The Neurobiology of Psychedelic Drugs: Implications for the Treatment

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, and release from, emotionally loaded of mood disorders 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 psychiatric disorders. Recent behavioural and neuroimaging data show that been reported to have therapeutic effects in 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 cancer18–23 (BOX 2). neuroplasticity. Unfortunately, throughout the 1960s and 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.

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 resistant37. 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 disorder34 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 rating37. This symptom relief was not related Given that 71% of the patients met response (Clinicaltrials.gov: NCT00947791). Its poten- to the dose of the psych edelic 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 effect37. 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.

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

Anxiety 10 20 30 40 50 60 70 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 ideation4,132,134. 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 neurobiology of psychedelic drugs (ClinicalTrials.gov: NCT00920387) in the interact to some degree with 5-HT1, 5-HT4, 12 treatment of anxiety and depression in The enormous progress that has been made 5-HT5, 5-HT6 and 5-HT7 receptors . 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, cluster period aborted attacks, terminated the and anxiety. selectively restoring 5-HT2A receptors in

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, 56 60,61 subjective effects in humans . Recent stud- PFC . 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 55,58,59 and non-hallucinogenic 5-HT2A agonists receptors 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 activity59,62. 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 56 activation of 5-HT2A receptors by classical are potent modulators of prefrontal network alterations . 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 hallucinogens 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 By 1953, two forms of lysergic acid diethylamide (LSD) therapy based on different theoretical of the hallucinogen DOI transiently frameworks were emerging. These have been named psychedelic (mind-manifesting)136 and increased the dendritic spine size in corti- 69 psycholytic (psyche-loosening)15 therapies. In psychedelic therapy, which was practised mostly in cal neurons 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 — 128,129 subject . 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-HT receptors — might underlie some of drug-free sessions were crucial for an optimal outcome130. Promising therapeutic effects of this 2A therapy were found in people with terminal cancer20,137, in severe alcoholics138,139, in people who the therapeutic effects of hallucinogens in the were addicted to narcotics140 and in patients with neurosis141. For example, a series of studies treatment of depression, anxiety and chronic 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- 143 centres . 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 78 regulation of 5-HT2A receptors in rats and in recollection and release of emotionally loaded repressed memories, and by increasing the 79 transference reaction15,22,144–147. A review of 42 studies reported impressive improvement rates in 5-HT2A knockout mice reduced anxiety-like (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 148 (in 50% of patients) and obsessive–compulsive disorders (in 42% of patients) . 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 82 of depression and anxiety disorders. factor (CRF) , and administration of CRF into the mPFC of mice enhanced anxiety-like

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 additional therapeutic potential for hallucinogens ↑ Glutamate 5-HT neuron in individuals with chronic pain. 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 ionotropic channel14 (FiG. 1b). The psychoac- 5-HT Psilocin/ 2A 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/ complex87. 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 markedly increases glutamate release in the ↑ Glutamate mPFC88,89 concomitant with an increase in Ketamine release NMDAR 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 AMPAR in cortical and/or subcortical structures and to the subsequent reduction of inhibitory + Interneuron control over prefrontal glutamatergic neu- 92 BDNF rons . The increased extracellular glutamate NMDAR levels in the mPFC seem to contribute to the 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 dimethyltryptamine (DMT), increase extracellular glutamate levels in Nathetur prefrontale Reviews cortex| Neuroscienc throughe 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- 95 addition, hallucinogens directly activate 5-HT2A receptors located on cortical pyramidal neurons. This tion of AMPA receptor antagonists . 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 receptors. The increased AMPA-receptor-mediated throughput relative to NMDA-receptor-mediated antagonists increase extracellular prefrontal 89,93 throughput is thought ultimately to lead to increased expression of BDNF. and mesolimbic dopamine and prefrontal serotonin89 levels in rats, presumably 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 83 the PFC . 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 20 control serotonergic activity in the dorsal patients , it is of note that prefrontal 5-HT2A the extent of ketamine-induced psychotic

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 anxiety114 show reduced PFC 100 in healthy volunteers . 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 activity115,116. tor gating101 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 18 18 imaging studies using fluorodeoxyglucose [ FDG] positron emission tomographyNature Revie (Pwse T)| Neur revealedoscienc thate 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 107,109 cortex and associated limbic regions and in subcortical structures, including the thalamus . 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 have demonstrated that the degree to which each of the psychedelic-induced key dimensions of psychedelics might be useful in the treat- 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

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. 128–130 modulate 5-HT2A receptor signalling suggests in psychedelic therapy and was rated Enantiomers that they may improve subtypes of anxiety as among the most personally meaningful 131,132 two stereoisomeric molecules that are mirror images of and stress-related disorders. Studies that use experiences , 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-HT receptors in parallel with administration of psychedelics. One might Existentially oriented psychotherapy 2A A form of therapy that emphasizes the development of a clinical end points would be essential not only interpret this concept as an early example of 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 46 Regression prolonged psychosis, persisting perception patients , 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 development. large sample of psychotherapeutically well- here. Thus, further blind, controlled studies 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 efficacy24,94. 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- Franz X. Vollenweider and Michael Kometer are at the Self-actualization bin and ketamine. Further evaluations of the the motivation to realize all of one’s potential. Neuropsychopharmacology and Brain Imaging 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. Transference to only rarely produce anxious dissociative Correspondence to F.X.V. 126 A phenomenon in psychoanalysis characterized by symptoms in controlled settings (BOX 1) e‑mail: [email protected] 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

