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Nature Reviews Neuroscience | AOP, published online 18 August 2010; doi:10.

1038/nrn2884

PeRSPecTiveS
and the negative symptoms (social with-
OpiniOn
drawal and apathy) of schizophrenia
through antagonism at NMDA (N-methyl-d-
The neurobiology of psychedelic aspartate) glutamate receptors13,14.
Emphasis has also been placed on the
drugs: implications for the treatment early observation that LSD can enhance
self-awareness and facilitate the recollection
of mood disorders of, and release from, emotionally loaded
memories15,16. This perspective appealed
to psychiatrists as a unique property that
Franz X. Vollenweider and Michael Kometer could facilitate the psychodynamic process
during psychotherapy. In fact, by 1965 there
Abstract | After a pause of nearly 40 years in research into the effects of psychedelic were more than 1,000 published clinical
drugs, recent advances in our understanding of the neurobiology of psychedelics, studies that reported promising therapeutic
such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to effects in over 40,000 subjects17. LSD,
renewed interest in the clinical potential of psychedelics in the treatment of various psilocybin and, sporadically, ketamine have
been reported to have therapeutic effects in
psychiatric disorders. Recent behavioural and neuroimaging data show that
patients with anxiety and obsessive–
psychedelics modulate neural circuits that have been implicated in mood and compulsive disorders (OCD), depression,
affective disorders, and can reduce the clinical symptoms of these disorders. These sexual dysfunction and alcohol addiction,
findings raise the possibility that research into psychedelics might identify novel and to relieve pain and anxiety in
therapeutic mechanisms and approaches that are based on glutamate-driven patients with terminal cancer 18–23 (BOX 2).
Unfortunately, throughout the 1960s and
neuroplasticity.
1970s LSD and related drugs became
increasingly associated with cultural rebel-
Psychedelic drugs have long held a special Depending on the individual taking the lion; they were widely popularized as drugs
fascination for mankind because they pro- drug, their expectations, the setting in which of abuse and were depicted in the media as
duce an altered state of consciousness that is the drug is taken and the drug dose, psych- highly dangerous. Consequently, by about
characterized by distortions of perception, edelics produce a wide range of experiential 1970, LSD and related drugs were placed
hallucinations or visions, ecstasy, dissolu- states, from feelings of boundlessness, unity in Schedule i in many western countries.
tion of self boundaries and the experience and bliss on the one hand, to the anxiety- Accordingly, research on the effects of
of union with the world. As plant-derived inducing experiences of loss of ego-control classical psychedelics in humans was
materials, they have been used traditionally and panic on the other hand4–7. Researchers severely restricted, funding became
by many indigenous cultures in medical from different theoretical disciplines and difficult and interests in the therapeutic
and religious practices for centuries, if experimental perspectives have emphasized use of these drugs faded, leaving many
not millennia1. different experiential states. One emphasis avenues of inquiry unexplored and
However, research into psychedelics has been placed on the LSD-induced percep- many questions unanswered.
did not begin until the 1950s after the tual distortions — including illusions and With the development of sophisticated
breakthrough discovery of the classical hallucinations, thought disorder and neuroimaging and brain-mapping tech-
hallucinogen lysergic acid diethylamide experiences of split ego7,8 — that are also niques and with the increasing understand-
(LSD) by Albert Hofmann2 (timeline). The seen in naturally occurring psychoses9–11. ing of the molecular mechanisms of action
classical hallucinogens include indoleam- This perspective has prompted the use of of psychedelics in animals, renewed interest
ines, such as psilocybin and LSD, and psychedelics as research tools for unravelling in basic and clinical research with psyche-
phenethylamines, such as mescaline and the neuronal basis of psychotic disorders, delics in humans has steadily increased since
2,5-dimethoxy-4-iodo-amphetamine such as schizophrenia spectrum disorder. the 1990s. In this Perspective, we review
(DOI). Research into psychedelics was The most recent work has provided com- early and current findings of the therapeutic
advanced in the mid 1960s by the finding pelling evidence that classical hallucino- effects of psychedelics and their mechanisms
that dissociative anaesthetics such as keta- gens primarily act as agonists of serotonin of action in relation to modern concepts of
mine and phencyclidine (PCP) also pro- (5-hydroxytryptamine) 2A (5-HT2A) the neurobiology of psychiatric disorders.
duce psychedelic-like effects3 (BOX 1). Given receptors12 and mimic mainly the so- We then evaluate the extent to which
their overlapping psychological effects, called positive symptoms (hallucinations psychedelics may be useful in therapy —
both classes of drugs are included here and thought disorder) of schizophrenia10. aside from their established application as
as psychedelics. Dissociative anaesthetics mimic the positive models of psychosis3,11.

