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Psychedelic Drug an overview

Thus, the psilocybin state is characterized by a larger repertoire of states (i.e., novel motifs that are exclusive to the psychedelic state). Early autoradiographic studies by Jueptner and Weiller indicated that perisynaptic activity, representing primarily input and local processing in the cortex, rather than cell bodies, accounts for the major part of cortical metabolic energy demands. Consistent with that finding, simultaneous measurement of intracortical activity and fMRI in the nonhuman primate has demonstrated that local field potential generated by a local neuronal network is more closely related to the BOLD signal than multiunit activity of the same network (Logothetis et al., 2001). Arvanian et al. carried out a study in which rats received a staggered double hemisection at postnatal day two of the left hemicord at T11 and the right hemicord at T12. A second group had a complete transection at T11 , with a third group serving as a sham-operated control.

Schmid et al. tested whether 5-HT2A receptor regulation by β-arrestins contributes to serotonergic responsiveness in vivo by comparing WT mice with mice that lack β-arrestin-2. Most recently, Leth-Petersen et al. identified the basis for the high first-pass effect of NBOMe compounds and the likely basis for their inactivity after oral administration. Using in vivo studies in pigs, they determined that the 5-methoxy of the trisubstituted phenyl ring is rapidly O-demethylated. After intravenous administration of 25B-NBOMe [N-(2-methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (Cimbi-36)] to a pig, analysis revealed that plasma levels of the parent drug rapidly declined, with a new metabolite rapidly appearing and accumulating in plasma. At the 30-minute mark, there was more than twice as much of this metabolite present in plasma as there was of the parent compound.

Animal studies of effects of psychedelics on time perception have been reported, a few of which will be briefly discussed here. Two studies of time perception after psilocybin administration to humans have also been reported and are also reviewed here. To further characterize the role of 5-HT1A/2A receptors in visual processing, Kometer et al. assessed the effect of psilocybin (125 and 250 μg/kg) versus placebo on spatiotemporal dynamics of modal object completion in 17 healthy volunteers. Modal object recognition refers to the illusory perception of object boundaries and their enclosing surface when there is no direct sensory information to depict those boundaries or surfaces. The authors employed visual evoked potential recordings in conjunction with topographic mapping and source analysis.

Only the 5-HT2A–selective antagonist blocked the DOI-induced antipunishment effect, suggesting that the anxiolytic effect of DOI was mediated through the 5-HT2A receptor. The authors discuss many possible mechanisms whereby 5-HT2A receptor activation could affect other neurotransmitter systems known to be involved in anxiety, such as GABA or noradrenergic pathways, but the mechanism through which DOI exerts an anxiolytic effect remains to be elucidated. In another study, Dave et al. were able to relate the production of head bobs to 5-HT2A receptor density in the cortex. BOL and MDL11939 were injected subcutaneously prior to DOI administration to block acute effects of DOI or were given as eight daily injections for studies of chronic effects on 5-HT2A receptor density. The number of head bobs induced by DOI was significantly blocked by pretreatment with MDL11939 or BOL.

They demonstrate that DOI disrupts cortical activity by reducing low frequency oscillations and by desynchronizing pyramidal discharge from active phases of slow oscillations. Slow oscillatory activity reflects alternating periods of activity and silence (“up” and “down” states) of cortico–thalamo–cortical networks that result from synchronized changes in membrane potential and synaptic activity of neuronal ensembles. This view is consistent with the information integration theory of consciousness , which proposes that the thalamus and thalamocortical system play a key role in integrating information and ensuing consciousness. Psychedelics may alter thalamocortical transmission by stimulating 5-HT2A receptors located in several key components of the CSTC loops (Vollenweider et al., 2007; Geyer and Vollenweider, 2008). The field of cognitive neuroscience is addressing the challenge of attempting to understand consciousness and how it arises within the brain. Surely the psychedelics, one of the most potent drug classes known that alter consciousness, should play an increasingly important role in that investigation.

The reduction in the P and C scores was significant after the low, medium, or high dose, whereas the reduction in the Q score was significant only after the peak effect of the high dose of psilocybin. Psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30-millisecond ISI, but not with the concomitant increases in PPI observed at long ISIs. Psilocybin also produced a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia. Thus, Lee et al. measured H-reflex amplitude after a standardized incomplete contusive SCI in rats and measured the H-wave/M-wave ratio. To study the role of 5-HT2 receptors in the response, they carried out experiments in which they administered either intrathecal DOI or a 5-HT2A antagonist.

The desensitization of 5-HT2A receptors is most likely attributable to post-translational modifications of the receptor (e.g., phosphorylation), Gαq or Gα11 proteins, altering the 5-HT2A receptor to G protein interface. Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD.

Behavioral responses were recorded and high-density electrical mapping with source analysis was used, allowing for the measurement of the spatiotemporal brain dynamics of visual modal object completion and its association with the appearance of visual hallucinations. Imaging studies have provided evidence that the intermediate lateral occipital complex as well as the early visual area V2 probably play a major role in modal completion. Psychedelics Electrophysiological studies have demonstrated that modal object completion of simple figures such as Kanizsa figures is predominantly indexed by modulation of the N170 component (see references in Kometer et al., 2011). The LC sends noradrenergic projections to the cortex, where α1 adrenergic and serotonin 5-HT2A receptors both share a similar laminar distribution and similar signaling pathways in pyramidal cells.

Many psychedelics are classified under Schedule I of the United Nations Convention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses. In addition, many countries have analogue laws; for example, in the United States, the Federal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to illicit or prohibited substances if sold for human consumption. Aldous Huxley had suggested his own coinage phanerothyme (Greek phaneroein- "visible" and Greek thymos "soul", thus "visible soul") to Osmond in 1956. Recently, the term entheogenic has come into use to denote the use of psychedelic drugs, as well as various other types of psychoactive substances, in a religious, spiritual, and mystical context.