1. Hofmann, A. & Schultes, R. E. Plants of the Gods 28. Price, R. B., Nock, M. K., Charney, D. S. & Mathew, S. J. 52. Aghajanian, G. K. & Marek, G. J. Serotonin, via (McGraw-Hill Book Company, Maidenhead, UK, Effects of intravenous ketamine on explicit and implicit 5-HT2A receptors, increases EPSCs in layer V 1979). measures of suicidality in treatment-resistant pyramidal cells of prefrontal cortex by an 2. Hofmann, A. in Chemical Constitution and depression. Biol. Psychiatry 66, 522–526 (2009). asynchronous mode of glutamate release. Brain Res. Pharmacodynamic Actions (ed. Burger, A.) 169–235 29. Aan het Rot, M. et al. Safety and efficacy of repeated- 825, 161–171 (1999). (M.Dekker, New York, 1968). dose intravenous ketamine for treatment-resistant 53. Wing, L. L., Tapson, G. S. & Geyer, M. A. 5HT-2 3. Domino, E. F., Kamenka, J. M. & Gneste, P. The joint depression. Biol. Psychiatry 67, 139–145 (2010). mediation of acute behavioral effects of hallucinogens French–US seminar on phencyclidine and related 30. Mathew, S. J. et al. Riluzole for relapse prevention in rats. Psychopharmacology 100, 417–425 (1990). arylcyclohexylamines. Trends Pharmacol. Sci. 9, following intravenous ketamine in treatment-resistant 54. Sipes, T. E. & Geyer, M. A. DOI disruption of prepulse 363–367 (1983). depression: a pilot randomized, placebo-controlled inhibition of startle in the rat is mediated by 5-HT2A 4. Hasler, F., Grimberg, U., Benz, M. A., Huber, T. & continuation trial. Int. J. Neuropsychopharmacol. 13, and not by 5-HT2C receptors. Behav. Pharmacol. 6, Vollenweider, F. X. Acute psychological and 71–82 (2010). 839–842 (1995). physiological effects of psilocybin in healthy 31. Holsboer, F. How can we realize the promise of 55. Gonzalez-Maeso, J. et al. Hallucinogens recruit specific humans: a double-blind, placebo-controlled dose- personalized antidepressant medicines? Nature Rev. cortical 5-HT(2A) receptor-mediated signaling effect study. Psychopharmacology 172, 145–156 Neurosci. 9, 638–646 (2008). pathways to affect behavior. Neuron 53, 439–452 (2004). 32. Salvadore, G. et al. Anterior cingulate (2007). 5. Dittrich, A. in 50 Years of LSD. Current Status and desynchronization and functional connectivity with the 56. Vollenweider, F. X., Vollenweider-Scherpenhuyzen, Perspectives of Hallucinogens (eds Pletscher, A. & amygdala during a working memory task predict rapid M. F. I., Bäbler, A., Vogel, H. & Hell, D. Psilocybin Ladewig, D.) 101–118 (Parthenon, New York, 1994). antidepressant response to ketamine. induces schizophrenia-like psychosis in humans via 6. Fischer, R., Marks, P. A., Hill, R. M. & Rockey, M. A. Neuropsychopharmacology 35, 1415–1422 a serotonin-2 agonist action. Neuroreport 9, Personality structure as the main determinant of drug (2010). 3897–3902 (1998). induced (model) psychoses. Nature 218, 296–298 33. Salvadore, G. et al. Increased anterior cingulate 57. Schmid, C. L., Raehal, K. M. & Bohn, L. M. (1968). cortical activity in response to fearful faces: a Agonist-directed signaling of the serotonin 2A 7. Leuner, H. Die Experimentelle Psychose (Springer, neurophysiological biomarker that predicts rapid receptor depends on b-arrestin-2 interactions in vivo. Berlin Göttingen Heidelberg, 1962). antidepressant response to ketamine. Biol. Psychiatry Proc. Natl Acad. Sci. USA 105, 1079–1084 (2008). 8. Hoch, P. H., Cattell, J. P. & Pennes, H. H. Effects of 65, 289–295 (2009). 58. Puig, M. V., Celada, P., az-Mataix, L. & Artigas, F. mescaline and lysergic acid (d-LSD-25). Am. 34. Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. In vivo modulation of the activity of pyramidal neurons J. Psychiatry 108, 579–584 (1952). Targeting the glutamatergic system to develop novel, in the rat medial prefrontal cortex by 5-HT2A 9. Chapman, J. The early symptoms of schizophrenia. improved therapeutics for mood disorders. Nature receptors: relationship to thalamocortical afferents. Br. J. Psychiatry 112, 225–251 (1966). Rev. Drug Discov. 7, 426–437 (2008). Cereb. Cortex 13, 870–882 (2003). 