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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 Aβ-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aβ 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.
European Neuropsychopharmacology 76 (2023) 3–16
The potential of psychedelics for the
treatment of Alzheimer’s disease and
related dementias
Michael James Winkelman
, Attila Szabo
b , c , , Ede Frecska
School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, United States
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction,
Oslo University Hospital, Oslo, Norway
KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Received 8 March 2023; received in revised form 3 July 2023; accepted 5 July 2023
Alzheimer’s Disease (AD) is a currently incurable but increasingly prevalent fatal and progres-
sive neurodegenerative disease, demanding consideration of therapeutically relevant natural
products and their synthetic analogues. This paper reviews evidence for effectiveness of nat-
ural 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 behav-
ioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal
survival and glutamate-driven neuroplasticity. Muscimol modulation of GABA
R reduces A β-
induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in A βtoxicity.
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 re-
ceptor target genes and induction of synaptic, structural, and functional changes in neurons
Corresponding author at: NORMENT, Institute of Clinical Medicine, Bygg 49, Ullevål sykehus, P. O . box 4956 Nydalen, Oslo 0424, Norway.
E-mail address: (A. Szabo).
0924-977X/ ©2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license
( )
M.J. Winkelman, A. Szabo and E. Frecska
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.
©2023 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY license
( )
1. Introduction
Alzheimer’s disease (AD) is the most common cause of de-
mentia and a leading cause of death globally (7th), reach-
ing a staggering population prevalence above 30% in peo-
ple over 85 ( Gauthier et al., 2021 ). Currently, there are
no medical cures for AD, creating an urgent need for new
treatments. Central features of AD and other neurodegener-
ative disorders are manifested in dysfunctions from cellular
to neural network levels that contribute to global cognitive
decline ( Saeger and Olson, 2022 ). Animal research shows
that the serotonergic system has direct relevance for AD
through its effects in modulating learning and memory func-
tions and by addressing the selective neurodegeneration in
serotonin receptor pathways and reduced activity at sero-
tonergic synapses ( Garcia-Romeu et al., 2022 ). Psychedelics
such as psilocybin, N,N-dimethyltryptamine (DMT) and ly-
sergic acid diethylamide (LSD) exhibit neuromodulatory ef-
fects mainly via the serotonin (5-hydroxytryptamine, 5-HT)
2A receptors ( Nichols 2016 ).
We review evidence that neurotrophic and neuroplas-
togenic mechanisms elicited by “classic” (serotonergic,
mainly 5HT2A agonists) natural psychedelic compounds and
their synthetic analogues indicate they are potential ther-
apeutic agents for addressing both causes and symptoms
of AD and other dementias. A search in PubMed on Au-
gust 20, 2022 using the MeSH term Alzheimer’s AND the fol-
lowing terms found few articles and none involving clinical
studies in humans: Psychedelic-5; Hallucinogen-5; Ibogaine-
1; Muscarine-8; Muscimol-4; Harmine-8; Psilocybin-0; LSD-
0. The most significant of these findings are incorporated
into our narrative review that also includes other rele-
vant literature on psychedelics’ effects as plastogens and
neuroplasticity agents with potential applications to AD.
( Aleksandrova and Phillips, 2021 ; Garcia-Romeu et al., 2022 ;
Inserra et al., 2021 ; Lukasiewicz et al., 2021 ; Ly et al.,
2018 ; Martin and Nichols, 2016 ; Saeger and Olson, 2022 ;
Var gas et al., 2021 ; Vollenweider and Smallridge, 2022 ).
The potential therapeutic applications of psychedelics
in AD is an emerging topic, and recent, outstanding pa-
pers provide a forum for relevant scientific discussions in
this field ( Jones and O’Kelly, 2020 ; Garcia-Romeu et al.,
2022 ). Here we offer a different approach to the topic by in-
cluding several additional receptor systems in the discourse
other than serotonergic ones (e.g. cholinergic, GABAergic,
sigma receptors, etc., and their modulators, e.g. musci-
mol, ibogaine, etc.) at the intersection of dementia and
psychedelic research. Furthermore, we also offer an in-
depth overview on the molecular neurobiology of interact-
ing downstream pathways and effects of psychedelics on
cell types other than neurons, such as glial and immune
2. The neuropathology of AD
AD is a neurodegenerative disorder with a clinical presenta-
tion of severe impairment in memory, speech, object recog-
nition and visuospatial processing-related executive func-
tions ( Knopman et al., 2021 ). AD and other dementias have a
neurodegenerative component that impairs the brain’s abil-
ity to compensate for progressive injury. However, preser-
vation of a variety of functions in AD, and individual differ-
ences in disease progression, suggest a potential for neuro-
plastic responses, especially in early-onset cases ( Hill et al.,
2011 ).
AD primarily involves synaptic dysfunction resulting from
cellular, molecular, micro- and macroscale cortical defi-
ciencies that render cortical information processing de-
fective and maladjusted. AD’s multifaceted pathophysiol-
ogy encompasses observable subcellular and morphologi-
cal alterations such as: the presence of β-amyloid contain-
ing extracellular deposits, called A βplaques ( Chen et al.,
2017 ); the accumulation of tau-containing neurofibrillary
tangles in neurons; and the loss of glial and neuronal
homeostasis and neuronal network integrity ( Golde et al.,
2018 ; Knopman et al., 2021 ). Knowledge of the biochem-
ical processes of tau and A β/APP and how their interac-
tions relate to AD etiology and pathophysiology is incom-
plete ( van der Kant et al., 2020 ). Hypotheses regarding their
intra and intercellular interactions include glial cells, the
synaptic cleft and associated structures, and the endoso-
mal/proteasomal/lysosomal system ( Leyns et al., 2019 ).
