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The Neurobiology of Psychedelic Drugs: Implications for the Treatment of Mood Disorders

Abstract and Figures

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.
| Activation of the prefrontal network and glutamate release by psychedelics. a | The figure shows a model in which hallucinogens, such as psilocin, lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT), increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic serotonin (5-hydroxytryptamine) 2A (5-HT 2A ) receptors that are located on large glutamatergic pyramidal cells in deep cortical layers (v and vi) projecting to layer v pyramidal neurons. This glutamate release leads to an activation of AMPA (α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) and NMDA (N-methyl-d-aspartate) receptors on cortical pyramidal neurons. in addition, hallucinogens directly activate 5-HT 2A receptors located on cortical pyramidal neurons. This activation is thought to ultimately lead to increased expression of brain-derived neurotrophic factor (BDNF). b | The figure shows a model in which dissociative NMDA antagonists, such as ketamine, block inhibitory GABA (γ-aminobutyric acid)-ergic interneurons in cortical and subcortical brain areas, leading to enhanced firing of glutamatergic projection neurons and increased extracellular glutamate levels in the prefrontal cortex. As ketamine also blocks NMDA receptors on cortical pyramidal neurons, the increased glutamate release in the cortex is thought to stimulate cortical AMPA more than NMDA receptors. The increased AMPA-receptor-mediated throughput relative to NMDA-receptor-mediated throughput is thought ultimately to lead to increased expression of BDNF.
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Psychedelic drugs have long held a special
fascination for mankind because they pro-
duce an altered state of consciousness that is
characterized by distortions of perception,
hallucinations or visions, ecstasy, dissolu-
tion of self boundaries and the experience
of union with the world. As plant-derived
materials, they have been used traditionally
by many indigenous cultures in medical
and religious practices for centuries, if
not millennia1.
However, research into psychedelics
did not begin until the 1950s after the
breakthrough discovery of the classical
hallucinogen lysergic acid diethylamide
(LSD) by Albert Hofmann2 (TIMELINE). The
classical hallucinogens include indoleam-
ines, such as psilocybin and LSD, and
phenethylamines, such as mescaline and
(DOI). Research into psychedelics was
advanced in the mid 1960s by the finding
that dissociative anaesthetics such as keta-
mine and phencyclidine (PCP) also pro-
duce psychedelic-like effects3 (BOX 1). Given
their overlapping psychological effects,
both classes of drugs are included here
as psychedelics.
Depending on the individual taking the
drug, their expectations, the setting in which
the drug is taken and the drug dose, psych-
edelics produce a wide range of experiential
states, from feelings of boundlessness, unity
and bliss on the one hand, to the anxiety-
inducing experiences of loss of ego-control
and panic on the other hand4–7. Researchers
from different theoretical disciplines and
experimental perspectives have emphasized
different experiential states. One emphasis
has been placed on the LSD-induced percep-
tual distortions — including illusions and
hallucinations, thought disorder and
experiences of split ego7,8 — that are also
seen in naturally occurring psychoses9–11.
This perspective has prompted the use of
psychedelics as research tools for unravelling
the neuronal basis of psychotic disorders,
such as schizophrenia spectrum disorder.
The most recent work has provided com-
pelling evidence that classical hallucino-
gens primarily act as agonists of serotonin
(5-hydroxytryptamine) 2A (5-HT2A)
receptors12 and mimic mainly the so-
called positive symptoms (hallucinations
and thought disorder) of schizophrenia10.
Dissociative anaesthetics mimic the positive
and the negative symptoms (social with-
drawal and apathy) of schizophrenia
through antagonism at NMDA (N-methyl--
aspartate) glutamate receptors13,14.
Emphasis has also been placed on the
early observation that LSD can enhance
self-awareness and facilitate the recollection
of, and release from, emotionally loaded
memories15,16. This perspective appealed
to psychiatrists as a unique property that
could facilitate the psychodynamic process
during psychotherapy. In fact, by 1965 there
were more than 1,000 published clinical
studies that reported promising therapeutic
effects in over 40,000 subjects17. LSD,
psilocybin and, sporadically, ketamine have
been reported to have therapeutic effects in
patients with anxiety and obsessive–
compulsive disorders (OCD), depression,
sexual dysfunction and alcohol addiction,
and to relieve pain and anxiety in
patients with terminal cancer18–23 (BOX 2).
Unfortunately, throughout the 1960s and
1970s LSD and related drugs became
increasingly associated with cultural rebel-
lion; they were widely popularized as drugs
of abuse and were depicted in the media as
highly dangerous. Consequently, by about
1970, LSD and related drugs were placed
in Schedule I in many western countries.
Accordingly, research on the effects of
classical psychedelics in humans was
severely restricted, funding became
difficult and interests in the therapeutic
use of these drugs faded, leaving many
avenues of inquiry unexplored and
many questions unanswered.
With the development of sophisticated
neuroimaging and brain-mapping tech-
niques and with the increasing understand-
ing of the molecular mechanisms of action
of psychedelics in animals, renewed interest
in basic and clinical research with psyche-
delics in humans has steadily increased since
the 1990s. In this Perspective, we review
early and current findings of the therapeutic
effects of psychedelics and their mechanisms
of action in relation to modern concepts of
the neurobiology of psychiatric disorders.
We then evaluate the extent to which
psychedelics may be useful in therapy —
aside from their established application as
models of psychosis3,11.
The neurobiology of psychedelic
drugs: implications for the treatment
of mood disorders
Franz X. Vollenweider and Michael Kometer
Abstract | After a pause of nearly 40 years in research into the effects of psychedelic
drugs, recent advances in our understanding of the neurobiology of psychedelics,
such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to
renewed interest in the clinical potential of psychedelics in the treatment of various
psychiatric disorders. Recent behavioural and neuroimaging data show that
psychedelics modulate neural circuits that have been implicated in mood and
affective disorders, and can reduce the clinical symptoms of these disorders. These
findings raise the possibility that research into psychedelics might identify novel
therapeutic mechanisms and approaches that are based on glutamate-driven
© 20 Macmillan Publishers Limited. All rights reserved10
Current therapeutic studies
Several preclinical studies in the 1990s
revealed an important role for the NMDA
glutamate receptor in the mechanism of
action of antidepressants. These findings
consequently gave rise to the hypothesis that
the NMDA-antagonist ketamine might have
potential as an antidepressant24. This hypoth-
esis was validated in an initial double-blind
placebo-controlled clinical study in seven
medication-free patients with major depres-
sion. Specifically, a significant reduction in
depression scores on the Hamilton depression
rating scale (HDRS) was observed 3 hours
after a single infusion of ketamine (0.5 mg
per kg), and this effect was sustained for at
least 72 hours25. Several studies have since
replicated this rapid antidepressant effect of
ketamine using larger sample sizes and treat-
ment-resistant patients with depression26–30.
Given that 71% of the patients met response
criteria (defined as a 50% reduction in HDRS
scores from baseline) within 24 hours26, this
rapid effect has a high therapeutic value. In
particular, patients with depression who are
suicidal might benefit from such a rapid and
marked effect as their acute mortality risk is
not considerably diminished with conven-
tional antidepressants owing to their long
delay in onset of action (usually 2–3 weeks).
Indeed, suicidal ideations were reduced
24 hours after a single ketamine infusion28.