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Current therapeutic studies other strategies should be tested in further higher regulatory hurdles to overcome and
Several preclinical studies in the 1990s studies. Moreover, the use of biomarkers may have negative connotations as a drug
revealed an important role for the NMDA that are rooted in psychopathology, neuro- of abuse.
glutamate receptor in the mechanism of psychology and/or genetics might help to A recent study by Moreno and
action of antidepressants. These findings predict whether ketamine therapy will be colleagues37 evaluated case reports and
consequently gave rise to the hypothesis that appropriate for a given patient with findings from studies performed in the
the NMDA-antagonist ketamine might have depression31. In line with this idea, decreased 1960s that indicated that psilocybin and LSD
potential as an antidepressant24. This hypoth- activation of the anterior cingulate cortex are effective in the treatment of OCD22,38–40.
esis was validated in an initial double-blind (ACC) during a working memory task32 and They subsequently carried out a study show-
placebo-controlled clinical study in seven increased activation of the ACC during an ing that psilocybin given on four different
medication-free patients with major depres- emotional facial processing task33, as well occasions at escalating doses (ranging from
sion. Specifically, a significant reduction in as a positive family history of alcohol sub-hallucinogenic to hallucinogenic doses)
depression scores on the Hamilton depression abuse27, were associated with a stronger markedly decreased OCD symptoms
rating scale (HDRS) was observed 3 hours antidepressant response to ketamine. (by 23–100%) on the Yale–brown obsessive
after a single infusion of ketamine (0.5 mg Ketamine therapy could be extended to compulsive scale in patients with OCD who
per kg), and this effect was sustained for at other disorders in which NMDA receptors were previously treatment resistant 37. The
least 72 hours25. Several studies have since are implicated in the pathophysiology — for reduction in symptoms occurred rapidly, at
replicated this rapid antidepressant effect of example, bipolar disorder 34 and addic- about 2 h after the peak psychedelic effects,
ketamine using larger sample sizes and treat- tion35. The use of ketamine for the treatment and endured up to the 24-h post-treatment
ment-resistant patients with depression26–30. of bipolar disorder is currently being tested rating 37. This symptom relief was not related
Given that 71% of the patients met response (Clinicaltrials.gov: NCT00947791). Its poten- to the dose of the psychedelic drug or to the
criteria (defined as a 50% reduction in HDRS tial as a treatment for addiction is supported by intensity of the psychedelic experience, and
scores from baseline) within 24 hours26, this results from a double-blind, randomized clini- extended beyond the observed acute
rapid effect has a high therapeutic value. In cal trial in which 90 heroin addicts received psychological effect of 4–6 h, raising
particular, patients with depression who are either existentially oriented psychotherapy in intriguing questions regarding the mecha-
suicidal might benefit from such a rapid and combination with a high dose (2.0 mg per kg) nisms that underlie this protracted effect 37.
marked effect as their acute mortality risk is or a low dose of ketamine (0.2 mg per kg). Further research on how this initial relief of
not considerably diminished with conven- Follow-up studies in the first 2 years revealed symptoms in response to psilocybin — and
tional antidepressants owing to their long a higher rate of abstinence, greater and the subsequent return of symptoms — is
delay in onset of action (usually 2–3 weeks). longer-lasting reductions in craving, and a linked to functional changes in the brain
Indeed, suicidal ideations were reduced positive change in nonverbal, unconscious could contribute not only to a mechanistic
24 hours after a single ketamine infusion28. emotional attitude in subjects who had been explanation of the potentially beneficial
However, despite these impressive and treated with a high dose, compared with a low effects of psychedelics but also to the
rapid effects, all but 2 of the patients relapsed dose, of ketamine36. development of novel treatments for OCD.
within 2 weeks after a single dose of keta- In contrast to the rapidly increasing The chronicity and disease burden of
mine26. Previous relapse prevention strategies, number of clinical studies with ketamine, OCD, the suboptimal nature of available
such as the administration of either five studies with classic hallucinogens are treatments and the observation that
additional ketamine infusions29 or riluzole emerging slowly. This slow progress may psilocybin was well tolerated in OCD
(Rilutek; Sanofi-aventis) on a daily basis30, be due to the fact that classic hallucinogens patients are clear indications that further
yielded success only in some patients and are placed in Schedule 1 and therefore have studies into the duration, efficacy and

Timeline | A brief history of psychedelic drugs

isolation and Synthesis Discovery of First LSD study isolation and LSD appears on Sandoz recalls Demonstration First neuroimaging
identification of PcP psychoactive in people with synthesis of the streets samples of of antagonistic study on psilocybin
of mescaline effects of LSD depression by psilocin and LSD and action of PcP at and ketamine
by A. Heffter by A. Hofmann c. Savage psilocybin by ceases NMDA receptors
A. Hofmann supplying it by N. Anis

1897 1919 1926 1938 1943 1947 1952 1953 1958 1962 1963 1965 1966 1970 1983 1988 1990 1999

Synthesis of Synthesis First LSD First clinic using Synthesis introduction LSD, psilocin Demonstration of Ketamine is
mescaline of LSD by study in LSD in psycholytic of ketamine of the term and mescaline agonistic action of placed in
by e. Späth A. Hofmann humans by therapy by ‘dissociative are placed in LSD at 5-HT2A schedule iii
W. Stoll R. Sandison anaesthetic’ Schedule i in receptors; first in the US
by e. Domino the US neuroimaging
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.