A β-containing plaques are derived from amyloid pre-
cursor protein (APP), a transmembrane protein expressed
in neuronal synapses ( Haass and Selkoe, 2007 ). Follow-
ing cleavage of APP by βand γ-secretases, A βpeptides
are produced and secreted into the extracellular space as
monomers ( Thinakaran and Koo, 2008 ). Due to their bio-
chemical structure, these monomers have the tendency to
aggregate. The aggregated, oligomeric form of A βis cy-
totoxic, interacting with several receptor types including
N-methyl- D -aspartate (NMDA), metabotropic glutamate re-
ceptor 5, α7 nicotinic acetylcholine receptor, as well as in-
sulin receptors ( Spires-Jones and Hyman, 2014 ). Proper ly
regulated APP cleavage has important physiological roles,
such as modulation of synaptic transmission, endosomal and
lysosomal functions, etc. ( Rice et al., 2019 ; Small and Pet-
sko, 2020 ). Improperly regulated APP processing may also
have deleterious effects on synaptic function in addition to
de facto neurotoxicity caused by accumulated A βplaques.
The gut microbiota can also release soluble forms of amy-
loid proteins and those may influence neurodegeneration
through the promotion of amyloid formation and by en-
hancing inflammatory responses to extracellular amyloid
deposits ( Friedland and Chapman, 2017 ).
European Neuropsychopharmacology 76 (2023) 3–16
The microtubule-associated protein tau is a normal
intracellular component in the axonal cytoplasm, and
is also present in the pre- and post-synaptic compart-
ments in close association with the nuclear membrane
( Eftekharzadeh et al., 2018 ). Its main function is micro-
tubule stabilization ( Eftekharzadeh et al., 2018 ), but it can
be prone to aggregation due to abnormal post-translational
modifications ( De Calignon et al., 2012 ). After pathological
aggregation, the hyperphosphorylated form of tau is accu-
mulated in cell bodies and dendrites and can subsequently
be released into the extracellular space by synaptic activ-
ity, where it is internalized by postsynaptic neurons and glial
cells ( Wu et al., 2016 ) and may exert direct cytotoxic and
neuroinflammatory effects.
Neuroinflammation and dysregulated immune responses
in the brain are core facets of AD pathology and related de-
mentias ( Leng and Edison, 2021 ). Overactive microglia and
abnormal microglia-astroglia crosstalk may drive an inflam-
matory environment in the CNS that consequently allows the
ingress of peripheral immune cells into the brain, provoking
a vicious cycle of amplified neuroinflammation. Activated
immunocompetent cells produce inflammatory cytokines
and chemokines in the brain and attract and activate blood
circulating lymphocytes and myeloid cells that favor a long-
term, chronic neuroinflammatory phenotype observed in
many neuropsychiatric disorders ( Khandaker et al., 2015 ;
Szabo et al., 2022 ). Chronic neuroinflammation exacerbates
both tau and A βpathologies and may be a crucial link and
central mechanism in the pathogenesis of AD ( Kinney et al.,
2018 ).
Elevated and prolonged neuroinflammation causes cellu-
lar stress with mitochondrial and endoplasmic reticulum in-
volvement which lead to unfolded protein response (UPR),
which if sustained causes apoptotic cell death. Ta r g e t i n g
several elements of the cellular stress like endoplasmic
reticulum stress, UPR, mitochondrial and oxidative stresses
may have benefits in treatment of AD ( Moren et al., 2022 ;
Sidhom et al., 2022 ; Trushina et al., 2022 ).
3. Neuromechanisms of potential AD
Pro-cognitive and neuroplasticity modulating capacities of
serotonin receptors are implicated in AD ( Svob Strac et al.,
2016 ; Vann Jones and O’Kelly, 2020 ) through several mech-
anisms: One involves 5-HT2A receptor modulation of gene
expression of neuroplasticity-enhancing neurotrophins in
the hippocampus and neocortex ( Vaidya et al., 1997 ). An-
other mechanism is from enriched 5-HT2A associated with
fine-tuning of cortical signaling regulating cognition, mem-
ory, and synaptic plasticity in cortical areas affected in
AD ( Zhang and Stackman, 2015 ). The classical view of
neurotransmitter receptors localized on the postsynaptic
membrane within the synaptic cleft and involved in the
transfer of action potentials between neurons cannot be
fully applied to serotonin receptors, which are mostly lo-
calized intraneurally at extrasynaptic locations and me-
diate long-lasting metabotropic effects ( Bockaert et al.,
2006 ). Serotonin output from the raphe nuclei is paramount
in restoring networks and their function after CNS injury
( Fabbiani et al., 2018 ; Leibinger et al., 2021 ). Serotonin is a
ubiquitous and important modulator of a vast array of pro-
cesses taking part in neural development, regeneration and
plasticity ( Salvan et al., 2023 ).
The opioid-like orphan receptor sigma-1 receptor (Sig-
1R) is a potential therapeutic target in multiple neurode-
generative disorders including AD ( Penke et al., 2018 ;
Ryskamp et al., 2019b ). Sig-1R is a small transmembrane
protein mostly expressed and enriched in the endoplasmic
reticulum (ER) - mitochondria-associated membrane system
( Hayashi and Su, 2007 ). It has a very important biochemical
chaperone role in assisting and controlling cellular stress re-
sponses, metabolic adaptation, and protein folding, and has
been proposed to play a role in the etiology and pathophys-
iology of neurodegenerative disorders.
Sig-1R plays a mitigating role in cellular stress signaling,
downregulating endoplasmic reticulum stress and UPR. Ac-
tivation of Sig-1R provides neuroprotection in cell cultures
and animal studies ( Bogar et al., 2022 ); the Sig-1R agonists
DMT and 5-MeO-DMT exert anti-inflammatory responses
( Szabo et al., 2014 ). Furthermore, clinical trials demon-
strated Sig-1R agonists (pridopidine, ANAVEX3–71, fluvox-
amine, dextrometorphan) have neuroprotective effects by
fine-tuning stress resilience, and modulating metabolic and
survival pathways in cortical neurons. Pathways targeted by
these experimental drugs are similar to those modulated by
psychedelics that display agonistic activity at Sig-1R sites
( Bogar et al., 2022 ).
Several Sig-1R agonists display anti-amnesic proper-
ties and protective roles in A βtoxicity ( Maurice and
Goguadze, 2017 ), boosting neurogenesis in the hippocam-
pus ( Moriguchi et al., 2013 ) and improving synaptic stabil-
ity and remodeling ( Ryskamp et al., 2019a ). Sig-1R agonists
are neuroprotective in vivo models of AD ( Tsa i et al., 2009 ).
