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Psychedelic drug Wikipedia

As Ray pointed out, different molecules may also have significant affinity for other types of brain receptors. 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. DOI (1 mg/kg) significantly reduced population activity in OFC compared with baseline, with larger doses of DOI producing greater population suppression.

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. This metabolite was definitively identified as the 5-O-glucuronide using liquid chromatography/mass spectrometry and chemical synthesis. Evidently, the highly hydrophobic nature of the N-benzyl phenethylamines readily targets them to the mixed function oxidases in the endoplasmic reticulum, where they are efficiently 5-O-demethylated and then very quickly glucuronidated. Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs.

Evidence from animal studies suggests that some psychedelics may alleviate anxiety, in particular DOI, a nonselective 5-HT2A/2C agonist, which has been perhaps the most widely studied drug in this class. The four-plates test–retest paradigm in mice is an animal model of anxiety that is broadly sensitive not only to benzodiazepines but also to nonbenzodiazepine-type compounds. DOI was first shown to possess an anxiolytic effect in this model by Nic Dhonnchadha et al. . Subsequently, Ripoll et al. assessed the ability of the four-plates to distinguish the anxiolytic effect of DOI from diazepam, alprazolam, paroxetine, and venlafaxine. In contrast with the other drugs, DOI was the only one able to restore the number of punished crossings to the same value seen in naïve saline-treated mice.

Halberstadt and Geyer reviewed the evidence and concluded that the 5-HT1A receptor can play an important role in the behavioral effects of tryptamine-type Psychedelics. Several examples illustrating the importance of 5-HT1A receptor activation in the action of tryptamine hallucinogens are provided in the later sections of this review on animal models, but two examples are provided now to illustrate how these conclusions were developed. Delille et al. subsequently coexpressed mGlu2 receptors in an inducible manner in a constitutive 5-HT2A background in HEK-293 cells. They determined the reciprocal influence of the two receptors on receptor expression and measured intracellular Ca+2 as well as cAMP levels after stimulation with agonists, antagonists, psychedelics, and positive allosteric modulators.

Celada et al. extended their earlier approach by showing the effect of DOI on burst firing and LFPs, in which firing rate was increased by DOI. Yet DOI markedly reduced the amplitude of low frequency oscillations in the mPFC, an effect that was completely blocked by M but was not attenuated by thalamic lesions, supporting an intracortical origin for the effects of DOI. 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. They simultaneously recorded BOLD and electrophysiological activity in primary visual cortex V1 of anesthetized monkeys while inducing a dissociation of MUA from LFP activity by local injections of the 5-HT1A agonist BP554.