Nature Reviews Neuroscience
| AOP AOP,, pulihe online 18 Augut 2010; oi:10.1038/n n2884
PeRSPecTiveS OpiniOn
The neurobiology of psychedelic drugs: implications implications for the treatment of mood disorders Franz X. Vollenweider and Michael Kometer
Abstrat | Aftr a paus of narly 40 yars n rsarh nto th ffts of psyhdl psyh dl drugs, rnt adans n our undrstandng of th t h nurobology of psyhdls, suh as lysrg ad dthylamd (LSD), psloybn and ktamn ha ld to rnwd ntrst n th lnal potntal potnt al of psyhdls n th tratmnt of arous psyhatr dsordrs. Rnt bhaoural and nuromagng data show that psyhdls modulat nural ruts that ha bn mplatd n mood and afft dsordrs, and an rdu th lnal symptoms of ths dsordrs. Ths fndngs ras th possblty that rsarh nto psyhdls mght dntfy nol thraput mhansms and approahs that ar basd on glutamat-drn nuroplastty. Pycheelic ug hae long hel a pecial facination fo mankin ecaue they pouce an altee tate of concioune that i chaacteize y itotion of peception, hallucination o iion, ectay, iolution of elf ounaie an the expeience of union with the wol. A plant-eie mateial, they hae een ue taitionally y many inigenou cultue in meical an eligiou pactice fo centuie, if not millennia1. Howee, eeach into pycheelic i not egin until the 1950 afte the eakthough icoey of the claical hallucinogen lyegic aci iethylamie (LSD) y Alet Hofmann 2 (timeline). The claical hallucinogen inclue inoleamine, uch a pilocyin an LSD, an phenethylamine, uch a mecaline an 2,5-imethoxy-4-ioo-amphetamine (DOI). Reeach into pycheelic wa aance in the mi 1960 y the fining that iociatie anaethetic uch a ketamine an phencycliine (PCP) alo pouce pycheelic-like effect 3 (BOX 1) . Gien thei oelapping pychological effect, oth clae of ug ae inclue hee a pycheelic.
Depening on the iniiual taking the ug, thei expectation, the etting in which the ug i taken an the ug oe, pycheelic pouce a wie ange of expeiential tate, fom feeling of ounlene, unity an li on the one han, to the anxietyinucing expeience of lo of ego-contol an panic on the othe han 4–7. Reeache fom iffeent theoetical icipline an expeimental pepectie hae emphaize iffeent expeiential tate. One emphai ha een place on the LSD-inuce peceptual itotion — incluing illuion an hallucination, thought ioe an expeience of plit ego 7,8 — that ae alo een in natually occuing pychoe 9–11. Thi pepectie ha pompte the ue of pycheelic a eeach tool fo unaelling the neuonal ai of pychotic ioe, uch a chizophenia pectum ioe. The mot ecent wok ha poie compelling eience that claical hallucinogen pimaily act a agonit of eotonin (5-hyoxytyptamine) (5-hyo xytyptamine) 2A (5-HT2A) ecepto12 an mimic mainly the ocalle poitie ymptom (hallucination an thought ioe) of chizophenia 10. Diociatie anaethetic mimic the poitie
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an the negatie ymptom (ocial withawal an apathy) of chizophenia though antagonim at NMDA ( N -methyl-d-methyl-d13,14 apatate) glutamate ecepto . Emphai ha alo een place on the ealy oeation that LSD can enhance elf-awaene an facilitate the ecollection of, an eleae fom, emotionally loae memoie 15,16. Thi pepectie appeale to pychiatit a a unique popety that coul facilitate the pychoynamic poce uing pychotheapy. In fact, y 1965 thee wee moe than 1,000 pulihe clinical tuie that epote pomiing theapeutic effect in oe 40,000 uject 17. LSD, pilocyin an, poaically, ketamine hae een epote to hae theapeutic effect in patient with anxiety an oeie– compulie ioe (OCD), epeion, exual yfunction an alcohol aiction, an to eliee pain an anxiety in patient with teminal cance 18–23 (BOX 2). Unfotunately,, thoughout the 1960 an Unfotunately 1970 LSD an elate ug ecame inceaingly aociate with cultual eellion; they wee wiely populaize a ug of aue an wee epicte in the meia a highly angeou. Conequently, y aout 1970, LSD an elate ug wee place in Schdu i in many weten countie. Accoingly,, eeach on the effect of Accoingly claical pycheelic in human wa eeely eticte, funing ecame ifficult an inteet in the theapeutic ue of thee ug fae, leaing many aenue of inquiy unexploe