Studies suggest that Sig-1R-related signaling interacts with
genes involved in AD (presenilin 1 and presenilin 2), with
mutations in these genes disrupting regulation of intracellu-
lar Ca
2 +
release from the ER. Sig-1R agonists might interfere
with this dysregulation in hippocampal neurons by modulat-
ing ER leakage, increasing stress resilience and improving
neuroplasticity ( Ryskamp et al., 2019b ).
AD, and dementias in general, are associated with ab-
normalities in cholinergic and noradrenergic neurotransmis-
sion ( Vos s et al., 2017 ), with AD neuropathology associ-
ated with loss of GABAergic inhibitory functions ( Huang and
Mucke, 2012 ). Cholinergic modulators and cholinesterase
inhibitors are reported effective in alleviating symp-
toms of dementias including AD and are currently being
tested as potential treatment options in these disorders
( Colovic et al., 2013 ).
3.1. Plastogens: general mechanisms of
psychedelics in addressing dementia
Psychoplastogens are compounds that can produce struc-
tural and functional neural plasticity in brain circuits, mak-
ing them promising treatments of neuropsychiatric diseases
through regenerating pathological neural circuitry, restor-
ing network-level functioning and enhancing diverse pro-
cesses of neuroplasticity ( Vargas et al., 2021 ). CNS plas-
ticity is produced through various processes (axonal sprout-
ing, long-term potentiation and expression of plasticity re-
M.J. Winkelman, A. Szabo and E. Frecska
lated genomic responses) and found across brain levels from
gene expression and signal transduction to synaptic and neu-
ronal levels and whole-brain networks ( De Gregorio et al.,
2021 ). Neuroplasticity (neural plasticity, synaptic plastic-
ity, cortical plasticity and cortical re-mapping) involve abil-
ities of the nervous system to change in response to both
internal and external stimuli via changes in its structure
and connections ( De Gregorio et al., 2021 ; Inserra et al.,
2021 ). Neurogenesis is a component of neuroplasticity that
involves processes that induce progenitor activity, stimulate
precursor cell division and promote cellular processes un-
derlying the growth of the dendrites and axons for synap-
tic formation. Neuroplasticity builds neural networks and
reorganizes neuronal activity, functions, and interconnec-
tions among networks by removing and adding new cellular
components (neurite branches, synaptic endings) and even
cells (nerve cells and associated glial cells) and their con-
nections and structures. Neuroplasticity is both a cellular
substrate for learning and memory formation and a complex
dynamic of functional changes associated with development
of synapses (synaptic plasticity), axon and dendrite regener-
ation. Cellular mechanisms of neuroplasticity include mod-
ification of synaptic transmission, synaptogenesis, synaptic
restructuring, neurogenesis, dendritic remodeling, and ax-
onal sprouting ( Teter and Ashford, 2002 ). Neuroplasticity
also manifests through higher-order phenomenological pro-
cesses involving changes in neurobehavioral patterns and
psychological and sociological activities ( Teter and Ash-
ford, 2002 ) and guiding adaptive behavior in adjusting to
a dynamic environment ( Aleksandrova and Phillips, 2021 ).
3.2. Psychedelics as plastogens
Recent peer-reviewed articles ( Aleksandrova and
Phillips, 2021 ; Garcia-Romeu et al., 2022 ; Inserra et al.,
2021 ; Lukasiewicz et al., 2021 ; Ly et al., 2018 ; Martin and
Nichols, 2016 ; Saeger and Olson, 2022 ; Var gas et al., 2021 ;
Vollenweider and Smallridge, 2022 ) address the potential
of psychedelics for treatment of AD by slowing down or
reversing brain atrophy and enhancing cognitive function,
suggesting that they could provide novel pharmacotherapies
for a range of heretofore incurable dementias. Lukasiewicz
et al. ( Lukasiewicz et al., 2021 ) call psychedelics psy-
choplastogens in reference to their broad therapeutic
effectiveness through acting as catalysts for increased
brain neuroplasticity and reconfiguring neuronal networks.
Psychedelics produce neuroplastic effects through stimu-
lation of neurotrophic pathways, increasing neurogenesis
and cognitive flexibility and producing long-lasting neural
changes ( De Gregorio et al., 2021 ; Varga s et al., 2021 ).
Psychedelics’ rapid plastogenic effects on diverse
processes of cognition, learning and memory ( Garcia-
Romeu et al., 2022 ; Saeger and Olson, 2022 ) and their
robust and sustained therapeutic effects involve stimula-
tion of structural and functional dynamics of neuroplastic-
ity, modification of synaptic plasticity, induction of anti-
inflammatory effects, and rewiring pathological neurocir-
cuitry ( Aleksandrova and Phillips, 2021 ; Bogenschutz et al.,
2015 ). This makes them ideal agents to address neurolog-
ical, behavioral and psychological features of cortical or
subcortical atrophy exhibited in neurodegenerative condi-
tions. Convergent downstream mechanisms of action occur
via effector mechanisms of serotonin receptor target genes,
inducing and regulating synaptic, structural, and func-
tional changes in PFC pyramidal neurons ( Aleksandrova and
Phillips, 2021 ).
Studies ( Inserra et al., 2021 ; Ly et al., 2018 ) on roles
of neural plasticity in therapeutic effects of psychedelic
serotonergic 5HT2A agonists illustrates they promote struc-
tural and functional plasticity of synapses and enhance
brain functional connectivity. Serotonergic psychedelics
promote neuroplasticity through (post-acute) changes in
signaling pathways and anti-inflammatory effects ( Garcia-
Romeu et al., 2022 ), illustrating their relevance for AD
treatments as neuroplasticity-enhancing agents capable
of addressing diverse mechanisms underlying degenerative
neurological disorders ( De Vo s et al., 2021 ).