10. Gouzoulis-Mayfrank, E. et al. Hallucinogenic drug 35. Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in 59. Beique, J. C., Imad, M., Mladenovic, L., Gingrich, J. A. induced states resemble acute endogenous psychoses: synaptic plasticity and neuropsychiatric disorders. & Andrade, R. Mechanism of the 5-hydroxytryptamine results of an empirical study. Eur. Psychiatry 13, Nature Rev. Neurosci. 8, 413–426 (2007). 2A receptor-mediated facilitation of synaptic activity in 399–406 (1998). 36. Krupitsky, E. et al. Ketamine psychotherapy for heroin prefrontal cortex. Proc. Natl Acad. Sci. USA 104, 11. Geyer, M. A. & Vollenweider, F. X. Serotonin research: addiction: immediate effects and two-year follow-up. 9870–9875 (2007). contributions to understanding psychoses. Trends J. Subst. Abuse Treatment 23, 273–283 (2002). 60. Aghajanian, G. K. & Marek, G. J. Serotonin and Pharmacol. Sci. 29, 445–453 (2008). 37. Moreno, F. A., Wiegand, C. B., Taitano, E. K. & hallucinogens. Neuropsychopharmacology 21, 12. Nichols, D. E. Hallucinogens. Pharmacol. Ther. 101, Delgado, P. L. Safety, tolerability, and efficacy of 16S–23S (1999). 131–181 (2004). psilocybin in 9 patients with obsessive-compulsive 61. Marek, G. J., Wright, R. A., Gewirtz, J. C. & 13. Krystal, J. H. et al. Subanesthetic effects of the disorder. J. Clin. Psychiatry 67, 1735–1740 (2006). Schoepp, D. D. A major role for thalamocortical noncompetitive NMDA antagonist, ketamine, in 38. Brandrup, E. & Vanggaard, T. LSD treatment in a afferents in serotonergic hallucinogen receptor humans. Arch. Gen. Psychiatry 51, 199–214 severe case of compulsive neurosis. Acta Psychiatr. function in the rat neocortex. Neuroscience 105, (1994). Scand. 55, 127–141 (1977). 379–392 (2001). 14. Anis, N. A., Berry, S. C., Burton, N. R. & Lodge, D. 39. Leonard, H. L. & Rapoport, J. L. Relief of obsessive– 62. Aghajanian, G. K. Modeling ‘psychosis’ in vitro by The dissociative anesthetics, ketamine and compulsive symptoms by LSD and psilocin. Am. inducing disordered neuronal network activity in phencyclidine selective reduce excitation of central J. Psychiatry 144, 1239–1240 (1987). cortical brain slices. Psychopharmacology (Berlin) mammalian neurons by N-methyl-D-aspartate. 40. Moreno, F. A. & Delgado, P. L. Hallucinogen-induced 206, 575–585 (2009). Br. J. Pharmacol. 79, 565–575 (1983). relief of obsessions and compulsions. Am. 63. Zhang, C. & Marek, G. J. AMPA receptor involvement 15. Sandison, R. A. Psychological aspects of the LSD J. Psychiatry 154, 1037–1038 (1997). in 5-hydroxytryptamine2A receptor-mediated pre- treatment of neuroses. J. Ment Sci. 100, 508–515 41. Sewell, R. A., Halpern, J. H. & Pope, H. G. Jr. frontal cortical excitatory synaptic currents and DOI- (1954). Response of cluster headache to psilocybin and LSD. induced head shakes. Prog. Neuropsychopharmacol. 16. Schmiege, G. R. Jr. LSD as a therapeutic tool. J. Med. Neurology 66, 1920–1922 (2006). Biol. Psychiatry 32, 62–71 (2008). Soc. N.J. 60, 203–207 (1963). 42. Gonzalez-Maeso, J. & Sealfon, S. C. Agonist-trafficking 64. Benneyworth, M. A. et al. A selective positive 17. Malleson, N. Acute adverse reactions to LSD in clinical and hallucinogens. Curr. Med. Chem. 16, 1017–1027 allosteric modulator of metabotropic glutamate and experimental use in the United Kingdom. (2009). receptor subtype 2 blocks a hallucinogenic drug model Br. J. Psychiatry 118, 229–230 (1971). 43. Winter, J. C. Hallucinogens as discriminative stimuli of psychosis. Mol. Pharmacol. 72, 477–484 (2007). 18. Hoffer, A. in The Uses and Implications of in animals: LSD, phenethylamines, and tryptamines. 65. Lambe, E. K. & Aghajanian, G. K. Hallucinogen- Hallucinogenic Drugs (eds Aaronson, B. & Psychopharmacology (Berlin) 203, 251–263 (2009). induced UP states in the brain slice of rat prefrontal Osmond, H.) 357–366 (Hogarth Press, London, 44. Large, C. H. Do NMDA receptor antagonist models of cortex: role of glutamate spillover and NR2B-NMDA 1970). schizophrenia predict the clinical efficacy of antipsychotic receptors. Neuropsychopharmacology 31, 1682– 19. Abramson, H. The use of LSD in Psychotherapy and drugs? J. Psychopharmacol. 