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Psychedelic Drug an overview

Their highest density is found in limbic regions of the brain such as the hippocampus (Hamon et al., 1990), areas where emotion and affect would be modified by agonist and antagonist drug interactions. Autoradiographic studies demonstrated the presence of 5-HT1A receptors in layer V of the rat PFC (Glaser et al., 1985; Pazos and Palacios, 1985), and neurons in the human neocortex contain mRNA for the 5-HT1A receptor, with pyramidal cells in layer III more heavily labeled than those in layer V (Burnet et al., 1995). González-Maeso et al. then compared effects on in vivo gene expression of three agonists evaluated in the HTR. Transcript levels in the mouse somatosensory cortex 1 hour after agonist injection were compared by quantitative reverse-transcription polymerase chain reaction to those from vehicle-injected controls. Thirteen transcripts showed significant changes after at least one agonist, with each agonist showing a unique and reproducible transcriptome fingerprints. Of the genes identified, only early growth response protein 1 (egr-1), early growth response protein 2 (egr-2), and period-1 were similarly activated by DOI and LSD but were unaffected by lisuride.

On Good Friday in 1962, 20 Christian theological student volunteers attended a 2.5-hour religious service in Boston University’s Marsh Chapel. The setting and preparation of the subjects was designed to optimize a spiritual or mystical experience. In a double-blind procedure, subjects were given either an oral dose of 30 mg psilocybin, or a 200-mg placebo dose of nicotinic acid, administered in identical capsules. Based on responses to a variety of instruments and questionnaires, subjects who received psilocybin had experiences that were indistinguishable from those experienced by mystics. Doblin reported a follow-up to the Pahnke study in 1989 and was able to locate and interview 19 of the original 20 experimental participants.

Hansen has compiled dozens of examples of shamanic trickery from the anthropological literature, adding that they may promote healing. As Cardeña and Beard argue, therapeutically speaking, pretense, role-playing, and performed illusions can go a long way in impressing onlookers, much more so than words alone. Undoubtedly, illusory cures can have concrete and real effects, as demonstrated by the placebo effect . The use of Psychedelics to enhance suggestibility could have conferred a number of selective advantages in enhancing the ritual-induced placebo and hypnotic effects , as well as through inducing shared world views, and enhancing stress-reducing spiritual adaptations.

Minuzzi et al. used raclopride PET in living pig brain to examine the effects of LSD on dopamine D2/3 receptor binding. They observed an unusual progressive displacement of the PET ligand that only reached a maximum 240 minutes after LSD administration. The authors speculate that “This time course seems consistent with the prolonged psychoactive action of LSD in humans.” Optimal receptor occupancy might be expected fairly quickly after intravenous LSD administration, however, not 4 hours later.

A group of Johns Hopkins researchers was the first to obtain regulatory approval in the United States to resume research with psychedelics in healthy volunteers who had no previous experience with psychedelics. Most psychedelics produce tolerance quickly, meaning you need to take larger doses to get the same effect. The effects of mixing psychedelics with other drugs, including alcohol, prescription medications and over-the-counter medicines, are often unpredictable. A 2022 study recognized signatures of psilocybin microdosing in natural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules. Psychedelics have a long history of use in traditional medicine and traditional religion, for their perceived ability to promote physical and mental healing.

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. The results of Delille et al. indicate that the functional interaction of mGlu2 and 5-HT2A receptors may not be mediated by heterodimer interaction. The selective mGlu2/3 agonist LY also attenuated the DOI-induced increase in c-fos mRNA in rat mPFC slices (Zhai et al., 2003). DOI enhanced the amplitude of the complex EPSP evoked in pyramidal neurons by 30%, an effect that was blocked by LY379268, demonstrating that excitatory glutamatergic responses of prefrontal cortical pyramidal neurons are positively and negatively modulated by agonists at 5-HT2A and mGlu2/3 receptors, respectively.

In the rat frontal cortex, 5-HT–enhanced spontaneous inhibitory postsynaptic potentials in pyramidal cells can be produced through activation of 5-HT2A receptors located on GABAergic interneurons . Thus, activation of 5-HT2A receptors in the cortex can produce both excitation and a feed-forward inhibition of cortical pyramidal cells. However, in current-clamp recordings in acute rat PFC slices, Béïque et al. noticed a subpopulation of large neurons in deep layers that was highly sensitive to 5-HT and that responded with strong membrane depolarizations capable of initiating spiking activity. Thus, their results indicated that within the cortex, there is a subpopulation of 5-HT2A–expressing cells that when excited by a 5-HT2A agonist leads to increases in the frequency of sEPSCs in layer V pyramidal neurons.

It has been recognized for some time that psychedelics (i.e., 5-HT2A agonists) increase levels of cortical glutamate (Aghajanian and Marek, 1997, 1999b; Béïque et al., 2007; also see the earlier section on glutamate in this review). Vollenweider and Kometer suggested that indirect activation of glutamate networks by classic psychedelics may enhance neuroplasticity through stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors and subsequent increase in the level of BDNF. Serum BDNF levels are abnormally low in depressed individuals and treatment with antidepressants is known to normalize BDNF levels (Sen et al., 2008). Serotonin neurotransmission plays a key role in amygdala activity (see earlier section III.G. in this review on 5-HT2A receptor expression in the amygdala) and may be implicated in the pathogenesis of depression.

Likewise, when psilocybin containing fungi were consumed in large enough quantities they caused dramatic alterations in perception and consciousness, drawing attention to their properties and their positive and negative effects on well-being. As a consequence, memories were formed regarding the identification of these species and the resulting effects of their ingestion. As has been hypothesized for non-human primate self-medicative behaviors , traditions of medicinal use of psychedelic mushrooms may have started as a result of ill, hungry hominins trying new foods during periods of extreme food scarcity, and upon recovery, associating their improved health with the new dietary item. Subsequently, local enhancement (i.e., naïve individuals having their attention drawn to species used by others) and social learning could have played a role in spreading the behavior though the group.

While observational evidence shows non-human mammals using plants for their psychoactivity (Siegel, 2005; Forbey et al., 2009) most animals are not particularly fond of mind-altering materials. This shows that human ancestors – in a taxonomically distinctive way – constructed a niche that functionally and adaptively integrated certain mind-altering substances (i.e., hallucinogens, stimulants, and narcotics) into culture. Niche-construction and gene-culture coevolutionary processes explain how dietary and societal incorporation of psychedelics may have become evolutionarily significant. Crucially, divination is a ritual and a tradition involving an ongoing dialog with more-than-human agents (Curry, 2010; Espírito, 2019).