Through up-regulation of neurotrophic factors they pro-
mote neuronal survival and produce persistent enhance-
ment in glutamate-driven neuroplasticity in frontocorticol-
imbic pyramidal neurons by stimulating interactions be-
tween glutamate and serotonin systems ( Aleksandrova and
Phillips, 2021 ), affecting regional synaptic homeostasis and
counteracting synaptic deficits and neuronal atrophy. Acute
psychedelic effects characterized by profound perceptual,
cognitive, and emotional changes may be mediated by
short-term action potential transfers through synaptic 5-
HT2A receptors or from fast-acting mechanisms that induce
long-lasting structural modifications ( Aleksandrova and
Phillips, 2021 ); but the bulk of long-term neuroplastic
changes are probably related to intracellular metabotropic
serotonin receptors ( Bockaert et al., 2006 ). These find-
ings suggest that psychedelics’ pharmacological modulation
of neurotransmitter systems may potentially reverse neu-
rocognitive deficits pertaining to dementias via fine-tuning
3.3. Classic psychedelics (Indolealkylamines and
phenylalkylamines) as modulators of
neuroplasticity and neuroprotection
Human psychopharmacological studies demonstrated the
binding profile of classic psychedelics in the brain is predom-
inantly characterized by 5-HT2A occupancy and functional
activity ( Madsen et al., 2019 ; Vollenweider et al., 1998 ).
Naturally occurring psychedelics are not strictly 5-HT2A
selective, with other receptors and receptor-systems also
mediating their neurophysiological effects ( Banks et al.,
2021 ; Pokorny et al., 2016 ). Indolealkylamine tryptamine-
and lysergic acid derivatives commonly have both 5-
HT2A and 1A receptor binding affinity and partial agonis-
tic activity at Sig-1R, dopamine, adrenergic and acetyl-
choline receptors ( Rickli et al., 2016 ). The receptor affin-
ity profile of phenylalkylamines, such as 2,5-dimethoxy-4-
iodoamphetamine (DOI) and mescaline, are more polarized
towards 5-HT2A and, to a lesser extent, to 5-HT2C recep-
tors ( Halberstadt and Geyer, 2011 ; Ray, 2010 ). These re-
ceptors are primary pharmacological mechanisms for classic
psychedelics’ neurological, psychological and behavioral ef-
fects although their therapeutic potential might also involve
other receptor types; recent studies indicate metabotropic
glutamate receptors are also involved ( Carbonaro et al.,
European Neuropsychopharmacology 76 (2023) 3–16
2015 ). Many psychedelics also target 5-HT6 and 5-HT7 sero-
tonin receptors that enhance plasticity and address neu-
rodegeneration ( Saeger and Olson, 2022 ). Vari ous serotoner-
gic tryptamines modulate Sig-1R receptors in both the cen-
tral nervous system and in peripheral tissues and cell types,
including immune cells ( Frecska et al., 2013 ; Szabo, 2015 ).
5-HT2A receptors directly signal via G-protein-coupled
receptors (GPCRs) of the G
q subtype. Stimulation of 5-
HT2A receptors triggers the intracellular synthesis of inosi-
tol triphosphate (IP3) by phospholipase C (PLC) activation,
which leads to mobilization of cytoplasmic Ca
2 +
, a common
downstream signaling effector of GPC-receptors. Release of
2 + from intracellular storage compartments modulates a
plethora of acute and long-term cellular physiological ef-
fects including changes in excitability, neurogenesis and dif-
ferentiation (neurons and neural stem cells), fine-tuning of
neurotransmission (via glial cells), as well as modulation
of functional pathways related to cell survival, apoptosis,
metabolic regulation and stress resilience (see Fig. 1 ). Sig-
naling through G
i/o family elements, another GPCR down-
stream pathway controlled by 5-HT2A receptor activation,
is associated with production of intracellular cyclic adeno-
sine monophosphate (cAMP), a critically important second
messenger in many biological processes. Modulation of both
and G
pathways via 5-HT2A can mobilize and promote
neuroplasticity and are implicated in therapeutic effects of
serotonergic psychedelics ( Fig. 1 ) ( Banks et al., 2021 ).
Classic psychedelics boost dendritic spine and neurite for-
mation via the modulation of the mammalian target of ra-
pamycin (mTOR) and tropomyosin receptor kinase B (TrkB)
by 5-HT2A both in vitro and in vivo ( Ly et al., 2018 ). This
is critically important, since these pathways are heavily in-
volved in the production of brain-derived neurotrophic fac-
tor (BDNF) and positive neuroplasticity changes in the pre-
frontal cortex (PFC) ( Banks et al., 2021 ; Meunier et al.,
2017 ). Psilocybin, ayahuasca alkaloids, and 5–methoxy-N,N-
dimethyltryptamine (5-MeO-DMT) also effectively induce
neurogenesis in the mammalian hippocampus ( Lima da Cruz
et al., 2018 ; Reckweg et al., 2022 ; Saeger and Olson, 2022 )
( Fig. 1 ). Psychedelic effects in promoting synaptic plasticity
depend on intracellular roles of both TrkB/BDNF and mTOR
signaling pathways ( De Gregorio et al., 2021 ; Inserra et al.,
2021 ; Lukasiewicz et al., 2021 ). Psychedelics share the abil-
ity with BDNF and TrkB agonists to activate mTOR, intracel-
lular effector pathways highly expressed in brain regions re-
lated to sensory and cognitive processing that atrophy in AD
and related dementias ( Saeger and Olson, 2022 ). Changes
induced by psilocybin positively affected memory, atten-
tion span and perception in humans ( Barrett et al., 2020 ;
Preller et al., 2020 ), which suggests their therapeutic po-
tential in AD and related dementias ( Fig. 1 ).
Serotonergic psychedelics may also drive systems-
level, neurotrophin-based functional changes in the brain
parenchyma via 5-HT2A that could contribute to signifi-
cant therapeutic effects in dementias through modulation
of persistent, long-term changes that underlie cognitive im-
provements. Classic psychedelics increase brain connectiv-
ity and neuroplasticity in healthy adults ( Preller et al., 2018 ,
2019 ) and the resultant connectivity alterations in higher-
order regions ( Barrett et al., 2020 ; Preller et al., 2020 ;
Roseman et al., 2014 ; Sampedro et al., 2017 ) illustrate
the importance of investigating their potential long-term
cognitive-behavioral effects.
Martin and Nichols (2016) provide evidence that spe-
cific 5-HT2A-expressing excitatory neurons are activated by
psychedelics, and this recruits astrocytes and inhibitory so-
matostatin and parvalbumin GABAergic interneurons. They
conclude that DOI (and presumably other serotonergic
psychedelics) transcriptionally activate heterogeneous pop-
ulations of inhibitory and excitatory cells that subsequently
activate heterogeneous populations of cells in the medial
PFC (mPFC) and somatosensory cortex. While the imme-
diate early gene induction varies across brain region and
cell type, psychedelics activate specific 5-HT2A-expressing
neurons in the mPFC, somatosensory cortex, and claus-
trum, including 5-HT2A-excitatory neurons, which subse-
quently recruit somatostatin and parvalbumin interneurons
( Martin and Nichols, 2016 ).