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Box 1 | Assessing altered states of consciousness

Elementary Elementary
visual visual
alterations alterations
Disembodiment Disembodiment
Audio–visual Audio–visual
synesthaesia synesthaesia
Impaired control
and cognition Impaired control
and cognition

Vivid imagery Vivid imagery

10 20 30 40 50 60 70 Anxiety Anxiety
20 30 40 50 60

Changed meaning Changed meaning


of percepts of percepts

Blissful state Blissful state

Insightfulness Insightfulness

Religious Experience Religious Experience


experience of unity experience of unity

Psilocybin 115–125 µg per kg (n = 72)


Ketamine 6 µg per kg per min (n = 42)
Psilocybin 215–270 µg per kg (n = 214)
Ketamine 12 µg per kg per min (n = 92)
Psilocybin 315 µg per kg (n = 41)

Quantifying altered states of consciousness was problematic in the early years In general, the intensity of these psychedelic-induced alterations of
of hallucinogen research. Today, however, there are validated instruments consciousness and perception is dose-dependent, so that hallucinations
for assessing various aspects of consciousness. According to Dittrich133, that involve disorientation in person, place and time rarely, if ever, occur
Nature Reviews | Neuroscience
hallucinogen-induced altered states of consciousness can be reliably measured with low to medium doses4–6. However, at larger doses — and depending
by the five-dimensional altered states of consciousness (5DASC) on the individual, his or her expectations and the setting — the same
rating scale. This scale comprises five primary dimensions and their respective hallucinogen might produce a pleasurable loss of ego boundaries combined
subdimensions (see the figure). The primary dimensions are ‘oceanic with feelings of oneness or might lead to a more psychotic ego dissolution
boundlessness’ (shown by orange boxes), referring to positively experienced that involves fear and paranoid ideation 4,132,134. Such experiential
loss of ego boundaries that are associated with changes in the sense of phenomena are otherwise rarely reported except in dreams, contemplative
time and emotions — ranging from heightened mood to sublime happiness or religious exaltation and acute psychoses11,135. The figure shows that the
and feelings of unity with the environment; ‘anxious ego-disintegration’ classical hallucinogen psilocybin (0.015–0.027 g per kg, by mouth) (see
(shown by purple boxes), including thought disorder and loss of self-control; the figure, left) and the dissociative s-ketamine (6–12 μg per kg per min,
‘visionary restructuralization’ (shown by blue boxes), referring to perceptual intravenously) (see the figure, right) produce a set of overlapping
alterations (such as visual illusions and hallucinations), and altered meaning of psychological experiences, measured by the 5DASC rating scale and
percepts; acoustic alterations (not shown), including hypersensitivity to sound respective subscales. The scales indicate the percentage scored of the
and auditory hallucinations; and altered vigilance (not shown). maximum score.

mechanisms of action of psilocybin or of or extended the remission period in people Classical hallucinogens. The classical hallu-
related compounds in the treatment of OCD suffering from cluster headaches41. Taken cinogens are comprised of three main chem-
are warranted. together, these findings support early obser- ical classes: the plant-derived tryptamines
Encouraged by early findings (BOX 2), vations in the 1960s that classical hallucino- (for example, psilocybin) and phenethyl-
several clinical centres have begun to inves- gens have antinociceptive potential and may amines (for example, mescaline), and the
tigate the potential beneficial effects of psi- not only reduce symptoms but also induce semisynthetic ergolines (for example, LSD)48.
locybin (ClinicalTrials.gov: NCT00302744, long-lasting adaptive processes. Although all classical hallucinogens display
NCT00957359 and NCT00465595) and LSD high affinity for 5-HT2 receptors, they also
(ClinicalTrials.gov: NCT00920387) in the neurobiology of psychedelic drugs interact to some degree with 5-HT1, 5-HT4,
treatment of anxiety and depression in The enormous progress that has been made 5-HT5, 5-HT6 and 5-HT7 receptors12. In con-
patients with terminal cancer, using state in our understanding of the mechanisms of trast to the tryptamines, the ergolines also
of the art, double-blind, placebo-controlled action of psychedelics12,42–45 and the neurobi- show high intrinsic activity at dopamine D2
designs. One of these studies has recently ology of affective disorders34,46,47 has enabled receptors and at α-adrenergic receptors49.
been completed and revealed that moder- us to postulate new hypotheses regarding the Converging evidence from pharmaco-
ate doses of psilocybin improved mood and therapeutic mechanisms of psychedelics and logical50, electrophysiological51,52 and behav-
reduced anxiety and that this relief variably their clinical applications. Here we focus on ioural studies in animals53,54 suggests that
lasted between 2 weeks and 6 months in the glutamatergic and serotonergic mecha- classical hallucinogens produce their effects
patients with advanced cancer (C.S. Grob, nisms of action of psychedelics with regard in animals and possibly in humans primarily
personal communication). Finally, another to their most promising indications — that through agonistic actions at cortical 5-HT2A
recent study reported that psilocybin and LSD is, their use in the treatment of depression receptors (FiG. 1a). Consistent with this view,
aborted attacks, terminated the cluster period and anxiety. selectively restoring 5-HT2A receptors in