an many quetion unanwee. With the eelopment of ophiticate neuoimaging an ain-mapping technique an with the inceaing unetaning of the molecula mechanim of action of pycheelic in animal, enewe inteet in aic an clinical eeach with pycheelic in human ha teaily inceae ince the 1990. In thi Pepectie, we eiew ealy an cuent fining of the theapeutic effect of pycheelic an thei mechanim of action in elation to moen concept of the neuoiology of pychiatic ioe. We then ealuate the extent to which pycheelic may e ueful in theapy — aie fom thei etalihe application a moel of pychoi 3,11. ADvANCE ADv ANCE ONLINE PUbLICATION | 1
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PersPectives Curret theraeutc studes
Seeal peclinical tuie in the 1990 eeale an impotant ole fo the NMDA glutamate ecepto ecepto in the t he mechanim of action of antiepeant. Thee fining conequently gae ie to the hypothei that the NMDA-antagonit ketamine might hae potential a an antiepeant 24. Thi hypothei wa aliate in an initial oule-lin placeo-contolle placeo-conto lle clinical tuy in een meication-fee patient with majo epeion. Specifically, Specifically, a ignificant euction in epeion coe on the Hamilton epeion ating cale (HDRS) wa oee 3 hou afte a ingle infuion of ketamine (0.5 mg pe kg), an thi effect wa utaine fo at leat 72 hou25. Seeal tuie hae ince eplicate thi api antiepeant antiepeant effect of ketamine uing lage ample ize an teatment-eitant patient with epeion 26–30. Gien that 71% of the patient met epone citeia (efine a a 50% euction in HDRS coe fom aeline) within 24 hou 26, thi api effect ha a high theapeutic alue. In paticula,, patient with epeio paticula epeion n who ae uicial might enefit fom uch a api an make effect a thei acute motality ik i not coniealy iminihe with conentional antiepeant antiepeant owing to thei long elay in onet of action (uually 2–3 week). Inee, uicial ieation wee euce 24 hou afte a ingle ketamine infuion 28. Howee, epite thee impeie an api effect, all ut 2 of the patient elape within 2 week afte a ingle oe of ketamine26. Peiou elape peention tategie, uch a the aminitation of eithe fie aitional ketamine infuion 29 o ruzo (Rilutek; Sanofi-aenti) on a aily ai 30, yiele ucce only in ome patient an
othe tategie houl e tete in futhe tuie. Moeoe, the ue of iomake that ae oote in pychopathology, neuopychology an/o genetic might help to peict whethe ketamine theapy will e appopiate fo a gien patient with epeion 31. In line with thi iea, eceae actiation of the anteio cingulate cotex (ACC) uing a woking memoy tak 32 an inceae actiation of the ACC uing an emotional facial poceing tak 33, a well a a poitie family hitoy of alcohol aue27, wee aociate with a tonge antiepeant epone to ketamine. Ketamine theapy coul e extene to othe ioe in which NMDA ecepto ae implicate in the pathophyiology — fo example, ipola ioe 34 an aiction35. The ue of ketamine fo the teatment of ipola ioe i cuently eing tete (Clinicaltial.go: NCT00947791 NCT00947791). ). It potential a a teatment fo aiction aic tion i uppote y eult fom a oule-lin, anomize clinical tial in which 90 heoin aict eceie eithe xsay ord psychohrapy in comination with a high oe (2.0 mg pe kg) o a low oe of ketamine (0.2 mg pe kg). Follow-up Follow-u p tuie in the t he fit 2 yea eeale a highe ate of atinence, geate an longe-lating longe -lating euction in caing, an a poitie change in noneal, unconciou emotional attitue in uject who ha een teate with a high oe, compae with a low oe, of ketamine 36. In contat to the apily inceaing nume of clinical tuie with ketamine, tuie with claic hallucinogen ae emeging lowly. Thi low poge may e ue to the fact that claic hallucinogen ae place in Scheule 1 an theefoe hae
