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California could decriminalize psychedelics under new bill Los Angeles Times

LSD produced a pronounced alteration in waking consciousness that lasted for 12 hours and included visual hallucinations, audio-visual synesthesia, and positively experienced derealization and depersonalization phenomena. Compared with placebo, LSD increased subjective well-being, happiness, closeness to others, openness, and trust. Increases in blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine also were measured. The authors also described subjective effects on mood that were similar to those reported for MDMA that might be useful in psychotherapy.

SB 58 would allow only plant-based hallucinogens, such as psilocybin, the active ingredient in “magic mushrooms,” and dimethyltryptamine, or DMT, which is found in some plants used to brew ayahuasca. Other naturally occurring psychedelics that would be allowed under the bill include ibogaine, a psychoactive alkaloid found in the iboga shrub, and mescaline found in cacti other than peyote. Tweaking molecules in the laboratory can be a humbling experience, says Jackie von Salm, cofounder of the Tampa, Florida-based startup Psilera, which is using machine learning to help it identify potentially beneficial compounds.

Fortunately, the key brain target for psychedelics, the serotonin 5-HT2A receptor, is a prominent player in the brain physiology of all mammalian species and its activation can produce measurable behaviors. Other ancillary receptors that may be involved in the actions of psychedelics, such as the serotonin 5-HT1A and glutamate mGlu2 receptors, also appear to have similar roles in the brain physiology of lower mammalian species. In that respect, animal models have most often been used to confirm an effect that is already known in humans. For example, when a new “research chemical” appears on the illicit market and becomes popular for recreational use, animal models can be used to understand how this chemical compares with other known psychedelics. A sufficiently large database of known compounds in mouse and rat models has developed over the years so that it may be possible in some cases to predict whether a new chemical substance will possess psychedelic activity based on a behavioral readout. Research over the past 2 decades has clearly shown that psychedelics enhance glutamatergic transmission in the cortex at the neuronal level and also in behavioral responses.

The mGlu2/3 agonist LY was equipotent in suppressing both 5-HT–induced EPSCs and DOI-enhanced electrically evoked late EPSPs. Their findings were consistent with the hypothesis that mGlu2/3 receptors function as inhibitory autoreceptors in cortical glutamatergic terminals that are positively regulated by activation of 5-HT2A receptors. Using autoradiography, these authors further demonstrated that the highest density of mGlu2/3 receptor binding in the mPFC is expressed in cortical layers I and Va, in a laminar distribution similar to 5-HT2A receptor expression.

In humans, cross-tolerance occurs between mescaline and LSD and between psilocybin and LSD (Isbell et al., 1961). Tolerance and cross-tolerance to hallucinogens also develops in animal models (Freedman et al., 1958; Smythies et al., 1966; Appel and Freedman, 1968; Winter, 1971; Freedman and Boggan, 1974; Wallach et al., 1974; Trulson et al., 1977; Commissaris et al., 1980). In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M [-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol] . As discussed in the section on mouse models later in this review, the mouse head twitch has shown a high correlation with human psychedelic activity.

The Johns Hopkins Center for Psychedelic and Consciousness Research is leading the way in exploring innovative treatments using psilocybin. The molecular structure of psilocybin, a naturally occurring psychedelic compound found in 'magic mushrooms,' allows it to penetrate the central nervous system and the scientific and medical experts are just beginning to understand its effects on the brain and mind and its potential as therapeutics for mental illnesses. Despite the contrary perception of much of the public, psychedelic drugs are not addictive and are physiologically safe. Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine, which is produced in over 200 species of fungi. Of the Classical psychedelics psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences, although all psychedelics are capable of doing so to variable degrees. Additionally, replacement of a methyl group at the dimethylated nitrogen with an isopropyl or ethyl group yields 4-HO-MIPT and 4-HO-MET, respectively.

Saline, R-DOI (0.01, 0.1, or 0.3 μg/kg), and TNF-α (10 mg/kg) were administered intraperitoneally to C57BL/6J mice, with R-DOI given 30 minutes prior to TNF-α. The highest dose of R-DOI administered in that study (0.3 mg/kg) is the lowest dose that can be behaviorally detected by mice (Smith et al., 2003). R-DOI was found to block TNF-α–induced increases of these inflammatory markers in the vasculature .

The London-based company April19 Discovery was launched by computer scientists two years ago specifically to design new psychedelic drugs. Comparative ethnographic evidence reveals that one of the main shamanistic uses of Psychedelics is for divination, i.e., for procuring otherwise unattainable information (Dobkin de Ríos, 1984; Schultes et al., 2001; Rätsch, 2005). Divination practices are required for important collective decisions in many small-scale societies . Ingestion of a vision-inducing material is a common method to gain privileged nonempirical knowledge for decision-making .