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cortical pyramidal neurons is sufficient to those in layer v of the prefrontal cortex Activation of 5-HT2A and 5-HT1A recep-
rescue hallucinogen-induced head shaking (PFC)51,52,58,59 (FiG. 1a). This increase in tors in the medial PFC (mPFC) also has
in transgenic mice that lack 5-HT2A recep- glutamatergic synaptic activity was initially downstream effects on serotonergic and
tors53,55. Importantly, administration of the thought to result from stimulation of presy- dopaminergic activity through descend-
5-HT2A receptor antagonist ketanserin abol- naptic 5-HT2A receptors located on gluta- ing projections to the dorsal raphe and the
ishes virtually all of the psilocybin-induced matergic thalamocortical afferents to the ventral tegmental area (vTA). For example,
subjective effects in humans56. Recent stud- PFC60,61. However, more recent studies sug- activation of 5-HT2A receptors in the mPFC
ies have demonstrated that hallucinogenic gest that stimulation of postsynaptic 5-HT2A increases the firing rate of 5-HT neurons in
and non-hallucinogenic 5-HT2A agonists receptors55,58,59 on a subpopulation of pyram- the dorsal raphe and of dopamine neurons
differentially regulate intracellular signalling idal cells in the deep layers of the PFC59 leads in the vTA, resulting in an increased release
pathways in cortical pyramidal neurons and to an increase in glutamatergic recurrent of 5-HT in the mPFC58,66 and of dopamine in
that this results in a differential expression network activity 59,62. The increase in gluta- mesocortical areas67 in animals. In a study
of downstream signalling proteins, such as matergic synaptic activity can be abolished in humans, the hallucinogenic 5-HT2A agon-
early growth response protein 1 (EGR1), not only by specific 5-HT2A antagonists but ist psilocybin increased striatal dopamine
EGR2 and β-arrestin 255,57. This suggests that also by AMPA (α-amino-3-hydroxyl-5- concentrations, and this increase correlated
further elucidation of hallucinogen-specific methyl-4-isoxazole-propionic acid) recep- with euphoria and depersonalization
signalling pathways may aid the develop- tor antagonists63, by agonists51 and positive phenomena68. blocking dopamine D2
ment of functionally selective ligands with allosteric modulators of metabotropic receptors by haloperidol, however, reduced
specific therapeutic properties — for exam- glutamate receptor 2 (mGluR2)64, and by these effects by only about 30%. This
ple, ligands that have antidepressant effects selective antagonists of the NR2b subunit suggests that the dopaminergic system con-
but no hallucinogenic effects. of NMDA receptors65. Taken together, these tributes only moderately to the broad spec-
Several studies have demonstrated that findings indicate that classical hallucinogens trum of psilocybin-induced psychological
activation of 5-HT2A receptors by classical are potent modulators of prefrontal network alterations56.
hallucinogens or by serotonin leads to a activity that involves a complex interaction Interestingly, 5-HT2A receptor activation
robust, glutamate-dependent increase in the between the serotonin and glutamate not only seems to underlie the preponder-
activity of pyramidal neurons, preferentially systems in prefrontal circuits. ance of the acute psychedelic effects of hal-
lucinogens but may also lead to neuroplastic
adaptations in an extended prefrontal–limbic
Box 2 | Early therapeutic findings with psychedelics network. For example, in rats a single dose
of the hallucinogen DOI transiently
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 increased the dendritic spine size in corti-
psycholytic (psyche-loosening)15 therapies. In psychedelic therapy, which was practised mostly in cal neurons69 and repeated doses of LSD