Classic psychedelics also produce downstream modula-
tory effects on gamma-aminobutyric acid (GABA), dopamin-
ergic and glutamatergic systems ( Vollenweider and Small-
ridge, 2022 ). Effects on glutamatergic receptors are via
N-methyl- D -aspartate (NMDA) with additional effects on
the α-amino-3–hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor systems ( De Gregorio et al., 2021 ). Glu-
tamate neurotransmission also effects NMDARs, which
have a role in induction of long-term synaptic plasticity
( Aleksandrova and Phillips, 2021 ). LSD modulates gluta-
matergic neurotransmission, and since glutamate is an ex-
citatory neurotransmitter involved in neuroplasticity, cog-
nition, learning, memory and other homeostatic processes,
these results suggest a neuroplasticity-modulating poten-
tial for LSD ( De Vos et al., 2021 ; Ly et al., 2018 ). Molecu-
lar, electrophysiological, neuroimaging and clinical studies
show that 5HT2A psychedelics all modulate glutamatergic
neurotransmission and stimulate synaptic and network re-
modeling that facilitates synaptic, structural and behavioral
plasticity ( Aleksandrova and Phillips, 2021 ).
4. Non-serotonergic psychedelics
While serotonin 5HT2A receptors are implicated in the ma-
jor effects of classic psychedelics, especially visionary expe-
riences typified in the concept of hallucinogens, perturba-
tions in a variety of neurotransmitter systems also may re-
sult in visionary experiences. Hobson ( Hobson, 2001 ) shows
the reduction of serotonergic and noradrenergic control al-
lows for ascendance of acetylcholine and dopamine systems
that produce visual syndromes, typified in hallucinations.
Similarly, the following sections present evidence non-
serotonergic psychedelics have potential implications for
treatment of AD and related dementias through receptor-
affinity involving other receptor families (dopaminergic,
adrenergic, or cholinergic) ( Nichols, 2016 ).
4.1. Amanita muscaria and muscimol
The psychedelic mushroom Amanita muscaria (and other
Amanita species) contain the compounds muscimol and
ibotenic acid, as well as small amounts of muscarine and
M.J. Winkelman, A. Szabo and E. Frecska
Fig. 1 Interaction of receptors and pathways involved in the therapeutic action of classic and non-classic psychedelic substances.
Fig. 1 represents interacting pathways and typical receptors for psychedelics discussed in this paper. The center of the figure rep-
resents a neural or glial cell expressing these receptors. One pathway (upper left) involves glutamatergic presynaptic neurons that
express 5-HT2A receptors that modulate glutamate release, leading to the ligation and activation of AMPA, NMDA, and metabotropic
glutamate receptors (mGluR). Another pathway (upper right) involves presynaptic cholinergic neurons that release acetylcholine
(ACh) activating muscarinic (M1-M5 type) and nicotinic cholinergic receptors (nAChR). Classic serotonergic pathways (LSD, DMT,
psilocybin; upper center) mainly activate 5-HT2A receptors, which are 7-transmembrane G-protein-coupled receptors (GPCRs).
Atypical psychedelics activate either other types of GPCRs (e.g., ibogaine modulates the kappa-opioid receptor –KOR), GABA
(muscimol), or muscarinic receptors (muscarine). DMT and 5-MeO-DMT-modulated pathways (middle left) exhibit affinity at sigma-1
receptor (Sig-1R) sites at the mitochondria-associated endoplasmic reticulum membranes. Upon activation by their specific ligands,
these receptors converge into three major pathways: 1) Phospholipase C (PLC) - Protein kinase C (PKC) effector pathway that regu-
lates intracellular Ca
2 +
levels and control transcription factors modulating cellular survival/death, neuroprotection and metabolic
fine-tuning (in the center; involving diacylglycerol –DAG); 2) Catalyze the formation of cyclic AMP (cAMP) from ATP (Adenosine
triphosphate) by AC (Adenylate cyclase), and thereby activating Protein kinase A that controls several survival- and neuroplasticity-
related genes (lower left); 3) Phosphoinositide 3-kinase (PI3K) –AKT mammalian target of rapamycin (mTOR) effector axis that
regulates protein synthesis, stress-adaptation, neurorestorative and neuroplasticity-related genes and mechanisms. This effector
pathway also likely involves genes controlled by the nuclear factor CREB (cAMP response element-binding protein; lower right).
Both classic and non-classic psychedelics can modulate inflammation control via the modulation of the transcription factor Nuclear
factor kappa-light-chain-enhancer of activated B cells (NF- κB) and its target genes via unknown mechanisms. In immunocompetent
glial cells, such as microglia and astrocytes, this mechanism involves pattern recognition receptors (PRRs) and inflammasomes that
are expressed either on the cell surface or localized on intracellular membranes or in the cytoplasm. PRRs recognize various sets of
pathogenic or self-derived structures (pathogen-associated molecular patterns PAMPS, or endogenous damage-associated molecu-
lar patterns –DAMPs), and transduce signals through the NF- κB pathways. The interaction of a specific PAMP/DAMP with PRRs results
in downstream signaling through various adaptor proteins. This receptor-adaptor interaction leads to the activation of specific ki-
nases, and leads to the subsequent phosphorylation of NF- κB. This transcription factor then translocates into the nucleus regulating
the transcription of inflammatory cytokine and chemokine genes, such as IL-1 β, IL-6, IL-8, IL-18, and TNF α. Classic psychedelics,
typically via 5-HT2A and/or Sig-1R signaling, can modulate intracellular Ca
2 + levels through inositol trisphosphate (IP3). 5-HT2A
and Sig-1R can also interfere with both PKC and PRR-mediated NF- κB signaling. Thus, the NF- κB and PKC downstream pathways
may have a cardinal role in both the collaboration and essential signaling processes of PRRs, 5-HT2A, and Sig-1R in modulating
inflammation-control in general, and local neuroinflammation in the brain. Arrows represent activation, red T-arrows represent
inhibition/inhibitory effect. Created with .
muscazone ( Michelot and Melendez-Howell, 2003 ). The
psychedelic properties of Amanita are notable in spite
of their differences from psilocybin’s typical effects. In-
stead of the typical serotonergic agonist effects of 5-HT2A
psychedelics, the primary psychoactive agent of A. mus-
caria (muscimol) resembles the neurotransmitter GABA
and interacts with GABA receptors. The other psychoactive
compound, ibotenic acid acts on glutamate receptors.
