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Johns Hopkins Center for Psychedelic and Consciousness Research

Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and divinatory rituals. These mushrooms were known as teonanacatl, meaning “god’s flesh” (Ott and Bigwood, 1978; Schultes and Hofmann, 1979). The use of various psychoactive plant materials and substances was common in pre-Columbian Mesoamerican societies, including the Olmec, Zapotec, Maya, and Aztec cultures (Carod-Artal, 2015). The powerful psychologic effect of LSD was accidently discovered in 1943 , followed only a decade later in 1953 by the detection of serotonin in the mammalian brain . The presence of the tryptamine moiety within LSD was also quickly seen to be the scaffold for the chemical structure of serotonin (Fig. 1). This can lead to panic and unpredictable behaviour, like running across a road or attempting suicide.

All subjects reported that the onset of drug effect was very rapid and intense, with a duration of effect lasting 10–15 minutes. Altered somatosensory, visual, auditory, and proprioceptive sensations were reported, with 14 of 15 subjects describing perceptual changes as the primary effect of the drug. The report describes a variety of effects on cognition, mood, memory, and spiritual or mystical experiences. Overall, subjects found the experience difficult to describe, yet most found it pleasant and positive.

This study adds to growing evidence for supporting further investigation of psychedelic-assisted treatment for alcoholism or substance abuse. Johns Hopkins researchers report that a small number of longtime smokers who had failed many attempts to drop the habit did so after a carefully controlled and monitored use of psilocybin, the active hallucinogenic agent in so-called "magic mushrooms,” in the context of a cognitive behavioral therapy treatment program. The publication "Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance" Psychedelics on the safety and enduring positive effects of a single dose of psilocybin is widely considered the landmark study that sparked a renewal of psychedelic research world-wide. Previous studies by Johns Hopkins Medicine researchers showed that psychedelic treatment with psilocybin relieved major depressive disorder symptoms in adults for up to a month. Now, in a follow-up study of those participants, the researchers report that the substantial antidepressant effects of psilocybin-assisted therapy, given with supportive psychotherapy, may last at least a year for some patients.

Another possibility, not considered by the investigators, is that these tryptamines might be taken up into serotonin neuron terminals and might displace stored intraneuronal serotonin, in a mechanism similar to a 5-HT releasing agent such as MDMA. The release of stored serotonin would enhance synaptic levels of 5-HT, potentially adding an additional component to the pharmacology of certain tryptamines. Ray reported on receptor screening of 25 hallucinogens and analogs by the National Institute of Mental Health Psychoactive Drug Screening Program, with affinities of 10 additional drugs taken from the literature. The 35 drugs of the study had very diverse patterns of interaction, which may underlie some of the qualitative psychopharmacological differences between the drugs. Functional effects of the various compounds were not studied, however, which would have strengthened the conclusions and given more detailed insight into the possible relevance of receptors where some of the tested drugs had relatively high affinity.

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. Psychedelics of plant extraction such as mescaline and psilocybin have been used for millennia in cultures all across the globe, but Western science was not introduced to them until 1897, when Arthur Heffter isolated mescaline. Hofmann also identified the active component of “magic” mushrooms as psilocybin.2This was also made available by Sandoz as Indocybin. It should be noted that psilocybin is in effect a prodrug, and is converted into the active ingredient psilocin in the body. Viswanathan and Freeman used a dual microelectrode arrangement to make simultaneous colocalized extracellular measurements of tissue oxygen and neural activity in the cortex of the cat primary visual cortex to determine whether the BOLD signal reflected mainly neuronal input or neuronal output . They report that changes in tissue oxygen were more closely coupled with LFPs than with neuronal spikes.

Mescaline dose-dependently increased top activity in the novel tank test, also reducing immobility and disrupting the patterning of swimming. At the highest dose tested (20 mg/l), mescaline markedly increased shoaling behavior but had no effect on whole-body cortisol levels, in contrast with the effects of LSD reported by Grossman et al. . The pharmacology of LSD is more complex than mescaline, so it is not clear that all of the effects reported by Grossman et al. were due to 5-HT2A receptor–mediated effects. Gatch et al. trained male Sprague-Dawley rats under an FR10 food-reinforced paradigm to discriminate DMT (5 mg/kg) from saline and then tested the ability of LSD, R-(−)-DOM, (+)-methamphetamine, and racemic MDMA to substitute in these rats. DMT also was evaluated for drug-appropriate responding in rats trained to discriminate LSD, DOM, MDMA, or (+)-methamphetamine from saline. LSD, DOM, and MDMA all fully substituted in DMT-trained rats, but (+)-methamphetamine failed to substitute.

Hence, psychedelic brain states exhibit higher signal complexity and higher cognitive flexibility, but lower cause-effect information . According to Carhart-Harris and Friston , this broadens the volume and breadth of available sensory and mnemonic content and increases the potential for ‘out of the box’ ideas, novel insights, and new perspectives. All of this implies that psychedelic-assisted divination practices could provide access to new and unusual perspectives and innate and unconscious knowledge useful for construing judgments regarding the unknown, thereby constituting an active rhetorical coping and self-editing strategy against inevitable uncertainty. We propose that in this context, psychedelics’ effects were harnessed to modulate the strength and quality of social bonds. Ingestion of psilocybin induces euphoria, involuntary grinning, uncontrollable laughter, giddiness, playfulness, and exuberance ; it also enhances engagement with music (Kaelen et al., 2018) and eloquence .

It is a thin sheet of GABAergic neurons that has functionally distinct afferent and efferent connections with thalamic nuclei, the neocortex, the basal forebrain, and the brainstem. Rodríguez et al. found that the two major postsynaptic serotonin receptors in the reticular nucleus were of the 5-HT1A and 5-HT2A subtypes. Serotonergic projections from the dorsal raphe and supralemniscal nucleus were demonstrated to be the principal sources of raphe projections to the reticular nucleus. In addition to the cortex, the thalamus and reticular nucleus of the thalamus may also be important sites of action for psychedelics. The 5-HT2A receptor is expressed in the thalamus, primarily in sensory and “nonspecific” nuclei (Cornea-Hébert et al., 1999). In the rat brain, significant levels of 5-HT2A receptor mRNA are expressed in the reticular nucleus, lateral geniculate nucleus, zona incerta, and the anterodorsal and ventromedial nucleus of the thalamus (Cyr et al., 2000).