North America, a large dose of LSD (200–800 μg) was applied in a single session. This was thought downregulated cortical 5-HT2A but not
to induce an overwhelming and supposedly conversion-like peak experience that would bring the 5-HT1A receptors; effects that were the most
subject to a new level of awareness and self-knowledge. It was thought that that this would pronounced in the frontomedial cortex and
facilitate self-actualization and lead to permanent changes that would be beneficial to the ACC70,71. It is possible that such adaptations —
subject128,129. Furthermore, it was claimed that intensive psychotherapeutic preparation of the and specifically a downregulation of prefrontal
patient before the drug session and a follow-up integration of the peak experience in further 5-HT2A receptors — might underlie some of
drug-free sessions were crucial for an optimal outcome130. Promising therapeutic effects of this
the therapeutic effects of hallucinogens in the
therapy were found in people with terminal cancer20,137, in severe alcoholics138,139, in people who
treatment of depression, anxiety and chronic
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, pain. In favour of this hypothesis, 5-HT2A
surprisingly, that LSD had transient analgesic effects that were superior to those of receptor density was found to be increased
dihydromorphinone (also known as hydromorphone and Palladone SR (Napp)) and meperidine in the PFC in post-mortem samples72 and
(also known as pethidine)20. These effects were confirmed in later studies and the clinical efficacy in vivo73,74 in patients with major depression,
was linked with the intensity of the psychedelic experience129,141,142. and to be reduced after chronic treatment with
Psycholytic therapy was introduced by Ronald Sandison and applied in Europe at 18 treatment various antidepressants — the reduction coin-
centres143. In psycholytic therapy, low to moderate doses of LSD (50–100 μg), psilocybin (10–15 mg) ciding with the onset of clinical efficacy75–77. In
or, sporadically, ketamine were used repeatedly as an adjunct in psychoanalytically oriented addition, chronic, antisense-mediated down-
psychotherapy to accelerate the therapeutic process by facilitating regression and the
regulation of 5-HT2A receptors in rats78 and in
recollection and release of emotionally loaded repressed memories, and by increasing the
5-HT2A knockout mice79 reduced anxiety-like
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), behaviour, and selective restoration of 5-HT2A
depression (in 62% of patients), personality disorders (in 53–61% of patients), sexual dysfunction receptors in the PFC normalized anxiety-like
(in 50% of patients) and obsessive–compulsive disorders (in 42% of patients)148. behaviour in these 5-HT2A knockout mice.
Unfortunately, the majority of these studies had serious methodological flaws by contemporary These findings suggest that prefrontal 5-HT2A
standards. In particular, with the absence of adequate control groups and follow-up measurements receptors might modulate the activity of sub-
and with vague criteria for therapeutic outcome, the studies did not clearly establish whether it cortical structures, such as the amygdala79.
was the drug or the therapeutic engagement that produced the reported beneficial effect. It was Anxiety and depression are interrelated with
also difficult to draw firm conclusions regarding potential long-term efficacy. Nevertheless, the stress80, which also affects the serotonin sys-
studies provide a conceptual framework for the application of psychedelics, with the data
tem81. Stress elevates corticotropin-releasing
suggesting that the most promising indication for psychedelic use might be found in the treatment
factor (CRF)82, and administration of CRF
of depression and anxiety disorders.
into the mPFC of mice enhanced anxiety-like