21, 283–301 (2007). 1689 (2006). Alcoholism (Bobbs-Merrill, New York, 1967). 45. Quirk, M. C., Sosulski, D. L., Feierstein, C. E., 66. Celada, P., Puig, M. V., Casanovas, J. M., Guillazo, G. 20. Kast, E. in LSD: The Consciousness Expanding Drug Uchida, N. & Mainen, Z. F. A defined network of fast- & Artigas, F. Control of dorsal raphe serotonergic (ed. Solomon, D.) 241–256 (G.P. Putman, New York, spiking interneurons in orbitofrontal cortex: responses neurons by the medial prefrontal cortex: Involvement 1964). to behavioral contingencies and ketamine of serotonin-1A, GABA(A), and glutamate receptors. 21. Pahnke, W. N., Kurland, A. A., Goodman, L. E. & administration. Front. Syst. Neurosci. 3, 13 (2009). J. Neurosci. 21, 9917–9929 (2001). Richards, W. A. LSD-assisted psychotherapy with 46. DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. Cognitive 67. Vazquez-Borsetti, P., Cortes, R. & Artigas, F. Pyramidal terminal cancer patients. Curr. Psychiatr. Ther. 9, therapy versus medication for depression: treatment neurons in rat prefrontal cortex projecting to ventral 144–152 (1969). outcomes and neural mechanisms. Nature Rev. tegmental area and dorsal raphe nucleus express 22. Leuner, H. in 50 Years of LSD: Current Status and Neurosci. 9, 788–796 (2008). 5-HT2A receptors. Cereb. Cortex 19, 1678–1686 Perspectives of Hallucinogen Research (eds Pletscher, 47. Clark, L., Chamberlain, S. R. & Sahakian, B. J. (2009). A. & Ladewig, D.) 175–189 (Parthenon, New York, Neurocognitive mechanisms in depression: 68. Vollenweider, F. X., Vontobel, P., Hell, D. & Leenders, 1994). implications for treatment. Annu. Rev. Neurosci. 32, K. L. 5-HT modulation of dopamine release in basal 23. Kurland, A. A., Unger, S., Shaffer, J. W. & Savage, C. 57–74 (2009). ganglia in psilocybin-induced psychosis in man: A PET Psychedelic therapy utilizing LSD in the treatment of 48. Geyer, M. A., Nichols, D. E. & Vollenweider, F. X. study with [11C]raclopride. the alcoholic patient: a preliminary report. Am. in Encyclopedia of Neuroscience (ed. Squire, L. R.) Neuropsychopharmacology 20, 424–433 (1999). J. Psychiatry 123, 1202–1209 (1967). 741–748 (Academic Press, Oxford, 2009). 69. Jones, K. A. et al. Rapid modulation of spine 24. Skolnick, P., Popik, P. & Trullas, R. Glutamate-based 49. Marona-Lewicka, D., Thisted, R. A. & Nichols, D. E. morphology by the 5-HT2A serotonin receptor antidepressants: 20 years on. Trends Pharmacol. Sci. Distinct temporal phases in the behavioral through kalirin-7 signaling. Proc. Natl Acad. Sci. USA 30, 563–569 (2009). pharmacology of LSD: dopamine D2 receptor- 106, 19575–19580 (2009). 25. Berman, R. M. et al. Antidepressant effects of mediated effects in the rat and implications for 70. Buckholtz, N. S., Zhou, D. F., Freedman, D. X. & ketamine in depressed patients. Biol. Psychiatry 47, psychosis. Psychopharmacologia (Berlin) 180, Potter, W. Z. Lysergic acid diethylamide (LSD) 351–354 (2000). 427–435 (2005). administration selectively downregulates serotonin2 26. Zarate, C. A. Jr et al. A randomized trial of an 50. Glennon, R. A., Titeler, M. & McKenney, J. D. Evidence receptors in rat brain. Neuropsychopharmacology 3, N-methyl-D-aspartate antagonist in treatment- for 5-HT2 involvement in the mechanism of action of 137–148 (1990). resistant major depression. Arch. Gen. Psychiatry 63, hallucinogenic agents. Life Sci. 35, 2505–2511 71. Gresch, P. J., Smith, R. L., Barrett, R. J. & 856–864 (2006). (1984). Sanders-Bush, E. Behavioral tolerance to lysergic acid 27. Phelps, L. E. et al. Family history of alcohol 51. Aghajanian, G. K. & Marek, G. J. Serotonin induces diethylamide is associated with reduced serotonin-2A dependence and initial antidepressant response to an excitatory postsynaptic potentials in apical dendrites receptor signaling in rat cortex. N-methyl-D-aspartate antagonist. Biol. Psychiatry 65, of neocortical pyramidal cells. Neuropsychopharmacology 30, 1693–1702 181–184 (2009). Neuropsychopharmacology 36, 589–599 (1997). (2005).