However, despite these impressive and
rapid effects, all but 2 of the patients relapsed
within 2 weeks after a single dose of keta-
mine26. Previous relapse prevention strategies,
such as the administration of either five
additional ketamine infusions29 or riluzole
(Rilutek; Sanofi-aventis) on a daily basis30,
yielded success only in some patients and
other strategies should be tested in further
studies. Moreover, the use of biomarkers
that are rooted in psychopathology, neuro-
psychology and/or genetics might help to
predict whether ketamine therapy will be
appropriate for a given patient with
depression31. In line with this idea, decreased
activation of the anterior cingulate cortex
(ACC) during a working memory task32 and
increased activation of the ACC during an
emotional facial processing task33, as well
as a positive family history of alcohol
abuse27, were associated with a stronger
antidepressant response to ketamine.
Ketamine therapy could be extended to
other disorders in which NMDA receptors
are implicated in the pathophysiology — for
example, bipolar disorder34 and addic-
tion35. The use of ketamine for the treatment
of bipolar disorder is currently being tested
( NCT00947791). Its poten-
tial as a treatment for addiction is supported by
results from a double-blind, randomized clini-
cal trial in which 90 heroin addicts received
either existentially oriented psychotherapy in
combination with a high dose (2.0 mg per kg)
or a low dose of ketamine (0.2 mg per kg).
Follow-up studies in the first 2 years revealed
a higher rate of abstinence, greater and
longer-lasting reductions in craving, and a
positive change in nonverbal, unconscious
emotional attitude in subjects who had been
treated with a high dose, compared with a low
dose, of ketamine36.
In contrast to the rapidly increasing
number of clinical studies with ketamine,
studies with classic hallucinogens are
emerging slowly. This slow progress may
be due to the fact that classic hallucinogens
are placed in Schedule 1 and therefore have
higher regulatory hurdles to overcome and
may have negative connotations as a drug
of abuse.
A recent study by Moreno and
colleagues37 evaluated case reports and
findings from studies performed in the
1960s that indicated that psilocybin and LSD
are effective in the treatment of OCD22,38–40.
They subsequently carried out a study show-
ing that psilocybin given on four different
occasions at escalating doses (ranging from
sub-hallucinogenic to hallucinogenic doses)
markedly decreased OCD symptoms
(by 23–100%) on the Yale–Brown obsessive
compulsive scale in patients with OCD who
were previously treatment resistant37. The
reduction in symptoms occurred rapidly, at
about 2 h after the peak psychedelic effects,
and endured up to the 24-h post-treatment
rating37. This symptom relief was not related
to the dose of the psych edelic drug or to the
intensity of the psychedelic experience, and
extended beyond the observed acute
psychological effect of 4–6 h, raising
intriguing questions regarding the mecha-
nisms that underlie this protracted effect37.
Further research on how this initial relief of
symptoms in response to psilocybin — and
the subsequent return of symptoms — is
linked to functional changes in the brain
could contribute not only to a mechanistic
explanation of the potentially beneficial
effects of psychedelics but also to the
development of novel treatments for OCD.
The chronicity and disease burden of
OCD, the suboptimal nature of available
treatments and the observation that
psilocybin was well tolerated in OCD
patients are clear indications that further
studies into the duration, efficacy and
Timeline | A brief history of psychedelic drugs
1897 1919 1926 1938 1943 1947 1952 1953 1958 1962 1963 1965 1966 1970 1983 1988 1990 1999
Synthesis of
by E. Späth
Isolation and
of mescaline
by A. Heffter
of PCP
First LSD study
in people with
depression by
C. Savage
Isolation and
synthesis of
psilocin and
psilocybin by
A. Hofmann
of LSD by
A. Hofmann
First LSD
study in
humans by
W. Stoll
LSD appears on
the streets
of antagonistic
action of PCP at
NMDA receptors
by N. Anis
Sandoz recalls
samples of
LSD and
supplying it
First neuroimaging
study on psilocybin
and ketamine
Discovery of
effects of LSD
by A. Hofmann
First clinic using
LSD in psycholytic
therapy by
R. Sandison
of ketamine
of the term
by E. Domino
LSD, psilocin
and mescaline
are placed in
Schedule I in
the US
Ketamine is
placed in
schedule III
in the US
Demonstration of
agonistic action of
LSD at 5-HT2A
receptors; first
study on mescaline
LSD, lysergic acid diethylamide; NMDA, N-methyl-d-aspartate; PCP, phencyclidine. Discoveries relating to classical hallucinogens and to dissociative anaesthetics are
shown by black and red boxes, respectively.
© 20 Macmillan Publishers Limited. All rights reserved10
Nature Reviews | Neuroscience
Vivid imagery
10 20 30 40 50 60 70 20 30 40 50 60
Blissful state
Psilocybin 115–125 µg per kg (n = 72)
Psilocybin 215–270 µg per kg (n = 214)
Psilocybin 315 µg per kg (n = 41)
Changed meaning
of percepts
Changed meaning
of percepts
Vivid imagery
Blissful state
of unity
of unity
Impaired control
and cognition
Impaired control
and cognition
Ketamine 6 µg per kg per min (n = 42)
Ketamine 12 µg per kg per min (n = 92)
mechanisms of action of psilocybin or of
related compounds in the treatment of OCD
are warranted.
Encouraged by early findings (BOX 2),
several clinical centres have begun to inves-
tigate the potential beneficial effects of psi-
locybin ( NCT00302744,
NCT00957359 and NCT00465595) and LSD
( NCT00920387) in the
treatment of anxiety and depression in
patients with terminal cancer, using state
of the art, double-blind, placebo-controlled
designs. One of these studies has recently
been completed and revealed that moder-
ate doses of psilocybin improved mood and
reduced anxiety and that this relief variably
lasted between 2 weeks and 6 months in
patients with advanced cancer (C.S. Grob,
personal communication). Finally, another
recent study reported that psilocybin and LSD
aborted attacks, terminated the cluster period
or extended the remission period in people
suffering from cluster headaches41. Taken
together, these findings support early obser-
vations in the 1960s that classical hallucino-
gens have antinociceptive potential and may
not only reduce symptoms but also induce
long-lasting adaptive processes.
Neurobiology of psychedelic drugs
The enormous progress that has been made
in our understanding of the mechanisms of
action of psychedelics12,42–45 and the neurobi-
ology of affective disorders34,46,47 has enabled
us to postulate new hypotheses regarding the
therapeutic mechanisms of psychedelics and
their clinical applications. Here we focus on
the glutamatergic and serotonergic mecha-
nisms of action of psychedelics with regard
to their most promising indications — that
is, their use in the treatment of depression
and anxiety.
Classical hallucinogens. The classical hallu-
cinogens are comprised of three main chem-
ical classes: the plant-derived tryptamines
(for example, psilocybin) and phenethyl-
amines (for example, mescaline), and the
semisynthetic ergolines (for example, LSD)48.
Although all classical hallucinogens display
high affinity for 5-HT2 receptors, they also
interact to some degree with 5-HT1, 5-HT4,
5-HT5, 5-HT6 and 5-HT7 receptors12. In con-
trast to the tryptamines, the ergolines also
show high intrinsic activity at dopamine D2
receptors and at α-adrenergic receptors49.