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a density correlated with responses to tonic


Cortical layer V Deep cortical layers Brainstem 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
5-HT neuron in individuals with chronic pain.
↑ Glutamate
NMDAR release 5-HT2A
Dissociative anaesthetics. At sub-anaesthetic
+ doses, dissociative anaesthetics, such as
ketamine, primarily block the NMDA recep-
AMPAR tor at the PCP binding site in the receptor’s
Psilocin/
ionotropic channel14 (FiG. 1b). The psychoac-
5-HT2A
LSD/DMT tive potency of the s-ketamine enantiomer is
+ + three to four times higher than that of the
BDNF r-ketamine enantiomer. This is paralleled by
their relative affinities at the NMDA receptor
Psilocin/ complex 87. Systemic administration of
LSD/DMT non-competitive NMDA antagonists, such
b as ketamine, PCP and MK-801 (also
Cortex Subcortical areas
known as dizocilpine), in rats mark-
edly increases glutamate release in the
↑ Glutamate mPFC88,89 concomitant with an increase in
Ketamine release the firing rate of pyramidal neurons in this
NMDAR
area90. These effects are probably due to a
blockade of NMDA receptors on GAbA
(γ-aminobutyric acid)-ergic interneurons45,91
AMPAR in cortical and/or subcortical structures and
to the subsequent reduction of inhibitory
+ Interneuron control over prefrontal glutamatergic neu-
BDNF rons92. The increased extracellular glutamate
levels in the mPFC seem to contribute to the
NMDAR
psychotropic effects of ketamine and PCP,
as AMPA receptor antagonists88 or agonists
GABA Ketamine of mGluR2 and mGluR3 (ReF. 93) abolished
various behavioural effects of NMDA
Figure 1 | Activation of the prefrontal network and glutamate release by psychedelics. a | The antagonists in rats. Likewise, the behavioural
figure shows a model in which hallucinogens, such as psilocin, lysergic acid diethylamide (LSD) and effects of selective NR2b antagonists — such
Nature Reviews | Neuroscience
dimethyltryptamine (DMT), increase extracellular glutamate levels in the prefrontal cortex through
as CP-101,606 (also known as Traxoprodil),
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 which produces dose-dependent psycho-
neurons. This glutamate release leads to an activation of AMPA (α-amino-3-hydroxy-5-methyl-4- tropic effects similar to those of ketamine in
isoxazole propionic acid) and NMDA (N-methyl-d-aspartate) receptors on cortical pyramidal neurons. in humans94 — can be blocked by administra-
addition, hallucinogens directly activate 5-HT2A receptors located on cortical pyramidal neurons. This tion of AMPA receptor antagonists95. Finally,
activation is thought to ultimately lead to increased expression of brain-derived neurotrophic factor lamotrigine, which reduces presynaptic
(BDNF). b | The figure shows a model in which dissociative NMDA antagonists, such as ketamine, block glutamate release, attenuated the subjective
inhibitory GABA (γ-aminobutyric acid)-ergic interneurons in cortical and subcortical brain areas, lead- effects of s-ketamine in humans96.
ing to enhanced firing of glutamatergic projection neurons and increased extracellular glutamate In addition to having these glutamatergic
levels in the prefrontal cortex. As ketamine also blocks NMDA receptors on cortical pyramidal neurons, effects, non-competitive NMDA receptor
the increased glutamate release in the cortex is thought to stimulate cortical AMPA more than NMDA
antagonists increase extracellular prefrontal
receptors. The increased AMPA-receptor-mediated throughput relative to NMDA-receptor-mediated
throughput is thought ultimately to lead to increased expression of BDNF. and mesolimbic dopamine89,93 and pre-
frontal serotonin89 levels in rats, presum-
ably by stimulating corticofugal glutamate
behaviour in response to DOI through raphe are involved in stress responses67,85. release in the vTA97 and the dorsal raphe89,
sensitization of 5-HT2 receptor signalling in Together, these findings suggest that down- respectively. Studies into the contribution of
the PFC83. In humans, fronto-limbic 5-HT2A regulation of prefrontal 5-HT2A receptors by this dopaminergic and serotonergic activa-
receptor density is correlated not only with classical hallucinogens might underlie some tion to the behavioural effects of NMDA
anxiety but also with an individual’s difficul- of the effects of hallucinogens on depression antagonists are scant and the results are
ties in coping with stress84. Indeed, recent and anxiety. somewhat controversial. Specifically, in
studies showed that prefrontal 5-HT2A recep- Finally, with regard to the finding that two studies in humans, ketamine-induced
tors located on descending projections that LSD reduces anxiety and pain in cancer striatal dopamine release correlated with
control serotonergic activity in the dorsal patients20, it is of note that prefrontal 5-HT2A the extent of ketamine-induced psychotic

