The potential of psychedelics for the treatment of Alzheimer's disease and related dementias.

Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically relevant natural products and their synthetic analogues. This paper reviews evidence for effectiveness of natural and synthetic psychedelics in the treatment of AD causes and symptoms. The plastogenic effects of serotonergic psychedelics illustrate that they have efficacy for addressing multiple facets of AD pathology. We review findings illustrating neuroplasticity mechanisms of classic (serotonergic) and non-classic psychedelics that indicate their potential as treatments for AD and related dementias. Classic psychedelics modulate glutamatergic neurotransmission and stimulate synaptic and network remodeling that facilitates synaptic, structural and behavioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal survival and glutamate-driven neuroplasticity. Muscimol modulation of GABAAR reduces Aß-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aß toxicity. Classic psychedelics also activate mTOR intracellular effector pathways in brain regions that show atrophy in AD. The potential of psychedelics to treat AD involves their ability to induce structural and functional neural plasticity in brain circuits and slow or reverse brain atrophy. Psychedelics stimulate neurotrophic pathways, increase neurogenesis and produce long-lasting neural changes through rewiring pathological neurocircuitry. Psychedelic effects on 5-HT receptor target genes and induction of synaptic, structural, and functional changes in neurons and networks enable them to promote and enhance brain functional connectivity and address diverse mechanisms underlying degenerative neurological disorders. These findings provide a rationale for immediate investigation of psychedelics as treatments for AD patients.

Psychedelics, Sociality, and Human Evolution.

Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current understanding of: early hominins' paleodiet and paleoecology; primate phylogeny of mycophagical and self-medicative behaviors; and the biogeography of psilocybin-containing fungi. These lines of evidence indicate mushrooms (including bioactive species) have been a relevant resource since the Pliocene, when hominins intensified exploitation of forest floor foods. Psilocybin and similar psychedelics that primarily target the serotonin 2A receptor subtype stimulate an active coping strategy response that may provide an enhanced capacity for adaptive changes through a flexible and associative mode of cognition. Such psychedelics also alter emotional processing, self-regulation, and social behavior, often having enduring effects on individual and group well-being and sociality. A homeostatic and drug instrumentalization perspective suggests that incidental inclusion of psychedelics in the diet of hominins, and their eventual addition to rituals and institutions of early humans could have conferred selective advantages. Hominin evolution occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, i.e., the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics' effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness. We present interdisciplinary evidence for a model of psychedelic instrumentalization focused on four interrelated instrumentalization goals: management of psychological distress and treatment of health problems; enhanced social interaction and interpersonal relations; facilitation of collective ritual and religious activities; and enhanced group decision-making. The socio-cognitive niche was simultaneously a selection pressure and an adaptive response, and was partially constructed by hominins through their activities and their choices. Therefore, the evolutionary scenario put forward suggests that integration of psilocybin into ancient diet, communal practice, and proto-religious activity may have enhanced hominin response to the socio-cognitive niche, while also aiding in its creation. In particular, the interpersonal and prosocial effects of psilocybin may have mediated the expansion of social bonding mechanisms such as laughter, music, storytelling, and religion, imposing a systematic bias on the selective environment that favored selection for prosociality in our lineage.

The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology.

This review illustrates the relevance of shamanism and its evolution under effects of psilocybin as a framework for identifying evolved aspects of psychedelic set and setting. Effects of 5HT2 psychedelics on serotonin, stress adaptation, visual systems and personality illustrate adaptive mechanisms through which psychedelics could have enhanced hominin evolution as an environmental factor influencing selection for features of our evolved psychology. Evolutionary psychology perspectives on ritual, shamanism and psychedelics provides bases for inferences regarding psychedelics' likely roles in hominin evolution as exogenous neurotransmitter sources through their effects in selection for innate dispositions for psychedelic set and setting. Psychedelics stimulate ancient brain structures and innate modular thought modules, especially self-awareness, other awareness, "mind reading," spatial and visual intelligences. The integration of these innate modules are also core features of shamanism. Cross-cultural research illustrates shamanism is an empirical phenomenon of foraging societies, with its ancient basis in collective hominid displays, ritual alterations of consciousness, and endogenous healing responses. Shamanic practices employed psychedelics and manipulated extrapharmacological effects through stimulation of serotonin and dopamine systems and augmenting processes of the reptilian and paleomammalian brains. Differences between chimpanzee maximal displays and shamanic rituals reveal a zone of proximal development in hominin evolution. The evolution of the mimetic capacity for enactment, dance, music, and imitation provided central capacities underlying shamanic performances. Other chimp-human differences in ritualized behaviors are directly related to psychedelic effects and their integration of innate modular thought processes. Psychedelics and other ritual alterations of consciousness stimulate these and other innate responses such as soul flight and death-and-rebirth experiences. These findings provided bases for making inferences regarding foundations of our evolved set, setting and psychology. Shamanic setting is eminently communal with singing, drumming, dancing and dramatic displays. Innate modular thought structures are prominent features of the set of shamanism, exemplified in animism, animal identities, perceptions of spirits, and psychological incorporation of spirit others. A shamanic-informed psychedelic therapy includes: a preparatory set with practices such as sexual abstinence, fasting and dream incubation; a set derived from innate modular cognitive capacities and their integration expressed in a relational animistic worldview; a focus on internal imagery manifesting a presentational intelligence; and spirit relations involving incorporation of animals as personal powers. Psychedelic research and treatment can adopt this shamanic biogenetic paradigm to optimize set, setting and ritual frameworks to enhance psychedelic effects.

Identifying the nature of shamanism.

Singh conflates diverse religious statuses into a single category that includes practitioners with roles that differ significantly from empirical characteristics of shamans. The rejection of biological models of trance and conspicuous display models misses the evolutionary roots of shamanism involving the social functions of ritual in producing psychological and social integration and ritual healing.