72. Shelton, R. C., Sanders-Bush, E., Manier, D. H. & 94. Preskorn, S. H. et al. An innovative design to establish 113. Hasler, G. et al. Reduced prefrontal glutamate/ Lewis, D. A. Elevated 5-HT 2A receptors in proof of concept of the antidepressant effects of the glutamine and gamma-aminobutyric acid levels in postmortem prefrontal cortex in major depression is NR2B subunit selective N-methyl-D-aspartate major depression determined using proton magnetic associated with reduced activity of protein kinase, A. antagonist, CP-101,606, in patients with treatment- resonance spectroscopy. Arch. Gen. Psychiatry 64, Neuroscience 158, 1406–1415 (2008). refractory major depressive disorder. J. Clin. 193–200 (2007).

73. Bhagwagar, Z. et al. Increased 5-HT2A receptor binding Psychopharmacol. 28, 631–637 (2008). 114. Bishop, S. J. Trait anxiety and impoverished prefrontal in euthymic, medication-free patients recovered from 95. Maeng, S. et al. Cellular mechanisms underlying the control of attention. Nature Neurosci. 12, 92–98 depression: a positron emission study with [11C]MDL antidepressant effects of ketamine: role of α-amino- (2009). 100,907. Am. J. Psychiatry 163, 1580–1587 3-hydroxy-5-methylisoxazole-4-propionic acid 115. Bishop, S. J. Neural mechanisms underlying selective (2006). receptors. Biol. Psychiatry 63, 349–352 (2008). attention to threat. Ann. NY Acad. Sci. 1129, 74. Meyer, J. H. et al. Dysfunctional attitudes and 5-HT2 96. Anand, A. et al. Attenuation of the neuropsychiatric 141–152 (2008). receptors during depression and self-harm. Am. effects of ketamine with lamotrigine: support for 116. Johnstone, T., van Reekum, C. M., Urry, H. L., J. Psychiatry 160, 90–99 (2003). hyperglutamatergic effects of N-methyl-D-aspartate Kalin, N. H. & Davidson, R. J. Failure to regulate: 75. Sibille, E. et al. Antisense inhibition of receptor antagonists. Arch. Gen. Psychiatry 57, counterproductive recruitment of top-down prefrontal- 5-hydroxytryptamine2a receptor induces an 270–276 (2000). subcortical circuitry in major depression. J. Neurosci. antidepressant-like effect in mice. Mol. Pharmacol. 97. Jentsch, J. D., Tran, A., Taylor, J. R. & Roth, R. H. 27, 8877–8884 (2007). 52, 1056–1063 (1997). Prefrontal cortical involvement in phencyclidine- 117. Chen, C. H. et al. Functional coupling of the amygdala 76. Yamauchi, M., Miyara, T., Matsushima, T. & induced activation of the mesolimbic dopamine in depressed patients treated with antidepressant Imanishi, T. Desensitization of 5-HT2A receptor system: behavioral and neurochemical evidence. medication. Neuropsychopharmacology 33, function by chronic administration of selective Psychopharmacology (Berlin) 138, 89–95 (1998). 1909–1918 (2008). serotonin reuptake inhibitors. Brain Res. 1067, 98. Breier, A. et al. Effects of NMDA antagonism on 118. Fu, C. H. et al. Attenuation of the neural response to 164–169 (2006). striatal dopamine release in healthy subjects — sad faces in major depression by antidepressant 77. Gomez-Gil, E. et al. Decrease of the platelet 5-HT2A application of a novel PET approach. Synapse 29, treatment: a prospective, event-related functional receptor function by long-term imipramine treatment 142–147 (1998). magnetic resonance imaging study. Arch. Gen. in endogenous depression. Hum. Psychopharmacol. 99. Vollenweider, F. X., Vontobel, P., Leenders, K. L. & Psychiatry 61, 877–889 (2004). 19, 251–258 (2004). Hell, D. Effects of S-ketamine on striatal dopamine 119. Sheline, Y. I. et al. Increased amygdala response 78. Cohen, H. Anxiolytic effect and memory improvement release: a [11C] raclopride PET study of a model to masked emotional faces in depressed in rats by antisense oligodeoxynucleotide to psychosis in humans. J. Psych. Res. 34, 35–43 (2000). subjects resolves with antidepressant treatment: 5-hydroxytryptamine-2A precursor protein. Depress. 100. Krystal, J. H. et al. Interactive effects of subanesthetic an fMRI study. Biol. Psychiatry 50, 651–658 (2001). Anxiety. 22, 84–93 (2005). ketamine and haloperidol in healthy humans. 120. Martinowich, K., Manji, H. & Lu, B. New insights into 79. Weisstaub, N. V. et al. Cortical 5-HT2A receptor Psychopharmacology 145, 193–204 (1999). BDNF function in depression and anxiety. Nature signaling modulates anxiety-like behaviors in mice. 101. Varty, G. B., Bakshi, V. P. & Geyer, M. A. M100907, a Neurosci. 10, 1089–1093 (2007).