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symptoms98,99, but in another study systemic A common mechanism? There is accumulat- in response to emotional stimuli34,112,113 have
administration of the dopamine D2 recep- ing evidence that, despite their different pri- been reported in patients with depression.
tor antagonist haloperidol did not attenuate mary modes of action, classical hallucinogens Further, depressed individuals46 and subjects
ketamine-induced psychotic symptoms and dissociative anaesthetics both modulate with high trait anxiety 114 show reduced PFC
in healthy volunteers100. Although 5-HT2A glutamatergic neurotransmission in the pre- activity when executive control is engaged,
receptor antagonists reverse the disruptive frontal–limbic circuitry that is implicated in and might suffer from decreased top-
effects of NMDA antagonists on sensorimo- the pathophysiology of mood disorders. This down inhibition of amygdala activity 115,116.
tor gating 101 and on object recognition102 in modulation is evidenced by the observation Conversely, chronic treatment with selective
animals, no comparable studies of the role in rats that hallucinogens103,104 and dissocia- serotonin reuptake inhibitors (SSRIs) increases
of serotonin in the mechanism of action of tive anaesthetics88,89 have a similar effect in the functional connectivity between the amy-
NMDA antagonists have been conducted enhancing extracellular glutamate release gdala and the PFC117, and attenuates the
in humans. in the PFC, leading to increased activation amygdala response to the presentation of
The enhanced glutamate release that of pyramidal cells63,65,105,106. Furthermore, images showing sad faces in patients with
results from NMDA receptor blockade and congruent with these findings, human depression118,119. This suggests that the normal-
by ketamine leads to an increased activa- neuroimaging studies have shown that both ization of this dysregulated network might be
tion of AMPA receptors relative to NMDA psilocybin and ketamine markedly activate important in the recovery from depression46.
receptors95. The antidepressant-like effects prefrontal cortical areas, including the ACC Given that both psilocybin and ketamine
of ketamine and the selective NR2b antago- and insula and, to a lesser extent, temporal and increase extracellular glutamate levels in
nist CP-101,606 in animals can be blocked parieto-occipital regions107–111 (FiG. 2). the prefrontal–limbic circuitry in rats and
by administration of the AMPA receptor According to current models of emotion that the antidepressant effects of both drugs
antagonist 2,3-dihydroxy-6-nitro-7-sul- regulation the PFC, including the ACC, exerts outlast their acute psychotropic effects in
phamoyl-benzo[f]quinoxaline-2,3-dione ‘cognitive’, top-down control over emotion depressed patients, we propose that a
(NbQX)95, suggesting that enhanced AMPA and stress responses through its connec- normalization of this network through
activation in cortical circuits is crucial for tions to the amygdala and dorsal raphe47,85. a glutamate-dependent neuroplastic adapt-
the therapeutic effect of NMDA receptor Reduced prefrontal glutamate levels that are ation is the common therapeutic mechanism
antagonists34,95. associated with attenuated PFC activation of these drugs. Specifically, we posit that
psychedelics enhance neuroplasticity by
a b increasing AMPA-type glutamate receptor
s-Ketamine 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-
Psilocybin mate levels6,95 and to increase bDNF levels in
prefrontal and limbic brain areas in rats123–125.
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.
Figure 2 | Brain activity patterns in psychedelic-induced states of consciousness. a | Brain
imaging studies using 18fluorodeoxyglucose [18FDG] positron emission tomography (PeT)
Nature Reviews revealed that
| Neuroscience Conclusions and future directions
moderate doses of s-ketamine (top) and psilocybin (bottom) in healthy volunteers increased neuronal The clinical findings and current under-
activity. This is shown by changes in the cerebral metabolic rate for glucose (cMRglu) in the prefrontal standing of the mechanisms of action of
cortex and associated limbic regions and in subcortical structures, including the thalamus107,109. This classical hallucinogens and dissociative
similar prefrontal–limbic activation pattern supports the view that both classes of drugs have converg- anaesthetics converge on the idea that
ing effects on a final pathway or neurotransmitter system. b | Recent [18FDG] PeT brain imaging studies
psychedelics might be useful in the treat-
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 ment of major depression, anxiety disorders
cortical and limbic regions and subcortical structures, including the basal ganglia and thalamus. For and OCD. These are serious, debilitating,
example, the intensity of experience of the key dimension ‘oceanic boundlessness’ correlated with life-shortening illnesses, and as the cur-
the s-ketamine- and psilocybin-induced activation (red) of a prefrontal–parietal network and the rently available treatments have high failure
deactivation (blue) of a striato–limbic amygdalocentric network149. rates, psychedelics might offer alternative