Converging evidence from pharmaco-
logical50, electrophysiological51,52 and behav-
ioural studies in animals53,54 suggests that
classical hallucinogens produce their effects
in animals and possibly in humans primarily
through agonistic actions at cortical 5-HT2A
receptors (FIG. 1a). Consistent with this view,
selectively restoring 5-HT2A receptors in
Box 1 | Assessing altered states of consciousness
Quantifying altered states of consciousness was problematic in the early years
of hallucinogen research. Today, however, there are validated instruments
for assessing various aspects of consciousness. According to Dittrich133,
hallucinogen-induced altered states of consciousness can be reliably measured
by the five-dimensional altered states of consciousness (5DASC)
rating scale. This scale comprises five primary dimensions and their respective
subdimensions (see the figure). The primary dimensions are ‘oceanic
boundlessness’ (shown by orange boxes), referring to positively experienced
loss of ego boundaries that are associated with changes in the sense of
time and emotions — ranging from heightened mood to sublime happiness
and feelings of unity with the environment; ‘anxious ego-disintegration’
(shown by purple boxes), including thought disorder and loss of self-control;
‘visionary restructuralization’ (shown by blue boxes), referring to perceptual
alterations (such as visual illusions and hallucinations), and altered meaning of
percepts; acoustic alterations (not shown), including hypersensitivity to sound
and auditory hallucinations; and altered vigilance (not shown).
In general, the intensity of these psychedelic-induced alterations of
consciousness and perception is dose-dependent, so that hallucinations
that involve disorientation in person, place and time rarely, if ever, occur
with low to medium doses4–6. However, at larger doses — and depending
on the individual, his or her expectations and the setting — the same
hallucinogen might produce a pleasurable loss of ego boundaries combined
with feelings of oneness or might lead to a more psychotic ego dissolution
that involves fear and paranoid ideation4,132,134. Such experiential
phenomena are otherwise rarely reported except in dreams, contemplative
or religious exaltation and acute psychoses11,135. The figure shows that the
classical hallucinogen psilocybin (0.015–0.027 g per kg, by mouth) (see
the figure, left) and the dissociative s-ketamine (6–12 g per kg per min,
intravenously) (see the figure, right) produce a set of overlapping
psychological experiences, measured by the 5DASC rating scale and
respective subscales. The scales indicate the percentage scored of the
maximum score.
© 20 Macmillan Publishers Limited. All rights reserved10
cortical pyramidal neurons is sufficient to
rescue hallucinogen-induced head shaking
in transgenic mice that lack 5-HT2A recep-
tors53,55. Importantly, administration of the
5-HT2A receptor antagonist ketanserin abol-
ishes virtually all of the psilocybin-induced
subjective effects in humans56. Recent stud-
ies have demonstrated that hallucinogenic
and non-hallucinogenic 5-HT2A agonists
differentially regulate intracellular signalling
pathways in cortical pyramidal neurons and
that this results in a differential expression
of downstream signalling proteins, such as
early growth response protein 1 (EGR1),
EGR2 and β-arrestin 255,57. This suggests that
further elucidation of hallucinogen-specific
signalling pathways may aid the develop-
ment of functionally selective ligands with
specific therapeutic properties — for exam-
ple, ligands that have antidepressant effects
but no hallucinogenic effects.
Several studies have demonstrated that
activation of 5-HT2A receptors by classical
hallucinogens or by serotonin leads to a
robust, glutamate-dependent increase in the
activity of pyramidal neurons, preferentially
those in layer V of the prefrontal cortex
(PFC)51,52,58,59 (FIG. 1a). This increase in
glutamatergic synaptic activity was initially
thought to result from stimulation of presy-
naptic 5-HT2A receptors located on gluta-
matergic thalamocortical afferents to the
PFC60,61. However, more recent studies sug-
gest that stimulation of postsynaptic 5-HT2A
receptors55,58,59 on a subpopulation of pyram-
idal cells in the deep layers of the PFC59 leads
to an increase in glutamatergic recurrent
network activity59,62. The increase in gluta-
matergic synaptic activity can be abolished
not only by specific 5-HT2A antagonists but
also by AMPA (α-amino-3-hydroxyl-5-
methyl-4-isoxazole-propionic acid) recep-
tor antagonists63, by agonists51 and positive
allosteric modulators of metabotropic
glutamate receptor 2 (mGluR2)64, and by
selective antagonists of the NR2B subunit
of NMDA receptors65. Taken together, these
findings indicate that classical hallucinogens
are potent modulators of prefrontal network
activity that involves a complex interaction
between the serotonin and glutamate
systems in prefrontal circuits.
Activation of 5-HT2A and 5-HT1A recep-
tors in the medial PFC (mPFC) also has
downstream effects on serotonergic and
dopaminergic activity through descend-
ing projections to the dorsal raphe and the
ventral tegmental area (VTA). For example,
activation of 5-HT2A receptors in the mPFC
increases the firing rate of 5-HT neurons in
the dorsal raphe and of dopamine neurons
in the VTA, resulting in an increased release
of 5-HT in the mPFC58,66 and of dopamine in
mesocortical areas67 in animals. In a study
in humans, the hallucinogenic 5-HT2A agon-
ist psilocybin increased striatal dopamine
concentrations, and this increase correlated
with euphoria and depersonalization
phenomena68. Blocking dopamine D2
receptors by haloperidol, however, reduced
these effects by only about 30%. This
suggests that the dopaminergic system con-
tributes only moderately to the broad spec-
trum of psilocybin-induced psychological
Interestingly, 5-HT2A receptor activation
not only seems to underlie the preponder-
ance of the acute psychedelic effects of hal-
lucinogens but may also lead to neuroplastic
adaptations in an extended prefrontal–limbic
network. For example, in rats a single dose
of the hallucinogen DOI transiently
increased the dendritic spine size in corti-
cal neurons69 and repeated doses of LSD
downregulated cortical 5-HT2A but not
5-HT1A receptors; effects that were the most
pronounced in the frontomedial cortex and
ACC70,71. It is possible that such adaptations —
and specifically a downregulation of prefrontal
5-HT2A receptors — might underlie some of
the therapeutic effects of hallucinogens in the
treatment of depression, anxiety and chronic
pain. In favour of this hypothesis, 5-HT2A
receptor density was found to be increased
in the PFC in post-mortem samples72 and
in vivo 73,74 in patients with major depression,
and to be reduced after chronic treatment with
various antidepressants — the reduction coin-
ciding with the onset of clinical efficacy75–77. In
addition, chronic, antisense-mediated down-
regulation of 5-HT2A receptors in rats78 and in
5-HT2A knockout mice79 reduced anxiety-like
behaviour, and selective restoration of 5-HT2A
receptors in the PFC normalized anxiety-like
behaviour in these 5-HT2A knockout mice.
These findings suggest that prefrontal 5-HT2A
receptors might modulate the activity of sub-
cortical structures, such as the amygdala79.
Anxiety and depression are interrelated with
stress80, which also affects the serotonin sys-
tem81. Stress elevates corticotropin-releasing
factor (CRF)82, and administration of CRF
into the mPFC of mice enhanced anxiety-like
Box 2 | Early therapeutic findings with psychedelics
By 1953, two forms of lysergic acid diethylamide (LSD) therapy based on different theoretical
frameworks were emerging. These have been named psychedelic (mind-manifesting)136 and
psycholytic (psyche-loosening)15 therapies. In psychedelic therapy, which was practised mostly in
North America, a large dose of LSD (200–800 g) was applied in a single session. This was thought
to induce an overwhelming and supposedly conversion-like peak experience that would bring the
subject to a new level of awareness and self-knowledge. It was thought that that this would
facilitate self-actualization and lead to permanent changes that would be beneficial to the
subject128,129. Furthermore, it was claimed that intensive psychotherapeutic preparation of the
patient before the drug session and a follow-up integration of the peak experience in further
drug-free sessions were crucial for an optimal outcome130. Promising therapeutic effects of this
therapy were found in people with terminal cancer20,137, in severe alcoholics138,139, in people who
were addicted to narcotics140 and in patients with neurosis141. For example, a series of studies
showed that LSD could reduce depression and decrease apprehension towards death and,
surprisingly, that LSD had transient analgesic effects that were superior to those of
dihydromorphinone (also known as hydromorphone and Palladone SR (Napp)) and meperidine
(also known as pethidine)20. These effects were confirmed in later studies and the clinical efficacy
was linked with the intensity of the psychedelic experience129,141,142.