Science 313, 536–540 (2006). serotonin 5-HT2A receptor antagonist and putative 121. Krystal, J. H. et al. Neuroplasticity as a target for the 80. Anisman, H., Merali, Z. & Stead, J. D. Experiential and antipsychotic, blocks dizocilpine-induced prepulse pharmacotherapy of anxiety disorders, mood genetic contributions to depressive- and anxiety-like inhibition deficits in sprague-dawley and wistar rats. disorders, and schizophrenia. Drug Discov. Today 14, disorders: clinical and experimental studies. Neurosci. Neuropsychopharmacology 20, 311–321 (1999). 690–697 (2009). Biobehav. Rev. 32, 1185–1206 (2008). 102. Snigdha, S. et al. Attenuation of phencyclidine-induced 122. Machado-Vieira, R., Salvadore, G., DiazGranados, N. 81. Lukkes, J., Vuong, S., Scholl, J., Oliver, H. & Forster, G. object recognition deficits by the combination of & Zarate, C. A. Jr. Ketamine and the next Corticotropin-releasing factor receptor antagonism atypical antipsychotic drugs and pimavanserin (ACP generation of antidepressants with a rapid onset within the dorsal raphe nucleus reduces social anxiety- 103), a 5-hydroxytryptamine(2A) receptor inverse of action. Pharmacol. Ther. 123, 143–150 (2009). like behavior after early-life social isolation. agonist. J. Pharmacol. Exp. Ther. 332, 622–631 (2010). 123. Vaidya, V. A., Marek, G. J., Aghajanian, G. K. & J. Neurosci. 29, 9955–9960 (2009). 103. Scruggs, J. L., Schmidt, D. & Deutch, A. Y. The Duman, R. S. 5-HT2A receptor-mediated regulation 82. Reul, J. M. & Holsboer, F. Corticotropin-releasing hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]- of brain-derived neurotrophic factor mRNA in the factor receptors 1 and 2 in anxiety and depression. 2-aminopropane (DOI) increases cortical extracellular hippocampus and the neocortex. J. Neurosci. 17, Curr. Opin. Pharmacol. 2, 23–33 (2002). glutamate levels in rats. Neurosci. Lett. 346, 2785–2795 (1997). 83. Magalhaes, A. C. et al. CRF receptor 1 regulates 137–140 (2003). 124. Cavus, I. & Duman, R. S. Influence of estradiol, stress, anxiety behavior via sensitization of 5-HT2 receptor 104. Muschamp, J. W., Regina, M. J., Hull, E. M., and 5-HT2A agonist treatment on brain-derived signaling. Nature Neurosci. 13, 622–629 (2010). Winter, J. C. & Rabin, R. A. Lysergic acid diethylamide neurotrophic factor expression in female rats. Biol. 84. Frokjaer, V. G. et al. Frontolimbic serotonin 2A and [-]-2,5-dimethoxy-4-methylamphetamine increase Psychiatry 54, 59–69 (2003). receptor binding in healthy subjects is associated with extracellular glutamate in rat prefrontal cortex. Brain 125. Garcia, L. S. et al. Ketamine treatment reverses personality risk factors for affective disorder. Biol. Res. 1023, 134–140 (2004). behavioral and physiological alterations induced by Psychiatry 63, 569–576 (2008). 105. Kargieman, L., Santana, N., Mengod, G., Celada, P. & chronic mild stress in rats. Prog. 85. Amat, J. et al. Medial prefrontal cortex determines Artigas, F. Antipsychotic drugs reverse the disruption Neuropsychopharmacol. Biol. Psychiatry 33, how stressor controllability affects behavior and in prefrontal cortex function produced by NMDA 450–455 (2009). dorsal raphe nucleus. Nature Neurosci. 8, 365–371 receptor blockade with phencyclidine. Proc. Natl Acad. 126. Studerus, E., Kometer, M., Hasler, F. & (2005). Sci. USA 104, 14843–14848 (2007). Vollenweider, F. X. Acute, subacute and long-term 86. Kupers, R. et al. A PET [18F]altanserin study of 106. Shi, W. X. & Zhang, X. X. Dendritic glutamate-induced subjective effects of psilocybin in healthy humans: a 5-HT12A receptor binding in the human brain and bursting in the prefrontal cortex: further pooled analysis of experimental studies. responses to painful heat stimulation. Neuroimage characterization and effects of phencyclidine. J. Psychopharmacology (in the press). 44, 1001–1007 (2009). J. Pharmacol. Exp. Ther. 305, 680–687 (2003). 127. Perry, E. B. Jr et al. Psychiatric safety of ketamine in 87. Oye, I., Paulsen, O. & Maurset, A. Effects of ketamine 107. Vollenweider, F. X. et al. Metabolic hyperfrontality and psychopharmacology research. Psychopharmacology on sensory perception: Evidence for a role of psychopathology in the ketamine model of psychosis (Berlin) 192, 253–260 (2007). N-methyl-d-aspartate receptors. J. Pharmac. Exp. using positron emission tomography (PET) and [F-18]- 128. Savage, C., Savage, E., Fadiman, J. & Harman, W. W. Ther. 260, 1209–1213 (1992). fluorodeoxyglocose (FDG). Eur. LSD: Therapeutic effects of the psychedelic experience. 88. Moghaddam, B., Adams, B., Verma, A. & Daly, D. Neuropsychopharmacol. 7, 9–24 (1997). Psychol. Rep. 14, 111–120 (1964). Activation of glutamatergic neurotransmission by 108. Vollenweider, F. X. et al. Positron emission tomography 129. Pahnke, W. N., Kurland, A. A., Unger, S., Savage, C. & ketamine: a novel step in the pathway from NMDA and fluorodeoxyglucose studies of metabolic Grof, S. The experimental use of psychedelic (LSD) receptor blockade to dopaminergic and cognitive hyperfrontality and psychopathology in the psilocybin psychotherapy. JAMA 212, 1856–1863 (1970). disruptions associated with the prefrontal cortex. model of psychosis. Neuropsychopharmacology 16, 130. Kurland, A. A., Grof, S. & Panke, W. N. G. L. E. LSD in J. Neurosci. 17, 2921–2927 (1997). 357–372 (1997). the treatment of alcoholics. Pharmakopsychiatr. 89. Lopez-Gil, X. et al. Clozapine and haloperidol 109. Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D. & Neuropsychopharmakol. 4, 83–94 (1971). differently suppress the MK-801-increased Angst, J. Differential psychopathology and patterns of 131. Griffiths, R. R., Richards, W., Johnson, M., McCann, U. glutamatergic and serotonergic transmission in the cerebral glucose utilisation produced by (S)- and & Jesse, R. Mystical-type experiences occasioned by medial prefrontal cortex of the rat. (R)-ketamine in healthy volunteers measured by psilocybin mediate the attribution of personal Neuropsychopharmacology 32, 2087–2097 (2007). FDG-PET. Eur. Neuropsychopharmacol. 7, 25–38 meaning and spiritual significance 14 months later. 90. Jackson, M. E., Homayoun, H. & Moghaddam, B. (1997). J. Psychopharmacol. 22, 621–632 (2008). NMDA receptor hypofunction produces concomitant 110. Schreckenberger, M. et al. The psilocybin psychosis as 132. Griffiths, R. R., Richards, W. A., McCann, U. & Jesse, R. firing rate potentiation and burst activity reduction in a model psychosis paradigma for acute schizophrenia: Psilocybin can occasion mystical-type experiences the prefrontal cortex. Proc. Natl Acad. Sci. USA 101, a PET study with 18-FDG. Eur. J. Nucl. Med. 25, 877 having substantial and sustained personal meaning 8467–8472 (2004). (1998). and spiritual significance. Psychopharmacology 91. Homayoun, H. & Moghaddam, B. NMDA receptor 111. Gouzoulis-Mayfrank, E. et al. Neurometabolic effects (Berlin) 187, 268–283 (2006). hypofunction produces opposite effects on prefrontal of psilocybin, 3,4-methylenedioxyethylamphetamine 133. Dittrich, A. The standardized psychometric cortex interneurons and pyramidal neurons. (MDE) and d-methamphetamine in healthy volunteers. assessment of altered states of consciousness J. Neurosci. 27, 11496–11500 (2007). A double-blind, placebo-controlled PET study with (ASCs) in humans. Pharmacopsychiatry 31, 80–84 92. Jodo, E. et al. Activation of medial prefrontal cortex by [18F]FDG. Neuropsychopharmacology 20, 565–581 (1998). phencyclidine is mediated via a hippocampo-prefrontal (1999). 134. Vollenweider, F. X. Advances and pathophysiological pathway. Cereb. Cortex 15, 663–669 (2005). 112. Walter, M. et al. The relationship between aberrant models of hallucinogen drug actions in humans: a 93. Moghaddam, B. & Adams, B. W. Reversal of neuronal activation in the pregenual anterior preamble to schizophrenia research. phencyclidine effects by a group II metabotropic cingulate, altered glutamatergic metabolism, and Pharmacopsychiatry 31, 92–103 (1998). glutamate receptor agonist in rats. Science 281, anhedonia in major depression. Arch. Gen. Psychiatry 135. Fischer, R. A cartography of the ecstatic and 1349–1352 (1998). 66, 478–486 (2009). meditative states. Science 174, 897–904 (1971).