Recent analyses of trip reports by ( Feeney, 2020 ) suggest
that it is appropriate to characterize A. muscaria as a
European Neuropsychopharmacology 76 (2023) 3–16
psychedelic in spite of mostly distinct effects from seroton-
ergic psychedelics. More typical psychedelic effects include
a sense of unfamiliarity to reality, a surreal dream-like
quality to the experiences and reports of ego loss, and
dislocation of the mind’s eye from body perspective and
one’s head. Some of the unique constellation of effects of
Amanita include a frame reduction, involving a slowing of
processing of visual frames, prolonged visual frames, size
distortion of image, and visionary dreams experienced as
an entry into a hallucinatory dream-like reality separate
from the physical world.
Muscarine and muscimol hold promise for therapy of neu-
rodegenerative disorders associated with cognitive decline
and severe amnestic impairment. Muscarine is a high affin-
ity selective agonist of muscarinic acetylcholine receptors
(mAChRs), a group of GPCRs located on several neuron
types, including the postganglionic fibers of the parasympa-
thetic nervous system ( Eglen, 2006 ). Some of the subtypes
of mAChRs are enriched in the human cerebral cortex, espe-
cially the M1, M2, and M4 receptors which are predominant
in the CNS and involved in regulation of neuronal excitability
and neuroplasticity. Their localization and substantial func-
tional selectivity make them ideal targets in the treatment
of AD and schizophrenia. Although the naturally occurring
form of muscarine is not able to cross the blood-brain bar-
rier (BBB), its chemically modified BBB-crossing analogs may
offer promising treatment models in neurodegenerative dis-
orders ( Kruse et al., 2014 ).
Muscimol is a psychotropic isoxazole produced from
ibotenic acid via decarboxylation and thus the latter is
considered as a prodrug for muscimol in mammalian sys-
tems ( Bowden et al., 1965 ). Ibotenic acid is rapidly me-
tabolized by the liver to the more stable and bioactive
muscimol in mammals, which makes muscimol a more at-
tractive pharmacological target for therapeutic applications
( Stebelska, 2013 ). Upon enteral or parenteral administra-
tion, muscimol rapidly crosses the BBB, displaying selective
and potent agonistic activity at GABA
A receptor (GABA
sites, and consequently has depressant, sedative-hypnotic
and hallucinogenic characteristics ( Johnston, 2014 ).
Unlike other GABAergic drugs, such as benzodiazepines
and barbiturates that allosterically modulate the recep-
tor, muscimol binds directly to binding the site of GABA
( Frolund et al., 2002 ). GABA
Rs are widely expressed in
the human brain, displaying significant enrichment in cor-
tical areas and in the hippocampus. In vivo rodent studies
of AD treatment with muscimol showed potent enhancing
effects on memory and learning ( Pilipenko et al., 2015 ),
even at very low doses ( Pilipenko et al., 2018 ). This ef-
fect involves muscimol-mediated significant downregulation
of hippocampal and cortical proteins involved in neuroin-
flammation and astrocyte reactive gliosis, such as GFAP,
as well as modulated enzymes critical for GABA synthesis
( Pilipenko et al., 2018 ). These results are very important,
since large-scale neural network activity is abnormally in-
creased in the brain of patients with AD, and animal models
show decreased GABAergic inhibitory neuron activity may
contribute to the observed A β-induced cognitive deficits
( Xu et al., 2020 ). Chronic modulation of GABA
R with mus-
cimol greatly reduces A β-induced neurotoxicity in cultured
rat cortical neurons, an effect entirely inhibited/prevented
by bicuculine, a specific GABA
R antagonist ( Lee et al.,
2005 ). Low-dose muscimol adiminstered directly into sub-
thalamic nuclei also reversed Parkinsonism in a small human
study ( Levy et al., 2001 ), and ameliorated cognitive deficits
and improved spatial memory in an APP/PS1 mouse model
of AD ( Fu et al., 2019 ), suggesting the therapeutic poten-
tial of muscimol in both A βand tau neuropathologies and
4.2. Ibogaine
Ibogaine, a psychotropic indole alkaloid found in Tabernan-
the iboga and related species, exhibits high affinity for mul-
tiple receptor types, including μ- and κ-opioid receptors,
NMDA and sigma receptors, as well as serotonin transporters
( Floresta et al., 2019 ). Ibogaine has potent, selective ag-
onistic action at κ-opioid and Sig-2Rs ( Mach et al., 1995 )
and modulatory effects on dopamine release via sigma- and
NMDA receptors in striatal neurons ( Sershen et al., 1996 ),
but the cellular and systemic physiological effects remain
The neuroplasticity-enhancing and modulating effects of
ibogaine are associated with increasing BDNF levels and glial
cell-derived neurotrophic factor (GDNF), another potent
mammalian neurotrophin. Ibogaine increases production of
GDNF in the rat midbrain, including the ventral tegmental
area (VTA) and expression of elements of the GDNF path-
way, receptor, adaptors, and downstream kinases in the VTA
( He et al., 2005 ). An in vitro study demonstrated short-term
ibogaine exposure increases levels of GDNF mRNA, lead-
ing to GDNF protein expression and activation of its sig-
naling pathway via a long-lasting, autocrine feedback loop
( He and Ron, 2006 ). Low doses of ibogaine significantly in-
creased BDNF transcript levels in the nucleus accumbens,
substantia nigra and PFC of the rat brain, while large doses
(40 mg/kg) caused observable increase in BDNF mRNA lev-
els in the VTA ( Marton et al., 2019 ). GDNF mRNA was selec-
tively upregulated in the substantia nigra and VTA regions,
and large doses significantly increased GDNF secretion in the
VTA. Both low and high doses of ibogaine increased in vivo
protein levels of precursor BDNF (proBDNF) in the nucleus
accumbens ( Marton et al., 2019 ).