Psycholytic therapy was introduced by Ronald Sandison and applied in Europe at 18 treatment
centres143. In psycholytic therapy, low to moderate doses of LSD (50–100 g), psilocybin (10–15 mg)
or, sporadically, ketamine were used repeatedly as an adjunct in psychoanalytically oriented
psychotherapy to accelerate the therapeutic process by facilitating regression and the
recollection and release of emotionally loaded repressed memories, and by increasing the
transference reaction15,22,144–147. A review of 42 studies reported impressive improvement rates in
(mostly treatment-resistant) patients with anxiety disorders (improvement in 70% of patients),
depression (in 62% of patients), personality disorders (in 53–61% of patients), sexual dysfunction
(in 50% of patients) and obsessive–compulsive disorders (in 42% of patients)148.
Unfortunately, the majority of these studies had serious methodological flaws by contemporary
standards. In particular, with the absence of adequate control groups and follow-up measurements
and with vague criteria for therapeutic outcome, the studies did not clearly establish whether it
was the drug or the therapeutic engagement that produced the reported beneficial effect. It was
also difficult to draw firm conclusions regarding potential long-term efficacy. Nevertheless, the
studies provide a conceptual framework for the application of psychedelics, with the data
suggesting that the most promising indication for psychedelic use might be found in the treatment
of depression and anxiety disorders.
© 20 Macmillan Publishers Limited. All rights reserved10
Nature Reviews | Neuroscience
5-HT neuron
Subcortical areasCortex
Cortical layer V Deep cortical layers Brainstem
behaviour in response to DOI through
sensitization of 5-HT2 receptor signalling in
the PFC83. In humans, fronto-limbic 5-HT2A
receptor density is correlated not only with
anxiety but also with an individual’s difficul-
ties in coping with stress84. Indeed, recent
studies showed that prefrontal 5-HT2A recep-
tors located on descending projections that
control serotonergic activity in the dorsal
raphe are involved in stress responses67,85.
Together, these findings suggest that down-
regulation of prefrontal 5-HT2A receptors by
classical hallucinogens might underlie some
of the effects of hallucinogens on depression
and anxiety.
Finally, with regard to the finding that
LSD reduces anxiety and pain in cancer
patients20, it is of note that prefrontal 5-HT2A
density correlated with responses to tonic
pain but not with responses to short pha-
sic pain stimuli. This suggests a role of the
5-HT2A receptors in the cognitive evaluation
of pain experiences86 and points to addi-
tional therapeutic potential for hallucinogens
in individuals with chronic pain.
Dissociative anaesthetics. At sub-anaesthetic
doses, dissociative anaesthetics, such as
ketamine, primarily block the NMDA recep-
tor at the PCP binding site in the receptor’s
ionotropic channel14 (FIG. 1b). The psychoac-
tive potency of the -ketamine enantiomer is
three to four times higher than that of the
-ketamine enantiomer. This is paralleled by
their relative affinities at the NMDA receptor
complex87. Systemic administration of
non-competitive NMDA antagonists, such
as ketamine, PCP and MK-801 (also
known as dizocilpine), in rats mark-
edly increases glutamate release in the
mPFC88,89 concomitant with an increase in
the firing rate of pyramidal neurons in this
area90. These effects are probably due to a
blockade of NMDA receptors on GABA
(γ-aminobutyric acid)-ergic interneurons45,91
in cortical and/or subcortical structures and
to the subsequent reduction of inhibitory
control over prefrontal glutamatergic neu-
rons92. The increased extracellular glutamate
levels in the mPFC seem to contribute to the
psychotropic effects of ketamine and PCP,
as AMPA receptor antagonists88 or agonists
of mGluR2 and mGluR3 (REF. 93) abolished
various behavioural effects of NMDA
antagonists in rats. Likewise, the behavioural
effects of selective NR2B antagonists — such
as CP-101,606 (also known as Traxoprodil),
which produces dose-dependent psycho-
tropic effects similar to those of ketamine in
humans94 — can be blocked by administra-
tion of AMPA receptor antagonists95. Finally,
lamotrigine, which reduces presynaptic
glutamate release, attenuated the subjective
effects of -ketamine in humans96.
In addition to having these glutamatergic
effects, non-competitive NMDA receptor
antagonists increase extracellular prefrontal
and mesolimbic dopamine89,93 and pre-
frontal serotonin89 levels in rats, presum-
ably by stimulating corticofugal glutamate
release in the VTA97 and the dorsal raphe89,
respectively. Studies into the contribution of
this dopaminergic and serotonergic activa-
tion to the behavioural effects of NMDA
antagonists are scant and the results are
somewhat controversial. Specifically, in
two studies in humans, ketamine-induced
striatal dopamine release correlated with
the extent of ketamine-induced psychotic
Figure 1 | Activation of the prefrontal network and glutamate release by psychedelics. a | The
figure shows a model in which hallucinogens, such as psilocin, lysergic acid diethylamide (LSD) and
dimethyltryptamine (DMT), increase extracellular glutamate levels in the prefrontal cortex through
stimulation of postsynaptic serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors that are located
on large glutamatergic pyramidal cells in deep cortical layers (V and VI) projecting to layer V pyramidal
neurons. This glutamate release leads to an activation of AMPA (α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid) and NMDA (N-methyl-d-aspartate) receptors on cortical pyramidal neurons. In
addition, hallucinogens directly activate 5-HT2A receptors located on cortical pyramidal neurons. This
activation is thought to ultimately lead to increased expression of brain-derived neurotrophic factor
(BDNF). b | The figure shows a model in which dissociative NMDA antagonists, such as ketamine, block
inhibitory GABA (γ-aminobutyric acid)-ergic interneurons in cortical and subcortical brain areas, lead-
ing to enhanced firing of glutamatergic projection neurons and increased extracellular glutamate
levels in the prefrontal cortex. As ketamine also blocks NMDA receptors on cortical pyramidal neurons,
the increased glutamate release in the cortex is thought to stimulate cortical AMPA more than NMDA
receptors. The increased AMPA-receptor-mediated throughput relative to NMDA-receptor-mediated
throughput is thought ultimately to lead to increased expression of BDNF.
© 20 Macmillan Publishers Limited. All rights reserved10
Nature Reviews | Neuroscience
symptoms98,99, but in another study systemic
administration of the dopamine D2 recep-
tor antagonist haloperidol did not attenuate
ketamine-induced psychotic symptoms
in healthy volunteers100. Although 5-HT2A
receptor antagonists reverse the disruptive
effects of NMDA antagonists on sensorimo-
tor gating101 and on object recognition102 in
animals, no comparable studies of the role
of serotonin in the mechanism of action of
NMDA antagonists have been conducted
in humans.