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PersPectives

treatment strategies that could improve the psychedelics, such as psilocybin, and dis- dose of the NR2b antagonist CP-101,606 (in
well-being of patients and the associated sociative anaesthetics, such as ketamine, combination with an SSRI) had transient
economic burden on patients and society. alter glutamatergic neurotransmission in antidepressant effects in a small sample of
Accumulating evidence shows a crucial prefrontal–limbic circuitries, and that this patients with depression and only rarely
role for the glutamate system in the regula- leads to neuroplastic adaptations, presumably induced dissociative symptoms94.
tion of neuronal plasticity, and indicates that through enhancement of AMPA receptor To take the opposite perspective, it is
abnormalities in neuroplasticity contribute function. These adaptations may explain noteworthy that initial clinical applications of
to the pathophysiology of mood disorders. some of the shared and relatively sustained psychedelics in psychedelic and psycholytic
Thus, drugs that target neuronal plasticity antidepressant effects that are observed in therapy were based on the premise that the
may offer a novel approach to their treat- clinical studies with ketamine and psilocybin. drug-induced psychological experience had
ment. This Perspective proposes that classical To further validate this glutamate-induced an essential, facilitatory effect on the psycho-
neuroplasticity hypothesis the relationship therapeutic process — that is, it was a form
between measures of glutamatergic activity of pharmacology-assisted psychotherapy.
Glossary and clinical outcome needs to be established. Indeed, it has been shown that the transcend-
Cluster period Moreover, the finding that classical halluci- ent peak (mystical-type) experience, which
A period of time during which cluster headache attacks nogens (unlike dissociative anaesthetics) also has a key role in the therapeutic outcome
occur regularly.
modulate 5-HT2A receptor signalling suggests in psychedelic therapy 128–130 and was rated
Enantiomers
that they may improve subtypes of anxiety as among the most personally meaningful
two stereoisomeric molecules that are mirror images of and stress-related disorders. Studies that use experiences131,132, occurs in most cases only
each other and are not superimposable. biomarkers for genotypes or that use expres- in supportive settings and after high-dose
sion levels of 5-HT2A receptors in parallel with administration of psychedelics. One might
Existentially oriented psychotherapy
clinical end points would be essential not only interpret this concept as an early example of
A form of therapy that emphasizes the development of a
sense of self-direction through choice and of awareness in for clarifying the role of 5-HT2A receptors in the neuroplasticity hypothesis in which the
resolving existential conflicts (such as the inevitability of the therapeutic mechanism of classical hal- drug-induced experience and its integration
death, isolation and meaninglessness). lucinogens but also for the development of in the psychotherapeutic process is the cru-
personalized medicines in the treatment cial mechanism that enables neuroplasticity
Neurosis
A former term for a category of mental disorders
of anxiety and stress-related disorders. and behavioural changes. by contrast, cur-
characterized by anxiety and a sense of distress. this In addition, to optimize the clinical rent pharmacological strategies often assume
category includes disorders now classified as mood benefits of psychedelics and to reduce their that medication alone produces neuroplastic
disorders, anxiety disorders, dissociative disorders, unwanted side effects, a deeper understand- adaptations. However, drugs that increase
sexual disorders and somatoform disorders.
ing of various factors is necessary. These neuroplasticity, such as psychedelics, might
Psychoanalytically oriented psychotherapy include structure–activity relationships, dose– be particularly clinically efficient in com-
A therapy based on Freudian psychoanalysis in which response relationships and the influence of bination with psychotherapeutic interven-
unconscious conflicts that are thought to cause the psychotherapeutic approaches on the effects tions121. In support of this notion, cognitive
patient’s symptoms are brought into consciousness to
of psychedelics. In this context, it is interest- behavioural therapy was shown to normalize
create insight for the resolution of the problems.
ing to note that there was no indication of prefrontal–limbic functioning in depressed
Regression prolonged psychosis, persisting perception patients46, and could therefore enhance the
in Freudian psychoanalytic theory this term describes a disorder or subsequent drug abuse after psi- proposed neuroplastic effects of psychedelics
psychological strategy to cope with reality by means of locybin126 or ketamine127 administration in a in prefrontal–limbic structures as discussed
a temporary reversion of the ego to an earlier stage of
large sample of psychotherapeutically well- here. Thus, further blind, controlled studies
development.
prepared healthy subjects in a supportive are obviously now needed to test these
Riluzole research setting. Similar observations were alternative and opposing hypotheses.
A drug used to treat amyotrophic lateral sclerosis and that reported in small samples of patients with The potential of drugs to target glutama-
has nmDA (N-methyl-d-aspartate) receptor blocking
depression29 and OCD37. Nonetheless, it is tergic neurotransmission in prefrontal–
properties similar to those of ketamine.
often claimed that the dissociative effects of, limbic circuitries and to facilitate neuroplas-
Schedule 1 for example, ketamine may limit clinical use, tic adaptations may translate into promising
A legislative category containing controlled drugs that have despite its reported efficacy 24,94. In this sense, new treatment approaches for affective dis-
a high potential for abuse, a lack of accepted safety and no understanding the molecular mechanism orders. The novel hypotheses presented here
currently accepted medical use in treatments.
of action could inform the development of now need to be investigated using well-
Selective serotonin reuptake inhibitors novel ligands for 5-HT2A or NMDA receptors controlled clinical studies, keeping in mind
A class of compounds typically used as antidepressants. that display antidepressant properties but the controversial history of this class of drugs.
have fewer dissociative effects than psilocy-
Self-actualization Franz X. Vollenweider and Michael Kometer are at the
bin and ketamine. Further evaluations of the Neuropsychopharmacology and Brain Imaging
the motivation to realize all of one’s potential.
dose–response relationship may be another Research Unit, University Hospital of Psychiatry,
Structure–activity relationship approach to minimize unwanted side effects. Zurich, Switzerland.
(Often abbreviated to SAR.) this is the relationship between For example, low to moderate oral doses of Franz X. Vollenweider is also at the School of Medicine,
the chemical structure of a molecule and its biological activity. psilocybin (<0.215 mg per kg) were found University of Zurich, Switzerland.
to only rarely produce anxious dissociative Correspondence to F.X.V.
Transference
A phenomenon in psychoanalysis characterized by symptoms in controlled settings126 (BOX 1) e‑mail: vollen@bli.uzh.ch
unconscious redirection of feelings or desires from one but to reduce anxiety, depression and OCD doi:10.1038/nrn2884
person to another. symptoms in patients22,37. Similarly, a low Published online 18 August 2010

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