highe egulatoy hule to oecome an may hae negatie connotation a a ug of aue. A ecent tuy y Moeno an colleague 37 ealuate cae epot an fining fom tuie pefome in the 1960 that inicate that pilocyin an LSD ae effectie in the teatment of OCD 22,38–40. They uequently caie out a tuy howing that pilocyin gien on fou iffeent occaion at ecalating oe (anging fom u-hallucinogenic to hallucinogenic oe) makely eceae OCD ymptom (y 23–100%) on the Yale–bown oeie compulie cale in patient with OCD who wee peiouly teatment eitant 37. The euction in ymptom occue apily, at aout 2 h afte the peak pycheelic pycheelic effect, an enue up to the 24-h pot-teatment ating 37. Thi ymptom elief wa not elate to the oe of the pycheelic pych eelic ug o to the intenity of the pycheelic expeience, an extene eyon the oee acute pychological effect of 4–6 h, aiing intiguing quetion egaing the mechanim that unelie thi potacte effect 37. Futhe eeach on how thi initial elief of ymptom in epone to pilocyin — an the uequent etun of ymptom — i linke to functional change in the ain coul contiute not only to a mechanitic explanation of the potentially eneficial effect of pycheelic ut alo to the eelopment of noel teatment fo OCD. The chonicity an ieae uen of OCD, the uoptimal natue of aailale teatment an the oeation that pilocyin wa well toleate in OCD patient ae clea inication that futhe tuie into the uation, efficacy an
Tmln | A bref hstory of sychedelc drugs isolaton and dntfaton of msaln by A. Hfftr
1897
Synthss of PcP
1919
Synthss of msaln by e. Späth
1926
Dsory of psyhoat ffts of LSD by A. Hofmann
1938
Synthss of LSD by A. Hofmann
1943
Frst LSD study n popl wth dprsson by c. Saag
1947
Frst LSD study n humans by W. Stoll
1952
isolaton and synthss of pslon and psloybn by A. Hofmann
1953
Frst ln usng LSD n psyholyt thrapy by R. Sandson
1958
LSD appars on th strts
1962
Synthss of ktamn
1963
Sandoz ralls sampls of LSD and ass supplyng t
1965
introduton of th trm ‘dssoat anastht’ by e. Domno
1966
Dmonstraton of antagonst aton of PcP at NMDA rptors by N. Ans
1970
LSD, pslon and msaln ar plad n Shdul i n th US
1983
1988
Frst nuromagng study on psloybn and ktamn
1990
Dmonstraton of agonst aton of LSD at 5-HT2A rptors; frst nuromagng study on msaln
1999
Ktamn s plad n shdul iii n th US
LSD, lysrg ad dthylamd; NMDA, N-mthyl- d-aspartat; PcP, phnyldn. Dsors rlatng to lassal hallunogns and to dssoat anasthts ar shown by blak and rd boxs, rsptly.
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PersPectives Box 1 | Assessg altered states of coscousess Elementary visual alterations Audio–visual synesthaesia
Disembodiment Impaired control and cognition
Vivid imagery
Elementary visual alterations
Disembodiment
Audio–visual synesthaesia
Impaired control and cognition Vivid imagery
10 20 30 40 50 60 70 Anxiety
Changed meaning of percepts
20
30 40
50
60
Anxiety
Changed meaning of percepts Blissful state
Blissful state Insightfulness
Insightfulness Religious experience
Experience of unity
Psilocybin 115–125 µg per kg (n = 72) Psilocybin 215–270 µg per kg (n = 214) Psilocybin 315 µg per kg (n = 41)
Experience of unity
Ketamine 6 µg per kg per min (n = 42) Ketamine 12 µg per kg per min (n = 92)
Quantifying altered states of consciousness was problematic in the early years of hallucinogen research. Today, however, there are validated instruments for assessing various aspects of consciousnes consciousness. s. According to Dittrich133, hallucinogen-induced altered states of consciousness can be reliably measured by the five-dimensional altered states of consciousness (5DASC) rating scale. This scale comprises five primary dimensions and their respective subdimensions subdimensio ns (see the figure). The primary dimensions are ‘oceanic boundlessness’ (shown by orange boxes), referring to positively experienced loss of ego boundaries that are associated with changes in the sense of time and emotions — ranging from heightened mood to sublime happiness and feelings of unity with the environment; ‘anxious ego-disintegration’ (shown by purple boxes), including thought disorder and loss of self-control; ‘visionary restructuralization’ (shown by blue boxes), referring to perceptual alterations (such as visual illusions and hallucinations hallucinations), ), and altered meaning of percepts; acoustic alterations (not shown), including hypersensitivity to sound and auditory hallucinations; and altered vigilance (not shown).