The enhanced glutamate release that
results from NMDA receptor blockade
by ketamine leads to an increased activa-
tion of AMPA receptors relative to NMDA
receptors95. The antidepressant-like effects
of ketamine and the selective NR2B antago-
nist CP-101,606 in animals can be blocked
by administration of the AMPA receptor
antagonist 2,3-dihydroxy-6-nitro-7-sul-
(NBQX)95, suggesting that enhanced AMPA
activation in cortical circuits is crucial for
the therapeutic effect of NMDA receptor
A common mechanism? There is accumulat-
ing evidence that, despite their different pri-
mary modes of action, classical hallucinogens
and dissociative anaesthetics both modulate
glutamatergic neurotransmission in the pre-
frontal–limbic circuitry that is implicated in
the pathophysiology of mood disorders. This
modulation is evidenced by the observation
in rats that hallucinogens103,104 and dissocia-
tive anaesthetics88,89 have a similar effect in
enhancing extracellular glutamate release
in the PFC, leading to increased activation
of pyramidal cells63,65,105,106. Furthermore,
and congruent with these findings, human
neuroimaging studies have shown that both
psilocybin and ketamine markedly activate
prefrontal cortical areas, including the ACC
and insula and, to a lesser extent, temporal and
parieto-occipital regions107–111 (FIG. 2).
According to current models of emotion
regulation the PFC, including the ACC, exerts
cognitive’, top-down control over emotion
and stress responses through its connec-
tions to the amygdala and dorsal raphe47,85.
Reduced prefrontal glutamate levels that are
associated with attenuated PFC activation
in response to emotional stimuli34,112,113 have
been reported in patients with depression.
Further, depressed individuals46 and subjects
with high trait anxiety114 show reduced PFC
activity when executive control is engaged,
and might suffer from decreased top-
down inhibition of amygdala activity115,116.
Conversely, chronic treatment with selective
serotonin reuptake inhibitors (SSRIs) increases
the functional connectivity between the amy-
gdala and the PFC117, and attenuates the
amygdala response to the presentation of
images showing sad faces in patients with
depression118,119. This suggests that the normal-
ization of this dysregulated network might be
important in the recovery from depression46.
Given that both psilocybin and ketamine
increase extracellular glutamate levels in
the prefrontal–limbic circuitry in rats and
that the antidepressant effects of both drugs
outlast their acute psychotropic effects in
depressed patients, we propose that a
normalization of this network through
a glutamate-dependent neuroplastic adapt-
ation is the common therapeutic mechanism
of these drugs. Specifically, we posit that
psychedelics enhance neuroplasticity by
increasing AMPA-type glutamate receptor
trafficking and by raising the level of brain-
derived neurotropic factor (BDNF). Deficits
in these neuroplastic mechanisms have been
implicated in the pathophysiology of depres-
sion34,120. Normalization of these neuroplastic
deficits might contribute not only to the
relatively sustained antidepressant effects of
ketamine121,122 but also to those of psilocybin.
In line with this view, both classes of drugs
have been demonstrated to stimulate AMPA
receptors by increasing extracellular gluta-
mate levels6,95 and to increase BDNF levels in
prefrontal and limbic brain areas in rats123125.
A recent study in patients with depression,
however, failed to demonstrate an increase
in BDNF plasma levels in the first 4 h after
ketamine infusion122. Whether ketamine
treatment leads to an increase in BDNF levels
at a later time and whether such an increase
is associated with sustained antidepressant
effects warrants further investigation.
Conclusions and future directions
The clinical findings and current under-
standing of the mechanisms of action of
classical hallucinogens and dissociative
anaesthetics converge on the idea that
psychedelics might be useful in the treat-
ment of major depression, anxiety disorders
and OCD. These are serious, debilitating,
life-shortening illnesses, and as the cur-
rently available treatments have high failure
rates, psychedelics might offer alternative
Figure 2 | Brain activity patterns in psychedelic-induced states of consciousness. a | Brain
imaging studies using 18fluorodeoxyglucose [18FDG] positron emission tomography (PET) revealed that
moderate doses of s-ketamine (top) and psilocybin (bottom) in healthy volunteers increased neuronal
activity. This is shown by changes in the cerebral metabolic rate for glucose (CMRglu) in the prefrontal
cortex and associated limbic regions and in subcortical structures, including the thalamus107,109. This
similar prefrontal–limbic activation pattern supports the view that both classes of drugs have converg-
ing effects on a final pathway or neurotransmitter system. b | Recent [18FDG] PET brain imaging studies
have demonstrated that the degree to which each of the psychedelic-induced key dimensions of
altered states of consciousness (BOX 2) is manifested and correlated with functional alterations in
cortical and limbic regions and subcortical structures, including the basal ganglia and thalamus. For
example, the intensity of experience of the key dimension ‘oceanic boundlessness’ correlated with
the s-ketamine- and psilocybin-induced activation (red) of a prefrontal–parietal network and the
deactivation (blue) of a striato–limbic amygdalocentric network149.
© 20 Macmillan Publishers Limited. All rights reserved10
treatment strategies that could improve the
well-being of patients and the associated
economic burden on patients and society.
Accumulating evidence shows a crucial
role for the glutamate system in the regula-
tion of neuronal plasticity, and indicates that
abnormalities in neuroplasticity contribute
to the pathophysiology of mood disorders.
Thus, drugs that target neuronal plasticity
may offer a novel approach to their treat-
ment. This Perspective proposes that classical
psychedelics, such as psilocybin, and dis-
sociative anaesthetics, such as ketamine,
alter glutamatergic neurotransmission in
prefrontal–limbic circuitries, and that this
leads to neuroplastic adaptations, presumably
through enhancement of AMPA receptor
function. These adaptations may explain
some of the shared and relatively sustained
antidepressant effects that are observed in
clinical studies with ketamine and psilocybin.
To further validate this glutamate-induced
neuroplasticity hypothesis the relationship
between measures of glutamatergic activity
and clinical outcome needs to be established.
Moreover, the finding that classical halluci-
nogens (unlike dissociative anaesthetics) also
modulate 5-HT2A receptor signalling suggests
that they may improve subtypes of anxiety
and stress-related disorders. Studies that use
biomarkers for genotypes or that use expres-
sion levels of 5-HT2A receptors in parallel with
clinical end points would be essential not only
for clarifying the role of 5-HT2A receptors in
the therapeutic mechanism of classical hal-
lucinogens but also for the development of
personalized medicines in the treatment
of anxiety and stress-related disorders.
In addition, to optimize the clinical
benefits of psychedelics and to reduce their
unwanted side effects, a deeper understand-
ing of various factors is necessary. These
include structure–activity relationships, dose–
response relationships and the influence of
psychotherapeutic approaches on the effects
of psychedelics. In this context, it is interest-
ing to note that there was no indication of
prolonged psychosis, persisting perception
disorder or subsequent drug abuse after psi-
locybin126 or ketamine127 administration in a
large sample of psychotherapeutically well-
prepared healthy subjects in a supportive
research setting. Similar observations were
reported in small samples of patients with
depression29 and OCD37. Nonetheless, it is
often claimed that the dissociative effects of,
for example, ketamine may limit clinical use,
despite its reported efficacy24,94. In this sense,
understanding the molecular mechanism
of action could inform the development of
novel ligands for 5-HT2A or NMDA receptors
that display antidepressant properties but
have fewer dissociative effects than psilocy-
bin and ketamine. Further evaluations of the
dose–response relationship may be another
approach to minimize unwanted side effects.