Toxicity-related safety concerns have hindered clinical
research into effects of ibogaine in humans. However, taber-
nanthalog, a novel, non-psychoactive, nontoxic analog of
ibogaine, promotes robust structural neuroplasticity and
anti-depressant-like effects in rodents ( Cameron et al.,
2021 ), indicating a promising treatment option for neurode-
generative and neuropsychiatric disorders.
4.3. Harmine
The β-carboline alkaloid harmine is a reversible in-
hibitor of the monoamine oxidase enzyme (MAO-A) that
makes DMT sources in ayahuasca bioavailable after oral
ingestion. Harmine may have cognition-enhancing and
neuroprotective effects, resulting in improved memory
and learning in several animal models and producing
neuroprotective effects through increased BDNF levels
and reduced neurotoxicity, inflammation, and oxidative
M.J. Winkelman, A. Szabo and E. Frecska
stress ( Dos Santos and Hallak, 2017 ). Therapeutic mech-
anisms proposed include harmine’s dual-specificity tyro-
sine phosphorylation-regulated kinase 1A (DYRK1A) inhibitor
( Becker and Sippl, 2011 ) and neurogenic, progenitor stimu-
lating activity ( Morales-Garcia et al., 2017 ). DYRK1A regu-
lates cell proliferation and brain development and harmine
enhances proliferation of human neural progenitor cells,
suggesting DYRK1A inhibition was responsible for the effect
( Dakic et al., 2016 ). Several classes of DYRK1A inhibitors are
promising candidates for developing drugs against degener-
ative diseases ( Abbassi et al., 2015 ).
Harmine is neurotoxic in high doses, with elevated levels
in the blood associated with essential tremor ( Louis et al.,
2002 ). In humans, toxic symptoms appear above the 3 mg/kg
dose ( Marwat and Rehman, 2011 ). Nonetheless, cognition-
enhancing and neuroprotective effects of harmine should
be further investigated in animal and human studies of AD.
Appropriate dosing is crucial since memory impairment was
reported in rats at 5, 10, and 15 mg/kg doses ( Libanio et al.,
2021 ).
5. Discussion
The possible long-term therapeutic effects of serotoner-
gic psychedelics in dementias likely involve three different
1) The modulation of serotonergic/psychedelic-specific
alterations in the global brain transcriptome. A sin-
gle dose of psilocybin or 5-MeO-DMT causes significant
changes in neuroplasticity-related gene transcripts in
the hippocampus and PFC in vivo ( Jefsen et al.,
2021 ), and functionally related changes in the pro-
teome of human stem cell-derived cerebral organoids
( Dakic et al., 2017 ). DOI increases gene expression
of the neurotrophin BDNF and upregulates highly
neuroplasticity-specific gene pathways in the rodent
neocortex and hippocampus ( Desouza et al., 2021 ;
Tsybko et al., 2020 ) implicated in dementias with
a neurodegenerative component ( Allen et al., 2011 ;
Schindowski et al., 2008 ). Human clinical studies also
reported elevated plasma levels of BDNF following ad-
ministration of serotonergic psychedelics ( De Almeida
et al., 2019 ; Hutten et al., 2021 ) that may contribute
to long-term pro-neuroplastic effects at both the tran-
scriptomic and proteomic levels ( De Vos et al., 2021 ;
Martin and Nichols, 2018 ).
2) Modulation of the epigenetic landscape in the brain.
The epigenetic control of neuroplasticity-related genes
has global effects on brain functions, neural networks,
structural and functional recovery following acute in-
jury and in chronic conditions like AD ( Wang et al.,
2018 ). Histone modifications and direct methylation of
DNA associated with neurorestorative and neuropro-
tective mechanisms provide promising targets in AD.
Serotonin can directly act on the genome by modifying
histone proteins through serotonylation. Similar epi-
genetic mechanisms are implicated in neural plastic-
ity and their dysregulation is connected to age-related
memory decline and AD ( Maity et al., 2021 ). Pre-
clinical and genome-wide association studies suggest
memory, learning, and aging-related single or cluster-
like gene expression changes in the brain may oc-
cur independently of alterations in epigenetic patterns
( Lopez-Atalaya and Barco, 2014 ). Furthermore, most
of the epigenetic changes that affect memory, learn-
ing, neuroinflammation and age-related alterations in
AD occur in regulatory and enhancer regions, which
makes it extremely complicated to localize and/or
identify gene expression changes at the single-gene
level. DMT and related psychedelic tryptamines are
hypothesized to exert therapeutic activity via epige-
netic changes mediated by Sig-1R ( Inserra, 2018 ). This
is in agreement with previous in vitro results demon-
strating the neuroprotective effects of DMT in human
stem cell-derived cortical neurons and glia-like cells
( Szabo et al., 2016 ), and in rodents following experi-
mental stroke ( Nardai et al., 2020 ). Furthermore, LSD
administration significantly modulated DNA methyla-
tion in the mouse PFC and caused concomitant changes
in expression of gene pathways and proteins related to
neurotrophic- and neuroplasticity signaling and func-
tion ( Inserra et al., 2022 ). These results warrant fur-
ther investigations into the complex epigenetic effects
of psychedelics in neuropsychiatric disorders.
The relevance of epigenetic changes from psychedelics
are illustrated by the study of Ruffell et al.
( Ruffell et al., 2021 ) which performed an epigenetic
analysis on pre- and post- saliva samples collected at
an ayahuasca retreat. They report that DNA methy-
lation showed a statistically significant increase for
the Sig-1R assay. The changes in methylation scores
for Sig-1R were significantly correlated with scores
on a Childhood Trauma Questionnaire assessing emo-
tional, physical, and sexual abuse and emotional and
physical neglect indicating that ayahuasca increased
methylation for those with higher degree of childhood
trauma. They interpret their results as suggesting that
ayahuasca has effects on Sig-1R epigenetic regulation
but caution that it remains uncertain whether there
are biological impacts of this change in DNA methyla-
tion or any alterations to gene expression. Nonetheless
their findings suggest that there are potential epige-
netic processes that may regulate Sig-1R expression
relevant in the psychosocial context of healing trauma.
