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Schatz, Booker Call For More Research On Therapeutic Potential Of Psychedelic Drugs U S. Senator Brian Schatz

Although it is believed that dopaminergic systems are not directly involved in the mechanism of action of classic serotonergic hallucinogens, LSD is a unique agent with known high affinity and agonist activity at dopamine receptors (e.g., see Watts et al., 1995). Marona-Lewicka et al. first demonstrated that the effect of LSD as a training stimulus occurs in two temporal phases. When rats are trained to discriminate 0.08 mg/kg LSD, given 30 minutes prior to training , the stimulus generalizes to classic Psychedelics and is blocked by 5-HT2A receptor antagonists. If, however, LSD (0.16 mg/kg) is administered 90 minutes prior to training , the stimulus is no longer blocked by 5-HT2A antagonists, does not generalize to classic psychedelics, and is blocked by dopamine D2-like antagonists. In rats trained to discriminate LSD administered 90 minutes prior to training, the cue generalized to the dopamine D2-like agonists apomorphine, N-propyldihydrexidine, and quinelorane. Although a slightly larger dose of LSD is required to maintain the salience of the LSD cue out to 90 minutes, if the higher dose of LSD is administered 30 minutes prior to training, the cue is still found to be mediated by 5-HT2A receptor activation.

The mGlu5 negative allosteric modulator MPEP (30 mg/kg) also significantly increased locomotor activity in WT mice, measured as distance traveled, during the first 50 minutes of the 1-hour test session, but had no effect on activity in mGlu5 KO animals. DOM (0.5. mg/kg) increased locomotor activity in WT mice, but only during the third 10-minute block of testing, whereas DOM significantly and markedly increased locomotor activity in all six 10-minute blocks of testing in mGlu5 KO mice. Locomotor hyperactivity in mGlu5 KO mice was significantly attenuated by 1.0 mg/kg M100907, and M completely blocked the hyperactivity induced by MPEP. One possible explanation offered by Halberstadt et al. is that the loss of mGlu5 signaling may lead to increased 5-HT release, which activates the 5-HT2A receptor (see Stachowicz et al., 2007). The DOM potentiation of activity in mGlu5 KO mice could also be attributed to enhanced sensitivity of 5HT2A receptors in these mice, and the authors suggest that the mGlu5 receptor may regulate responses to 5-HT2A activation. Thus, they conclude that the mGlu5 receptor acts to attenuate 5-HT2A receptor–induced hyperactivity, and either the loss of the mGlu5 receptor, or a negative allosteric regulator of mGlu5, essentially unmasks the influence of the 5-HT2A receptor.

One can easily imagine that each and every structural change made in a series of agonist molecules might lead to distinct ligand-receptor complexes (i.e., a ligand-dependent state) and that these different complexes may lead to activation of different subsets of intracellular signaling molecules. Thus, although functional selectivity has already been demonstrated for the 5-HT2A receptor, it presently remains unknown which particular signaling pathway may be most relevant for the actions of psychedelics. Therefore, when a molecule is classified as a 5-HT2A agonist, what exactly does that mean in terms of cellular responses? Furthermore, how will different proportions of intracellular signaling events affect the qualitative aspects of a “psychedelic” intoxication? Damjanoska et al. examined levels of Gαq, Gα11, RGS4, and RGS7 proteins after chronic R-(−)-DOI treatment of rats.

Bonson K. Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Nonsignificant trends towards improvements in mood were observed, perhaps because of the small numbers and relatively low dose of psilocybin used. One was the development of neuroimaging and psychopharmacological studies conducted in healthy volunteers and the second from some small exploratory clinical studies.

Short agonist treatment also led to desensitization of 5-HT2A receptor–mediated phosphoinositide hydrolysis in transfected cell lines (Ivins and Molinoff, 1991; Roth et al., 1995; Gray and Roth, 2001). However, until we understand the fundamental nature of consciousness and its underlying neuronal substrates, as well as the unconscious, it will not be possible to scientifically test Grof’s hypothesis. What can be discussed are the findings that point to involvement of specific receptors in certain brain areas that lead to the overt effects of psychedelics. In addition, recent brain scanning technologies, including PET, fMRI, EEG, magnetoencephalography , and pharmacological magnetic resonance imaging , have also allowed the identification of key brain areas that must be involved in the actions of psychedelics.

Therefore, in smaller scale societies, psychedelic use is intimately linked with strategizing and decision-making through its central role in diagnostic, forecasting, and interventionist forms of divination. The fact that psychedelics induce an experience of well-being may have favored learning of their use by humans . Rodriguez et al. suggest hallucinogenic plants were initially used for the treatment of diseases due to their antiparasitic properties. As argued by Ferreira Júnior et al. , the overlap between medicinal and hallucinogenic uses may indicate that the initial consumption of a plant for medicinal purposes lead to the discovery of its use as a hallucinogen.