For example, low to moderate oral doses of
psilocybin (<0.215 mg per kg) were found
to only rarely produce anxious dissociative
symptoms in controlled settings126 (BOX 1)
but to reduce anxiety, depression and OCD
symptoms in patients22,37. Similarly, a low
dose of the NR2B antagonist CP-101,606 (in
combination with an SSRI) had transient
antidepressant effects in a small sample of
patients with depression and only rarely
induced dissociative symptoms94.
To take the opposite perspective, it is
noteworthy that initial clinical applications of
psychedelics in psychedelic and psycholytic
therapy were based on the premise that the
drug-induced psychological experience had
an essential, facilitatory effect on the psycho-
therapeutic process — that is, it was a form
of pharmacology-assisted psychotherapy.
Indeed, it has been shown that the transcend-
ent peak (mystical-type) experience, which
has a key role in the therapeutic outcome
in psychedelic therapy128–130 and was rated
as among the most personally meaningful
experiences131,132, occurs in most cases only
in supportive settings and after high-dose
administration of psychedelics. One might
interpret this concept as an early example of
the neuroplasticity hypothesis in which the
drug-induced experience and its integration
in the psychotherapeutic process is the cru-
cial mechanism that enables neuroplasticity
and behavioural changes. By contrast, cur-
rent pharmacological strategies often assume
that medication alone produces neuroplastic
adaptations. However, drugs that increase
neuroplasticity, such as psychedelics, might
be particularly clinically efficient in com-
bination with psychotherapeutic interven-
tions121. In support of this notion, cognitive
behavioural therapy was shown to normalize
prefrontal–limbic functioning in depressed
patients46, and could therefore enhance the
proposed neuroplastic effects of psychedelics
in prefrontal–limbic structures as discussed
here. Thus, further blind, controlled studies
are obviously now needed to test these
alternative and opposing hypotheses.
The potential of drugs to target glutama-
tergic neurotransmission in prefrontal–
limbic circuitries and to facilitate neuroplas-
tic adaptations may translate into promising
new treatment approaches for affective dis-
orders. The novel hypotheses presented here
now need to be investigated using well-
controlled clinical studies, keeping in mind
the controversial history of this class of drugs.
Franz X. Vollenweider and Michael Kometer are at the
Neuropsychopharmacology and Brain Imaging
Research Unit, University Hospital of Psychiatry,
Zurich, Switzerland.
Franz X. Vollenweider is also at the School of Medicine,
University of Zurich, Switzerland.
Correspondence to F.X.V.
Published online 18 August 2010
Cluster period
A period of time during which cluster headache attacks
occur regularly.
Two stereoisomeric molecules that are mirror images of
each other and are not superimposable.
Existentially oriented psychotherapy
A form of therapy that emphasizes the development of a
sense of self-direction through choice and of awareness in
resolving existential conflicts (such as the inevitability of
death, isolation and meaninglessness).
A former term for a category of mental disorders
characterized by anxiety and a sense of distress. This
category includes disorders now classified as mood
disorders, anxiety disorders, dissociative disorders,
sexual disorders and somatoform disorders.
Psychoanalytically oriented psychotherapy
A therapy based on Freudian psychoanalysis in which
unconscious conflicts that are thought to cause the
patient’s symptoms are brought into consciousness to
create insight for the resolution of the problems.
In Freudian psychoanalytic theory this term describes a
psychological strategy to cope with reality by means of
a temporary reversion of the ego to an earlier stage of
A drug used to treat amyotrophic lateral sclerosis and that
has NMDA (N-methyl-d-aspartate) receptor blocking
properties similar to those of ketamine.
Schedule 1
A legislative category containing controlled drugs that have
a high potential for abuse, a lack of accepted safety and no
currently accepted medical use in treatments.
Selective serotonin reuptake inhibitors
A class of compounds typically used as antidepressants.
The motivation to realize all of one’s potential.
Structure–activity relationship
(Often abbreviated to SAR.) This is the relationship between
the chemical structure of a molecule and its biological activity.
A phenomenon in psychoanalysis characterized by
unconscious redirection of feelings or desires from one
person to another.
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The authors would like to acknowledge the financial support
of the Swiss Neuromatrix Foundation (to F.X.V. and M.K.),
and of the Heffter Research Institute (to F.X.V.). The authors
thank D. Nichols for critical comments on the manuscript.
Competing interests statement
The authors declare no competing financial interests.
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b-arrestin 2 | EGR1 | EGR2 | mGluR2 | mGluR3
University of Zurich Neuropsychopharmacology and Brain
Imaging Group’s homepage:
Socioeconomic status and the brain:
mechanistic insights from human
and animal research
Daniel A. Hackman, Martha J. Farah and Michael J. Meaney
Abstract | Human brain development occurs within a socioeconomic context and
childhood socioeconomic status (SES) influences neural development
particularly of the systems that subserve language and executive function.
Research in humans and in animal models has implicated prenatal factors,
parent–child interactions and cognitive stimulation in the home environment in
the effects of SES on neural development. These findings provide a unique
opportunity for understanding how environmental factors can lead to individual
differences in brain development, and for improving the programmes and policies
that are designed to alleviate SES-related disparities in mental health and
academic achievement.
As the field of human neuroscience has
matured, it has progressed from describing
the ‘typical’ or ‘average’ human brain to
characterizing individual differences in
brain structure and function, and identify-
ing their determinants. Socioeconomic sta-
tus (SES), a measure of ones overall status
and position in society, strongly influences
an individual’s experiences from child-
hood and through adult life. Research is
beginning to shed light on the mechanisms
through which experiences in the social
world during early childhood affect the
structure and function of the brain.
Growing up in a family with low SES is
associated with substantially worse health
and impaired psychological well-being, and
impaired cognitive and emotional develop-
ment throughout the lifespan1–6. In con-
trast to sociological and epidemiological
approaches, neuroscience can identify the
underlying cognitive and affective systems
that are influenced by SES (BOX 1). In addi-
tion, neuroscience research — in animals
and in humans — has provided candidate
mechanisms for the cause–effect relation-
ships between SES and neural development.
This research has also demonstrated that at
least some of these effects are reversible. Such
a mechanistic understanding will enable the
design of more specific and powerful inter-
ventions to prevent and remediate the effects
of low childhood SES7–9.
Other recent reviews have discussed
research on SES-related differences in
neurocognitive development7–9. In this
Perspective, we focus on the candidate
mechanisms by which SES influences brain
development, drawing from research in
humans and in animal models. We first
describe studies in humans that show that
SES influences cognitive and affective func-
tion in children, adolescents and young
adults. We then discuss studies in human
populations that have identified possible
mediators of the effects of SES, and review
research in animals in which these factors
were directly manipulated to assess their
effect on offspring outcomes.
SES effects on mental health and cognition
SES is a complex construct that is based
on household income, material resources,
education and occupation, as well as related
neighbourhood and family characteristics,
such as exposure to violence and toxins,
parental care and provision of a cognitively
stimulating environment2,5,10,11 (for con-
troversies regarding the measurement and
defining levels of SES see REFS 1,10,11). Not
only the lowest stratum but all levels of SES
affect emotional and cognitive development
to varying degrees1,12–14. This implies that the
effects of SES that are reviewed here are
relevant to the entire population, although
it should be noted that the strongest effects
are often seen in people with the lowest
levels of SES.