136. Osmond, H. A review of the clinical effects of 147. Khorramzadeh, E. & Lotfy, A. O. The use of ketamine that are influenced by SES (BOX 1). In addi- psychotomimetic agents. Ann. NY Acad. Sci. 66, in psychiatry. Psychosomatics 14, 344–346 (1973). 418–434 (1957). 148. Mascher, E. in Neuro‑Psychopharmacology (eds Brill, H., tion, neuroscience research — in animals 137. Kurland, A. A. LSD in the supportive care of the Cole, J. O., Denker, P., Hippins, H. & Bradley, P. B.) and in humans — has provided candidate terminally ill cancer patient. J. Psychoactive Drugs 441–444 (Excerpta-Medica, Amsterdam, 2010). 17, 279–290 (1985). 149. Vollenweider, F. X. Brain mechanisms of hallucinogens mechanisms for the cause–effect relation- 138. Abramson, H. A. The Use of LSD in Psychotherapy and entactogens. Dialogues Clin. Neurosci. 3, ships between SES and neural development. and Alcoholism (Bobbs-Merrill, Indianapolis, 1967). 265–279 (2001). 139. Hollister, L. E., Shelton, J. & Krieger, G. A controlled This research has also demonstrated that at comparison of lysergic acid diethylamide (LSD) and Acknowledgements least some of these effects are reversible. Such dextroamphetmine in alcoholics. Am. J. Psychiatry The authors would like to acknowledge the financial support 125, 1352–1357 (1969). of the Swiss Neuromatrix Foundation (to F.X.V. and M.K.), a mechanistic understanding will enable the 140. Savage, C. & McCabe, O. L. Residential psychedelic and of the Heffter Research Institute (to F.X.V.). The authors design of more specific and powerful inter- (LSD) therapy for the narcotic addict. A controlled thank D. Nichols for critical comments on the manuscript. study. Arch. Gen. Psychiatry 28, 808–814 (1973). ventions to prevent and remediate the effects 141. Grof, S., Goodman, L. E., Richards, W. A. & Kurland, Competing interests statement of low childhood SES7–9. A. A. LSD-assisted psychotherapy in patients with The authors declare no competing financial interests. terminal cancer. Int. Pharmacopsychiatry 8, Other recent reviews have discussed 129–144 (1973). research on SES-related differences in 142. Pahnke, W. N. Psychedelic drugs and mystical DATABASES 7–9 experience. Int. Psychiatry Clin. 5, 149–162 clinicaltrials.gov: http://clinicaltrials.gov neurocognitive development . In this (1969). NcT00302744 | NcT00465595 | NcT00920387 | Perspective, we focus on the candidate 143. Grinspoon, L. & Bakalar, J. B. Psychedelic Drugs NcT00947791 | NcT00957359 Reconsidered (Basic Books., New York, 1979). UniProtKB: http://www.uniprot.org mechanisms by which SES influences brain 144. Crocket, R., Sandison, R. A. & Walk, A. in Proc. b-arrestin 2 | eGR1 | eGR2 | mGluR2 | mGluR3 development, drawing from research in R. Med–Psychol. Assoc. (Lewis & Co., London, 1963). FURTHER inFORMATiOn humans and in animal models. We first University of Zurich Neuropsychopharmacology and Brain 145. Leuner H. in Ethnopsychotherapie (eds Dittrich, A. & imaging Group’s homepage: http://www.dcp.uzh.ch/ describe studies in humans that show that Scharfetter, C.) 151–161 (Enke, Stuttgard, 1987) research/groups/neuropsychopharmacology.html 146. Geert-Jorgensen, E. Further observations regarding SES influences cognitive and affective func- hallucinogenic treatment. Acta Psychiatr. Scand. 203 All liNks Are Active iN the oNliNe pdf tion in children, adolescents and young (Suppl.), 195–200 (1968). 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 SCiEnCE AnD SOCiETy were directly manipulated to assess their effect on offspring outcomes.