mechanim of action of pilocyin o of elate compoun in the teatment of OCD ae waante. Encouage y ealy fining (BOX 2), eeal clinical cente hae egun to inetigate the potential eneficial effect of pilocyin (ClinicalTial.go: NCT00302744 NCT00302744,, NCT00957359 an NCT00465595 NCT00465595)) an LSD (ClinicalTial.go: NCT00920387 NCT00920387)) in the teatment of anxiety an epeion in patient with teminal cance, uing tate of the at, oule-lin, placeo-contolle eign. One of thee tuie ha ecently een complete an eeale that moeate oe of pilocyin impoe moo an euce anxiety an that thi elief aialy late etween 2 week an 6 month in patient with aance cance (C.S. Go, peonal communication). Finally, anothe ecent tuy epote that pilocyin an LSD aote attack, teminate the cusr prod
Religious experience
In general, the intensity of these psychedelic-induced alterations of consciousness and perception is dose-dependent, so that hallucinations that involve disorientation in person, place and time rarely, if ever, occur with low to medium doses 4–6. However, at larger doses — and depending on the individual, his or her expectations and the setting — the same hallucinogen might produce a pleasurable loss of ego boundari es combined with feelings of oneness or might lead to a more psychotic ego dissolution that involves fear and paranoid ideation 4,132,134 . Such experiential phenomena are otherwise rarely reported except in dreams, contemplative or religious exaltation and acute psychoses 11,135. The figure shows that the classical hallucinogen psilocybin (0.015–0.027 g per kg, by mouth) (see the figure, left) and the dissociative s-ketamine (6–12 μg per kg per min, intravenously) (see the figure, right) produce a set of overlapping psychological experiences, measured measured by the 5DASC rating scale and respective subscales. The scales indicate the percentage scored of the maximum score.
o extene the emiion peio in people uffeing fom clute heaache 41. Taken togethe,, thee fining uppot ealy oetogethe ation in the 1960 that claical hallucinogen hae antinociceptie potential an may not only euce ymptom ut alo inuce long-lating aaptie pocee. neurobology of sychedelc drugs
The enomou poge that ha een mae in ou unetaning of the mechanim of action of pycheelic 12,42–45 an the neuoiology of affectie ioe 34,46,47 ha enale u to potulate new hypothee egaing the theapeutic mechanim of pycheelic an thei clinical application. Hee we focu on the glutamategic an eotonegic mechanim of action of pycheelic with ega to thei mot pomiing inication — that i, thei ue in the teatment of epeion an anxiety.
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Classical hallucinogens. The claical hallucinogen ae compie of thee main chemical clae: the plant-eie typtamine (fo example, pilocyin) an phenethylamine (fo example, mecaline), an the emiynthetic egoline (fo example, LSD) 48. Although all claical hallucinogen iplay high affinity fo 5-HT 2 ecepto, they alo inteact to ome egee with 5-HT 1, 5-HT4, 5-HT5, 5-HT6 an 5-HT7 ecepto12. In contat to the typtamine, the egoline alo how high intinic actiity at opamine D2 ecepto an at α-aenegic ecepto 49. Coneging eience fom phamacological50, electophyiological 51,52 an ehaioual tuie in animal 53,54 ugget that claical hallucinogen pouce thei effect in animal an poily in human pimaily though agonitic agonitic action at cotical 5-HT2A ecepto (FiG. 1a). Conitent with thi iew, electiely etoing 5-HT2A ecepto in ADvANCE ADv ANCE ONLINE PUbLICATION | 3
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PersPectives cotical pyamial neuon i ufficient to ecue hallucinogen-inuce hea haking in tangenic mice that lack 5-HT2A ecepto53,55. Impotantly, aminitation of the 5-HT2A ecepto antagonit ketanein aolihe itually all of the pilocyin-in pilocyin-inuce uce 56 ujectie effect in human . Recent tuie hae emontate that hallucinogenic an non-hallucinogenic 5-HT2A agonit iffeentially egulate intacellula ignalling pathway in cotical pyamial neuon an that thi eult in a iffeential expeion of ownteam ignalling potein, uch a ealy gowth epone potein 1 ( EGR1 EGR1), ), EGR2 an β-aetin 2 55,57. Thi ugget that futhe eluciation of hallucinogen-pecific ignalling pathway may ai the eelopment of functionally electie ligan with pecific theapeutic popetie — fo example, ligan that hae antiepeant effect ut no hallucinogenic effect. Seeal tuie hae emontate that actiation of 5-HT2A ecepto y claical hallucinogen o y eotonin lea to a out, glutamate-epenent inceae in the actiity of pyamial neuon, pefeentially
