed a quantitative study of the expression of α1A, α1B, and α1D adrenergic receptors in pyramidal vesicular glutamate transporter 1–positive and GABAergic (GAD65/67–positive) cells of rat PFC. Given the common signaling pathways shared by 5-HT2A and α1 adrenergic receptors, they examined the coexpression of both receptors in the rat PFC using double in situ hybridization histochemistry.

In any event, differences in neuronal activity indices , and differences in the intensity, dynamics, and content of psilocybin-induced symptoms could potentially account for these apparent discrepancies. The resting state networks that exhibited the most significant changes correspond to higher brain systems such as the DMN, executive control, and attention networks, and not primary sensory and motor networks. The authors note that the increased amplitude fluctuations in the hippocampus are particularly intriguing considering early depth EEG studies that recorded similar abnormalities in hippocampal activity after LSD and mescaline (Schwarz et al., 1956; Monroe and Heath, 1961).

Studerus et al. reported that nearly 40% of the participants in their laboratory studies of psilocybin claimed positive long-term changes in aesthetic experience and in their relationship with the environment (i.e., nature) after their psilocybin sessions. At 8–16 months after psilocybin sessions, more than 60% of subjects rated the experience as “very enriching,” and more than 90% described it as enriching to at least a medium degree. These effects occurred despite the fact that no attempt was made in their experiments to optimize conditions for a spiritual or mystical experience, which contrasts with the setting and preparations used in the two Griffiths studies cited above. Given the robust alterations of perception and consciousness produced by psychedelics and their medicinal and religious importance in some traditional cultures, it has been hypothesized that their ingestion influenced human evolution.

MDL11939-treated animals also achieved a higher rate of conditioned response acquisition compared with controls. Animals who began acquisition training 8 days after the last MDL11939 injection, at a time when 5-HT2A receptor levels would have returned to baseline, demonstrated no significant difference from controls. Surprisingly, LSD and BOL, which produced 33% and 55% decreases in 5-HT2A receptor density, respectively, had no effect on conditioned response acquisition. Halberstadt et al. tested a series of phenylalkylamine psychedelics in C57BL/6J mice using the BPM to determine whether they increased locomotor activity by activating the 5-HT2A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine , 2,5-dimethoxy-4-n-propylamphetamine , 2,4,5-trimethoxyamphetamine (TMA-2), and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity, whereas a nonhallucinogenic phenethylamine DOTB did not alter activity at any dose tested.

P. argentipes at a dose of 0.1–1 g/kg significantly reduced the number of buried marbles without reducing locomotor behavior. This dose of psilocybin was higher than that calculated to be contained in the effective dose of P. argentipes, and the authors speculate that perhaps other tryptamine components of the mushrooms may also be involved in the effect. All of these results, taken together, along with the structural and functional knowledge that currently exists for the claustrum, strongly indicate that the claustrum must be seriously considered as a previously unrecognized target for the action of the psychedelics. There has been increasing interest in the functional role of the claustrum, particularly since the Crick and Koch proposal, and a more intense research focus on this area of the brain seems likely to lead to very important results.

These experiments were very strong evidence that 5-HT2A receptor signaling was not generating a retrograde messenger. Using a peptide composed of the i3 loop amino acids 252–328, purified and activated RSK2, and [γ32P]ATP, Strachan et al. were able to demonstrate robust incorporation into the purified i3 loop protein. The residue within i3 that was phosphorylated was then identified from among the 18 potential Ser/Thr kinase phosphorylation sites using trypsin digestion and tandem mass spectrometry. The investigators then created S280A and S314A mutants, rendering these sites phosphorylation deficient. Activated RSK2 incorporated into both WT and the S280A mutants to a similar extent, but the S314A mutation completely abolished RSK2 phosphorylation compared with the WT peptide. These studies were all carried out with the synthetic i3 peptide; the next experiments focused on the intact full-length 5-HT2A receptor, where it was confirmed that Ser314 was indeed phosphorylated.

In another experiment, they used GTPγS, a nonhydrolyzable GTP analog, to render G protein–mediated responses irreversible. AMS induced a small inward current that recovered on agonist removal from control cells, as well as an irreversible inward current in cells loaded with GTPγS. Importantly, however, the sEPSC increases for both types of cells recovered after agonist removal, something that would not be expected in cells with irreversible signal production by GTPγS.

The amphetamines also produced a more robust in vivo rat HTR, mediated through the 5-HT2A receptor. Although there is very strong evidence that Psychedelics act by an agonist or partial agonist action at 5-HT2A receptor, the past 15 years has seen increasing awareness of the fact that GPCRs can and do couple to more than one intracellular signaling pathway. That is, although the canonical signaling pathway for the 5-HT2A receptor is Gαq coupling and activation of PLC, it is now known that other signaling pathways can be activated. The relative activation of these different pathways is ligand dependent, has most often been referred to as “functional selectivity” (Urban et al., 2007), and has recently been reviewed (see Seifert, 2013; Zhou and Bohn, 2014). Both LSD (0.025 mg/kg, i.p.) and DOB (0.25 and 0.5 mg/kg, i.p.) induced significant shaking behavior, with LSD being about 10-fold more potent than DOB, although the maximal effect of LSD was much lower.

By contrast, the disruption of PPI by LSD was significantly attenuated by MDL11939, again illustrating that the disruption of PPI induced by psychedelics is mediated by activation of the 5-HT2A receptor. It had generally been assumed that the canonical PI hydrolysis signaling pathway was the most relevant for the behavioral actions of psychedelics, but there are certain problems with this hypothesis. First, it is well known that LSD has very low efficacy in activating PI turnover (Sanders-Bush et al., 1988; Egan et al., 1998). Subsequently, Rabin et al. pointed out the lack of correlation between potency in drug substitution in rats trained to discriminate LSD or DOM from saline and efficacy in stimulating PI hydrolysis. They concluded that 5-HT2A–mediated stimulation of PI hydrolysis does not appear to be the sole critical signaling mechanism involved in the discriminative effects of hallucinogens. As this review was being finalized, Nichols and Martin reported that serotonergic hallucinogens preferentially activate subsets of cortical neurons, interneurons, and glial cells in the rat claustrum and induce rapid redistribution of 5-HT2A receptor protein within neurons.

As you explore the promising world of psychedelic healing, MAPS is your partner for science-based information, learning, and experiences. Franciotti supported the psilocybin legalization measure in Colorado, telling NBC News this was the state’s chance to provide its residents with alternative treatment options and push back against existing drug policy. By 2017, the FDA had designated MDMA — also known as ecstasy and molly — as a “breakthrough therapy” for its potential to treat post-traumatic stress disorder more effectively than existing options. Of the 12 million adults in the U.S. who have PTSD in a given year, 5 in 10 respond to talk therapy and 4 in 10 are estimated to reach remission using medication alone, according to the U.S. Administering psychedelics can be a daylong experience, in which the patient is constantly monitored by trained practitioners.