In addition, de la Fuente Revenga et al. (2021) also
found evidence of psychedelic-induced epigenetic
changes in a study of a single administration to mice of
the phenethylamine DOI, which produced a variety of
effects via the 5-HT2A receptor that persisted for days
following a single administration. Their study found
changes in chromatin organization at enhancer regions
of genes involved in synaptic assembly ( de la Fuente
Revenga et al., 2021 ). The alterations in the neu-
ronal epigenome induced by DOI overlap with specific
genetic loci associated with a variety of mental disor-
ders, such as schizophrenia, depression, and attention
deficit hyperactivity disorder. They interpret their
findings as supporting other evidence of long-lasting
psychedelic action based in epigenomic-driven changes
in synaptic plasticity. The group characterize these DOI
induced changes in-depth molecular structures and re-
sultant modifications in behavioral adaptations of mice
European Neuropsychopharmacology 76 (2023) 3–16
as suggesting the molecular mechanisms of persistent
post-dose effects on synaptic plasticity likely reflect
brain plasticity mechanisms involving structural and
functional modification of dendritic spines. Their study
provides important and direct evidence of DOI’s post-
acute effects via 5-HT2AR-dependent mechanisms on
dendritic spine structure that underlie long-lasting
alterations in frontal cortex gene expression and chro-
matin organization ( de la Fuente Revenga et al., 2021 ).
These exogenous psychedelic effects on the epigenetic
landscape, particularly at the enhancer regions of
genes in the cortex, seem to be of particular interest
with regards to future therapeutic applications.
3) Modulation of neuroinflammation. Inflammation and
dysregulated inflammatory glial functions are core
mechanisms in the pathogenesis of AD and re-
lated dementias while modulation of the CNS sero-
tonergic system is associated with significant im-
munomodulatory potential and inflammation-control
( Herr et al., 2017 ; Szabo et al., 2018 ). Preclinical
studies demonstrated classic psychedelics display po-
tent anti-inflammatory effects via 5-HT2A and Sig-
1R receptors ( Flanagan et al., 2021 ; Flanagan and
Nichols, 2018 , 2019 ; Nau et al., 2013 ; Szabo, 2015 ;
Szabo et al., 2014 ; Thompson and Szabo, 2020 ). Mouse
studies show psychedelics enhance AD-associated cog-
nitive function by reducing neuroinflammation, sug-
gesting reduction in human AD pathology and symp-
toms could be achieved by decreasing neuroinflamma-
tion associated with inflammatory cytokine (e.g., TNF-
αand IL-1 β) related effector mechanisms ( Saeger and
Olson, 2022 ). This may result from psychedelics’ stimu-
lation of 5-HT2A receptors that modulate immunomod-
ulatory and anti-inflammatory responses ( De Gregorio
et al., 2021 ; Flanagan and Nichols, 2018 ) and promote
cortical neuron growth and neuronal survival mecha-
nisms that counter age-induced chronic inflammation
( Aleksandrova and Phillips, 2021 ). These selective anti-
inflammatory effects may derive from psychedelic-
mediated biased signaling cascades and 5-HT2A re-
ceptor stabilization that recruit anti-inflammatory sig-
nal transducers which inhibit TNF- αreceptor and NF-
kB transcription factor-mediated proinflammatory sig-
naling ( De Gregorio et al., 2021 ). The ability of 5-
HT2A psychedelics to suppress peripheral inflammation
caused by TNF- α( Flanagan et al., 2021 ) indicates that
AD pathology and symptoms induced by chronic inflam-
mation might be attenuated by enhanced function-
ing of microglial cells as these phagocytic cells selec-
tively remove dead neural cells from brain parenchyma
( Saeger and Olson, 2022 ).
Inflammatory cytokines, produced by activated im-
mune cells and immune-competent glia (microglia and
astrocytes), significantly interfere with complex, higher
level neural functions as reported in multiple neuropsy-
chiatric disorders with neurodegenerative, neuroinflam-
matory, and neurocognitive components ( Akkouh et al.,
2021 ; Khandaker et al., 2015 ; Miller and Raison, 2016 ;
Szabo et al., 2022 ). Neuroinflammation also aggravates all
facets of the neuropathology of AD, making it a target in re-
cent pharmacotherapies ( Kinney et al., 2018 ). A combined
therapeutic approach of modulating both neuroinflamma-
tion and neuroplasticity with serotonergic psychedelics is
now emerging in the clinical field, including a recent phase
1 trial involving older volunteers using LSD ( Banks et al.,
2021 ; Family et al., 2020 ).
5.1. A path forward to psychedelic trials for AD
AD patients represent a particularly vulnerable population
especially those individuals at the more advanced stage of
neurodegeneration ( Johnston et al., 2022 ). Direct immune
and inflammatory modulation must also be closely moni-
tored to avoid potential side effects, such as immunosup-
pression, impaired beta-amyloid phagocytosis, or decreased
cancer immunosurveillance in elderly patients. These cau-
tions have to be taken seriously and warrant further preclin-
ical and clinical research.
These sober assessments suggest that while some caution
is still necessary, appropriate management of psychedelic
dose and setting can provide new treatment opportunities
for AD. Given the known low toxicity risks of serotoner-
gic psychedelics, we do not have to bridle our optimism
for studying the potential contributions of psychedelics to
treatment of AD and other neurogenerative diseases. Vann
Jones and O’Kelly (2022) conclude that the “potential for
psychedelic compounds to influence and enhance functional
neuronal connectivity, stimulate neurogenesis, restore brain
plasticity, reduce inflammation and enhance cognition pro-
vides a new therapeutic target and compelling argument for
further investigation of the potential for psychedelics as a
disease modifying compound in conditions where currently
none exists.”
The known effects on inflammation, neuroplasticity and
neurophysiologic mechanisms indicate psychedelics have
the potential to enhance well-being in older adults. Given
the general lack of toxicity and high therapeutic index of
these substances and the lack of complications in the many
studies of younger populations, studies with small doses of
psychedelics in older adults may proceed without undue
concern. As noted earlier ( George and Hanson, 2019 ) “the
path to using psychedelics as therapeutic adjuncts in de-
mentia care is daunting, but worth consideration;” imple-
mentation of such psychedelic therapies necessitates train-
ing of caregivers in