Socioeconomic status and the brain: SES effects on mental health and cognition SES is a complex construct that is based mechanistic insights from human on household income, material resources, education and occupation, as well as related and animal research neighbourhood and family characteristics, such as exposure to violence and toxins, parental care and provision of a cognitively Daniel A. Hackman, Martha J. Farah and Michael J. Meaney stimulating environment2,5,10,11 (for con- Abstract | Human brain development occurs within a socioeconomic context and troversies regarding the measurement and ReFS 1,10,11 childhood socioeconomic status (SeS) influences neural development — defining levels of SES see ). Not only the lowest stratum but all levels of SES particularly of the systems that subserve language and executive function. affect emotional and cognitive development Research in humans and in animal models has implicated prenatal factors, to varying degrees1,12–14. This implies that the parent–child interactions and cognitive stimulation in the home environment in effects of SES that are reviewed here are the effects of SeS on neural development. These findings provide a unique relevant to the entire population, although opportunity for understanding how environmental factors can lead to individual it should be noted that the strongest effects are often seen in people with the lowest differences in brain development, and for improving the programmes and policies levels of SES. that are designed to alleviate SeS-related disparities in mental health and Compared with children and adolescents academic achievement. from higher-SES backgrounds, children and adolescents from low-SES backgrounds show higher rates of depression, anxiety, As the field of human neuroscience has through which experiences in the social attention problems and conduct disor- matured, it has progressed from describing world during early childhood affect the ders12,15–18, and a higher prevalence of inter- the ‘typical’ or ‘average’ human brain to structure and function of the brain. nalizing (that is, depression- or anxiety-like) characterizing individual differences in Growing up in a family with low SES is and externalizing (that is, aggressive and brain structure and function, and identify- associated with substantially worse health impulsive) behaviours6,19–21, all of which ing their determinants. Socioeconomic sta- and impaired psychological well-being, and increase with the duration of impoverish- tus (SES), a measure of one’s overall status impaired cognitive and emotional develop- ment12,21. In addition, childhood SES influ- and position in society, strongly influences ment throughout the lifespan1–6. In con- ences cognitive development; it is positively an individual’s experiences from child- trast to sociological and epidemiological correlated with intelligence and academic hood and through adult life. Research is approaches, neuroscience can identify the achievement from early childhood and beginning to shed light on the mechanisms underlying cognitive and affective systems through adolescence2,3,6,14,19,22,23.

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