Compared with children and adolescents
from higher-SES backgrounds, children
and adolescents from low-SES backgrounds
show higher rates of depression, anxiety,
attention problems and conduct disor-
ders12,15–18, and a higher prevalence of inter-
nalizing (that is, depression- or anxiety-like)
and externalizing (that is, aggressive and
impulsive) behaviours6,19–21, all of which
increase with the duration of impoverish-
ment12,21. In addition, childhood SES influ-
ences cognitive development; it is positively
correlated with intelligence and academic
achievement from early childhood and
through adolescence2,3,6,14,19,22,23.
© 20 Macmillan Publishers Limited. All rights reserved10
... Despite the complexity of their pharmacological mechanisms, compelling evidence suggests that serotonergic neurotransmission-especially the serotonin 2A receptor-plays a key role in the mediation of their effects. Unsurprisingly, some of these molecules show structural similarity to serotonin itself (Vollenweider and Kometer, 2010). Classic psychedelics can be further distinguished into three classes: tryptamine derivates (such as psilocybin and N,N-dimethyltryptamine [DMT]), phenylalkylamines such as mescaline, and ergoline derivatives such as LSD. ...
... Other neurotransmitter-modulations are diverse across substances, but a potential causal relationship between other neurotransmitters and characteristic classic psychedelic effects is still lacking. Classic psychedelics modulate different neuronal networks that process sensory perception, the experience of self, and emotion regulation, which are relevant for the neurobiology of depression (Vollenweider and Kometer, 2010;Vollenweider and Preller, 2020). Several studies demonstrated classic psychedelics-induced decreases as well as increases of brain resting state functional connectivity of the default mode and the salience networks (Palhano-Fontes et al., 2015;Speth et al., 2016;Carhart-Harris et al., 2017;Muller et al., 2018;Pasquini et al., 2020). ...
... Furthermore, current studies in animal-and in-vitromodels provide evidence for mostly glutamate-induced increases in neuroplasticity, likely also initiated by serotonin 2A receptor activation (Aleksandrova and Phillips, 2021;de Vos et al., 2021). Here, brain-derived neurotrophic factor (BDNF) is one of the most important mediators of neuroplasticity under psychedelics (Vollenweider & Kometer, 2010). The involved processes are responsible for the regulation of synaptogenesis, learning and memory consolidation. ...
Full-text available
This is a narrative review about the role of classic and two atypical psychedelics in the treatment of unipolar and bipolar depression. Since the 1990s, psychedelics experience a renaissance in biomedical research. The so-called classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, mescaline and ayahuasca. Characteristic effects like alterations in sensory perception, as well as emotion- and self-processing are induced by stimulation of serotonin 2A receptors in cortical areas. The new paradigm of psychedelic-assisted psychotherapy suggests a therapeutic framework in which a safely conducted psychedelic experience is integrated into a continuous psychotherapeutic process. First randomized, controlled trials with psilocybin show promising efficacy, tolerability, and adherence in the treatment of unipolar depression. On the other hand, classic psychedelics seem to be associated with the induction of mania, which is an important issue to consider for the design of research and clinical protocols. So called atypical psychedelics are a heterogeneous group with overlapping subjective effects but different neurobiological mechanisms. Two examples of therapeutic value in psychiatry are 3,4-methyl enedioxy methamphetamine (MDMA) and ketamine. Since 2020 the ketamine enantiomer esketamine has been granted international approval for treatment-resistant unipolar depression, and also first evidence exists for the therapeutic efficacy of ketamine in bipolar depression. Whether psychedelics will fulfil current expectations and find their way into broader clinical use will depend on future rigorous clinical trials with larger sample sizes. A well-considered therapeutic and legal framework will be crucial for these substances to create new treatment settings and a potential paradigm shift.
... Two articles in this issue, Ross et al. and Griffiths et al., describe the use of psilocybin in the treatment of depression and anxiety in cancer patients. In doing so, they contribute to a resurgence of interest in research on psychedelic medications that was abruptly banned by the Controlled Substances Act of 1970 because of their popularization and excessive recreational use (Nichols, 2016;Vollenweider and Kometer, 2010). Psilocybin is a plant alkaloid derived from the Psilocybe genus of mushrooms that has been used for centuries, if not millennia, by indigenous cultures for ritualized healing and religious purposes. ...
... A greater concern is the lack of understanding of the mechanism of action of psychedelic drugs. While we know that they are agonists at 5-HT-2A receptors (Nichols, 2016), which is believed to produce subjective effects of perceptual disturbances, sensations of spiritual oneness or mystical ecstasy, and, at times, paranoia or anxiety (Vollenweider and Kometer, 2010), the mechanism mediating such effects is incompletely understood. It is thought that 5-HT-2A receptor agonism may stimulate beta arrestin intracellular signaling pathways and modulate prefrontal cortical pyramidal neurons affecting neuroplastic adaptations. ...
Full-text available
... In addition to mediating subjective and behavioral effects, these receptors are also involved in therapeutic effects. For example, altered cortical expression of 5-HT1Ar, 5-HT2Ar, and 5-HT2Cr was found in post-mortem samples obtained from depressed patients, suggesting that these receptors are associated with the dysfunctional shifts in emotional processing observed in these patients (Vollenweider and Kometer, 2010;Baumeister et al., 2014). Moreover, animal models and clinical studies have shown that 5-HT1Ar agonists have anxiolytic and antidepressant properties (Nutt, 2005;Katzman, 2009;Baumeister et al., 2014), and 5-HT2Ar and 5-HT2Cr agonists can reduce anxiety-and depression behaviour in animals (Nic Dhonnchadha et al., 2003;Baumeister et al., 2014). ...
... Remarkably, the 5-HT2Ar and mGluR2/3 receptors display an overlapping distribution in the brain cortex (Marek et al., 2000). Indirect activation of glutamate networks by psilocybin increases neuroplasticity, particularly through the α-amino-3-hydroxyl-5-methyl4isoxazole-propionic acid (AMPA) receptor, with a subsequent increase in cellular expression of downstream signalling protein, such as brain-derived neurotrophic factor (BDNF) in prefrontal areas (Vollenweider and Kometer, 2010). There is evidence for increased glutamate-dependent activity in prefrontal areas, induced by 5-HT2Ar agonism by psilocin and other classical hallucinogens (Béïque et al., 2007). ...
Full-text available
Classical psychedelics represent a family of psychoactive substances with structural similarities to serotonin and affinity for serotonin receptors. A growing number of studies have found that psychedelics can be effective in treating various psychiatric conditions, including post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are extremely prevalent in the general population constituting a major problem for the public health. There are a wide variety of interventions for mental health disorders, including pharmacological therapies and psychotherapies, however, treatment resistance still remains a particular challenge in this field, and relapse rates are also quite high. In recent years, psychedelics have become one of the promising new tools for the treatment of mental health disorders. In this review, we will discuss the three classic serotonergic naturally occurring psychedelics, psilocybin, ibogaine, and N, N-dimethyltryptamine, focusing on their pharmacological properties and clinical potential. The purpose of this article is to provide a focused review of the most relevant research into the therapeutic potential of these substances and their possible integration as alternative or adjuvant options to existing pharmacological and psychological therapies.