thoe in laye v of the pefontal cotex (PFC)51,52,58,59 (FiG. 1a). Thi inceae in glutamategic ynaptic actiity wa initially thought to eult fom timulation of peynaptic 5-HT2A ecepto locate on glutamategic thalamocotical affeent to the PFC60,61. Howee, moe ecent tuie ugget that timulation of potynaptic 5-HT 2A ecepto55,58,59 on a upopulation of pyamial cell in the eep laye of the PFC 59 lea to an inceae in glutamategic ecuent netwok actiity 59,62. The inceae in glutamategic ynaptic actiity can e aolihe not only y pecific 5-HT2A antagonit ut alo y AMPA (α-amino-3-hyoxyl-5methyl-4-ioxazole-popionic aci) ecepto antagonit 63, y agonit 51 an poitie alloteic moulato of metaotopic glutamate ecepto 2 (mGluR2) 64, an y electie antagonit of the NR2b uunit of NMDA ecepto 65. Taken togethe, thee fining inicate that claical hallucinogen ae potent moulato of pefontal netwok actiity that inole a complex inteaction etween the eotonin an glutamate ytem in pefontal cicuit.
Box 2 | Early theraeutc fdgs wth sychedelcs By 1953, two forms of lysergic acid diethylamide (LSD) therapy based on different theoretical frameworks framewor ks were emerging. These have been named psychedelic (mind-manifesting) (mind-manifesting) 136 and 15 psycholytic (psyche-loosenin (psyche-loosening) g) therapies. In psychedelic therapy, which was practised mostly in North America, a large dose of LSD (200–800 μg) was applied in a single session. This was thought to induce an overwhelming and supposedly conversion-like peak experience that would bring the subject to a new level of awareness and self-knowledge. It was thought that that this would facilitate sf-acuazao and lead to permanent changes that would be beneficial to the subject128,129. Furthermore, it was claimed that intensive psychotherapeutic psychotherapeutic preparation of the patient before the drug session and a follow-up integration of the peak experience in further drug-free sessions were crucial for an optimal outcome 130. Promising therapeutic effects of this therapy were found in people with terminal cancer 20,137, in severe alcoholics138,139, in people who were addicted to narcotics140 and in patients with uross 141. For example, a series of studies showed that LSD could reduce depression and decrease apprehension towards death and, surprisingly,, that LSD had transient analgesic effects that were superior to those of surprisingly dihydromorphinone (also known as hydromorphone and Palladone SR (Napp)) and meperidine (also known as pethidine)20. These effects were confirmed in later studies and the clinical efficacy was linked with the intensity of the psychedelic experience 129,141,142. Psycholytic therapy was introduced by Ronald Sandison and applied in Europe at 18 treatment centres143. In psycholytic therapy, low to moderate doses of LSD (50–100 μg), psilocybin (10–15 mg) or, sporadically, ketamine were used repeatedly as an adjunct in psychoa psychoaaycay aycay ord psychohrapy to accelerate the therapeutic process by facilitating rgrsso and the recollection and release of emotionally loaded repressed memories, and by increasing the rasfrc reaction15,22,144–147. A review of 42 studies reported impressive improvement rates in (mostly treatment-resistant) treatment-resistant) patients with anxiety disorders (improvement in 70% of patients), depression (in 62% of patients), personality disorders (in 53–61% of patients), sexual dysfunction (in 50% of patients) and obsessive–compu obsessive–compulsive lsive disorders (in 42% of patients) 148. Unfortunately,, the majority of these studies had serious methodological flaws by contemporary Unfortunately standards. In particular, with the absence of adequate control groups and follow-up measurements and with vague criteria for therapeutic outcome, the studies did not clearly establish whether it was the drug or the therapeutic engagement that produced the reported beneficial effect. It was also difficult to draw firm conclusions regarding potential long-term efficacy. Nevertheless, the studies provide a conceptual framework for the application of psychedelics, with the data suggesting that the most promising indication for psychedelic use might be found in the treatment of depression and anxiety disorders.
