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California could decriminalize psychedelics under new bill Los Angeles Times

Subjective effects began within seconds, allowing the capture of the transition from normal waking consciousness to the psychedelic state. Approximately 6 minutes after the infusion, participants performed a visuomotor task designed to elicit stimulus-induced γ band oscillations in the primary visual and motor cortex. Five minutes of resting MEG was recorded; the participant was then infused with psilocybin over 60 seconds and 5 minutes of resting MEG was recorded immediately after infusion. The authors reported decreased oscillatory power across a broad frequency range after psilocybin, mainly localized to association cortices, with marked decreases in areas of the DMN such as the PCC.

We know now that there is no “seat” of consciousness, and that consciousness is not a property of a single brain location but more likely arises as the result of dynamic interactions among widely distributed groups of neurons that integrate a very large number of sensory inputs and motor responses occurring in parallel. Edelman emphasized that consciousness concerns the rapid integration of signals from a great variety of modalities and submodalities to create a unified, coherent scene or idea. When one considers all of the key brain areas noted in this review that either express or are directly affected by 5-HT2A agonist interactions, it should be no surprise that the psychopharmacology of psychedelics is so complex. Both DOI and 5-HT increased proliferative activity of MC3T3-E1 cells in a concentration-dependent manner, an effect that was blocked by ketanserin. DOI-induced cell proliferation and phosphorylation of ERK1 and ERK2 was blocked by PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and U0126 [1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene], selective inhibitors of mitogen-activated protein kinase kinase .

The average age of the samples, both of which contained mescaline, dated to 3780–3660 BCE (El-Seedi et al., 2005). This evidence supports the use of peyote by Native North Americans as long ago as 5700 years (Bruhn et al., 2002). Classic psychedelics that have been extensively studied include LSD, shown earlier, mescaline, psilocybin, and N,N-dimethyltryptamine (Fig. 2).

It is known that cerebral vasoconstrictors can cause an increase in deoxyhemoglobin concentration, resulting in a decrease in the BOLD baseline resting signal (Mulderink et al., 2002). Thus, using hemodynamic neuroimaging signals as proxy measures for neuronal activity makes off-target effects, including nonhallucinogenic and peripheral actions mediated by other receptor subtypes, an important consideration if a drug has vasoactive properties in addition to its effects on neurons. A recent fMRI study, however, reported an overall decrease of brain activity in the medial frontal cortex after intravenous administration of psilocybin (Carhart-Harris et al., 2012). Subjective observations support what might be described as a loosening of the “sense of self,” or a loss of ego structure, with feelings of unity and oneness with others and the world (Dittrich, 1998; Griffiths et al., 2006). As will be discussed shortly, the fMRI data from this study have been reanalyzed at least twice to develop further hypotheses about the psychedelic state. In the study by Vollenweider et al. , effective doses of psilocybin produced a global increase of CMRglu, with significant and most marked increases in the frontomedial and frontolateral cortex (24.3%), ACC (24.9%), and temporomedial cortex (25.3%).

Although several attempts have been made, starting in the 19th and 20th centuries, to define common phenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist. At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes are common.

Hanes reported on a 27-year-old male patient with body dysmorphic disorder who spent up to 4 hours every day checking his appearance in the mirror. The intensity of his somatic distress markedly improved on occasions when he had ingested psilocybin mushrooms, noting that at those times, when he looked in the mirror, he no longer appeared deformed. Where available, Ki values for cloned human 5-HT2A and 5-HT2C receptors are also listed for comparison. Early experiments found that LSD potently suppressed cell firing in the dorsal raphe nucleus if it was given systemically (Aghajanian et al., 1968, 1970) or applied by microiontophoresis directly to the raphe cell bodies (Aghajanian et al., 1972).

Pompeiano et al. also found 5-HT2A mRNA in the reticular nucleus, lateral geniculate, and zona incerta, but none in the midline or intralaminar nuclei. The thalamus, along with the amygdala, represents the major source of glutamate afferents innervating the neocortex. The thalamus not only processes somatosensory inputs, but it also receives afferents from both the raphe nuclei and the LC . It is interesting that very small bilateral lesions in the intralaminar nuclei, which project axons widely to all cortical areas, can lead to permanent loss of consciousness . In GABAergic interneurons, 5-HT2A mRNA was expressed in 45%–69% of parvalbumin and 61%–87% of calbindin-positive cells.

The lower density of 5-HT2A receptors correlates with changes in hallucinogen-like behavioral and cellular responses that require expression of the 5-HT2A receptor in the mouse brain cortex. Thus, chronic treatment with LY decreases LSD-dependent head-twitch behavior as well as LSD-dependent induction of expression of c-fos, egr-1, and egr-2 in the mouse somatosensory cortex. In conclusion, data from Moreno et al. support the hypothesis Psychedelics that chronic blockade of mGlu2 receptor–dependent signaling downregulates 5-HT2A receptor binding in the mouse somatosensory cortex and its hallucinogen-like cellular signaling and behavioral effects. Given that mGlu2 receptors are located presynaptically, their blockade would lead to excessive glutamate release, potentially resulting in feedback downregulation of 5-HT2A receptors expressed on the pyramidal apical dendrites.

One of the depth electrodes included a contact in the extreme capsule in close proximity to the anterior insular cortex and closest to the claustrum. Stimulation of this electrode led to immediate impairment of consciousness, 10 of 10 times, with the patient returning to baseline when the stimulation was stopped. A second explanation for the increase in cortical glutamate after hallucinogens was offered by Lambe and Aghajanian , who suggested that 5-HT2A receptor activation on postsynaptic cells might lead to release of a retrograde messenger. This substance would then diffuse out from the postsynaptic membrane and block K+ channels on presynaptic glutamate terminals, leading to glutamate release. Neither of these hypotheses survived further scientific scrutiny, however, because the ultimate source of glutamate was later identified by Béïque et al. , as discussed later. Buchborn et al. concluded that the differential receptor adaptations observed for DOB and LSD, respectively, indicate that tolerance to serotonergic hallucinogens can arise at two levels.