... Serotonin 2A receptor (5-HT 2A R) agonists, also known as classic psychedelics (Vollenweider & Kometer, 2010), have been utilized by humans for millennia. Classic psychedelics can be divided into the sub-classes of tryptamines and phenethylamines with substances like psylocibin, dimethyltryptamine, D-lysergic acid diethylamide (LSD) and ibogaine belonging to the former category and mescaline to the latter (Forstmann & Sagioglou, 2017). ...
Full-text available
Background and aims Despite promising findings indicating the therapeutic potential of psychedelic experience across a variety of domains, the mechanisms and factors affecting its efficacy remain unclear. The present paper explores this by focusing on two psychedelic states which have been suggested as therapeutically significant in past literature: ego-dissolution and connectedness. The aim of the study is to investigate the impact of ego-dissolution and connectedness on the therapeutic effects of the psychedelic experience. Methods The investigation was carried out as a mixed methods systematic review, with the data from four databases analysed thematically and results presented through narrative synthesis. Results The analysis and synthesis of findings from 15 unique studies ( n = 2,182) indicated that both ego-dissolution and connectedness are associated with a higher chance of improvement following a psychedelic experience. However, there seem to be differences in the way the two experiences affect individuals psychologically. Ego-dissolution appears to trigger psychological change but does not typically exceed the psychedelic experience in its duration, while connectedness can be more sustained and is associated with several positive, potentially therapeutic feelings. Conclusions Moreover, the findings of this review have implications for further theory-building about the mechanisms which enable therapeutic effects in psychedelic experience. This in turn might lead to improved models for psychedelic therapy practice. Emphasis on ego-dissolution during the preparation phase and on connectedness during integration is one suggestion presented here, alongside overarching implications for the mental health debate and general practice.
... Stimulation of 5-HT 2 receptors by serotonergic psychedelics enhances spontaneous excitatory postsynaptic potentials/currents in neocortical layer V pyramidal cells [62] and induces the release of glutamate from excitatory nerve terminals [63,64] (for review see [65]). The antidepressant activity of these 5-HT 2 stimulating psychedelic drugs has been conceptualized as facilitating glutamate signaling through mGluR2/3 receptors [66,67]. ...
Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are a potential target for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.
... Activation of this receptor results in increased cortical glutamate release and activation of AMPA (α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid) and NMDA (N-Methyld-aspartate) receptors. The consequence is the stimulation of cerebral neuroplasticity in two ways: increasing the expression of the transcription factor c-Fos in the anterior cingulate cortex and medial prefrontal cortex and increasing that of BDNF (brain-derived neurotrophic factor) in the prefrontal cortex [25,26]. ...
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Purpose of the Review We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action. Recent Findings Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants. Summary Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.
... Stimulation of 5-HT 2 receptors by serotonergic psychedelics enhances spontaneous excitatory postsynaptic potentials/currents in neocortical layer V pyramidal cells [62] and induces the release of glutamate from excitatory nerve terminals [63,64] (for review see [65]). The antidepressant activity of these 5-HT 2 stimulating psychedelic drugs has been conceptualized as facilitating glutamate signaling through mGluR2/3 receptors [66,67]. ...
Introduction: Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects. Areas covered: The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed. Expert opinion: Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu2/3 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.
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This paper provides a critical review of several possible mechanisms at different levels of analysis underlying the effects and therapeutic potential of psychedelics. At the (1) biochemical level, psychedelics primarily affect the 5-HT2a receptor, increase neuroplasticity, offer a critical period for social reward learning and have anti-inflammatory properties. At the (2) neural level, psychedelics have been associated with reduced efficacy of thalamo-cortical filtering, the loosening of top-down predictive signaling and an increased sensitivity to bottom-up prediction errors, and activation of the claustro-cortical-circuit. At the (3) psychological level, psychedelics have been shown to induce altered and affective states, they affect cognition, induce belief change, exert social effects and can result in lasting changes in behavior. We outline the potential for a unifying account of the mechanisms underlying psychedelics and contrast this with a model of pluralistic causation. Ultimately, a better understanding of the specific mechanisms underlying the effects of psychedelics could allow for a more targeted therapeutic approach. We highlight current challenges for psychedelic research and provide a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.
Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors is not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialled for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm versus the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.
Existing pharmacological treatments for psychiatric disorders have demonstrated limited efficacy, delayed onset of action, and significant burden of side effects. Recent findings from human studies with psychedelics have shown promise, demonstrating rapid and sustained clinical benefits of these compounds for a variety of psychiatric disorders. Classical psychedelics have a rich history and some of these compounds have been used in shamanic and spiritual ceremonies for millennia. The psychoactive effects of these drugs, particularly on human consciousness, have generated great scientific curiosity, and early research on psychedelics suggested their clinical benefits for psychiatric conditions, including alcohol use disorders and anxiety and depressive symptoms in terminal illness and life-threatening conditions. Since the 1990s, after a period of dormancy that followed the criminalization of psychedelic drugs since the Controlled Substance Act of 1970, the continued interest in their unique psychoactive effects along with the pursuit for novel and more effective treatments in psychiatry have led to a renewed interest in research on these compounds. While preliminary findings on psychedelics are encouraging, current evidence is still insufficient to support extensive use of these drugs routinely. Long-term safety and efficacy of these compounds remain unclear, and several clinical trials are underway and may add clarity to these questions. Therefore, this article intends to provide an overview of the evidence to date on psychedelic drugs – particularly psilocybin, MDMA, and LSD – for the treatment of psychiatric disorders.
Prepulse inhibition (PPI) of the startle response is used as a measure of sensorimotor inhibitory processes. Deficits in PPI have been found in patients with schizophrenia, obsessive compulsive disorder (OCD) and Huntington's disease. PPI can also be disrupted in animals through manipulations that augment serotonergic activity, such as administration of the serotonin (5-HT) agonists 8-OH-DPAT, RU 24969 and DOI. In the present experiment the identity of the 5-HT receptor subtype that mediates the DOI-induced disruption of PPI was examined. Dose-response studies revealed that the novel 5-HT(2A) antagonist, MDL 100,907 (0.01, 0.1 and 1.0 mg/kg, s.c.), but not the new 5-HT(2C) antagonist SDZ SER 082 (0.125, 0.25 and 0.5 mg/kg, s.c.), prevented the loss of PPI induced by DOI (0.25 or 0.5 mg/kg, s.c.). The results support the hypothesis that the 5-HT(2A) receptor is involved in the modulation of sensorimotor gating. Because deficits in PPI are used as a model of sensorimotor gating abnormalities found in schizophrenia, the present study supports the view that MDL 100,907 may be a novel atypical antipsychotic. Studies of the serotonergic substrates of PPI may provide a model of the possible serotonergic role in the sensorimotor gating abnormalities in schizophrenia and OCD patients.
The history of research with psychedelic drugs has produced a variety of methods for their use and conflicting claims about results. First came the wave of excitement among experimentalists in the 1950s when it was claimed that lysergic acid diethylamide (LSD) could produce a model psychosis which might be useful in understanding schizophrenia. While this promise was fading, enthusiastic reports about the possibility of LSD as an aid to psychotherapy in the treatment of alcoholism and other psychiatric disorders appeared. All these approaches were represented in 1959 at the first international conference devoted entirely to LSD.1 Since then, there have been at least five more published proceedings of such conferences on various aspects of psychedelic drugs.2-6 The most recent conference on various means of producing states of consciousness was sponsored by the Menninger Foundation and the American Association of Humanistic Psychology on April 7 to 11, 1969, in
Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor.Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured.Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure.Conclusions: These data indicate that N-methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.