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Actiation of 5-HT2A an 5-HT1A ecepto in the meial PFC (mPFC) alo ha ownteam effect on eotonegic an opaminegic actiity though ecening pojection to the oal aphe an the ental tegmental aea (vTA). Fo example, actiation of 5-HT2A ecepto in the mPFC inceae the fiing ate of 5-HT neuon in the oal aphe an of opamine neuon in the vTA, eulting in an inceae eleae of 5-HT in the mPFC 58,66 an of opamine in meocotical aea 67 in animal. In a tuy in human, the hallucinogenic 5-HT2A agonit pilocyin inceae tiatal opamine concentation, an thi inceae coelate with euphoia an epeonalization phenomena68. blocking opamine D2 ecepto y halopeiol, howee, euce thee effect y only aout 30%. Thi ugget that the opaminegic ytem contiute only moeately to the oa pectum of pilocyin-inuce pychological alteation56. Inteetingly,, 5-HT Inteetingly 5 -HT2A ecepto actiation not only eem to unelie un elie the peponeance of the acute pycheelic effect of hallucinogen ut may alo lea to neuoplatic aaptation in an extene pefontal–limic netwok. Fo example, in at a ingle oe of the hallucinogen DOI taniently inceae the enitic pine ize in cotical neuon69 an epeate oe of LSD ownegulate cotical 5-HT2A ut not 5-HT1A ecepto; effect that wee the mot ponounce in the fontomeial cotex an ACC70,71. It i poile that uch aaptation — an pecifically a ownegulation of pefontal 5-HT2A ecepto — might unelie ome of the theapeutic effect of hallucinogen in the teatment of epeion, anxiety an chonic pain. In faou of thi hypothei, 5-HT 2A ecepto enity wa foun to e inceae in the PFC in pot-motem ample 72 an in vivo73,74 in patient with majo epeion, an to e euce afte chonic teatment with aiou antiepeant — the euction coinciing with the onet of clinical efficacy 75–77. In In aition, chonic, antiene-meiate ownegulation of 5-HT2A ecepto in at 78 an in 5-HT2A knockout mice79 euce anxiety-like ehaiou, an electie etoation of 5-HT 2A ecepto in the PFC nomalize anxiety-like ehaiou in thee 5-HT2A knockout mice. Thee fining ugget that pefontal 5-HT 2A ecepto might moulate the actiity of ucotical tuctue, uch a the amygala 79. Anxiety an epeion ae inteelate with te80, which alo affect the eotonin ytem81. Ste eleate coticotopin-eleaing facto (CRF)82, an aminitation of CRF into the mPFC of mice enhance anxiety-like
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PersPectives a
Cortical layer V
Deep cortical layers
NMDAR
↑ Glutamate release
Brainstem
5-HT neuron
enity coelate with epone to tonic pain ut not with epone to hot phaic pain timuli. Thi ugget a ole of the 5-HT2A ecepto in the cognitie ealuation of pain expeience 86 an point to aitional theapeutic potential fo hallucinogen in iniiual with chonic pain.
5-HT2A
Dissociative anaesthet anaesthetics. ics. At u-anaethetic oe, iociatie anaethetic, uch a + ketamine, pimaily lock the NMDA ecepAMPAR to at the PCP ining ite in the ecepto’ ionotopic channel14 (FiG. 1b). The pychoacPsilocin/ 5-HT2A tie potency of the s-ketamine aor i LSD/DMT thee to fou time highe than that of the + + r-ketamine enantiome. Thi i paallele y BDNF thei elatie affinitie at the NMDA ecepto complex 87. Sytemic aminitation of Psilocin/ LSD/DMT non-competitie NMDA antagonit, uch a ketamine, PCP an MK-801 (alo b known a izocilpine), in at makCortex Subcortical areas ely inceae glutamate eleae in the ↑ Glutamate mPFC88,89 concomitant with an inceae in release the fiing ate of pyamial neuon in thi Ketamine NMDAR aea90. Thee effect ae poaly ue to a lockae of NMDA ecepto on GAbA (γ-aminoutyic aci)-egic inteneuon 45,91 AMPAR in cotical an/o ucotical tuctue an to the uequent euction of inhiitoy contol oe pefontal glutamategic neuInterneuron + on92. The inceae extacellula glutamate BDNF leel in the mPFC eem to contiute to the NMDAR pychotopic effect of ketamine an PCP, a AMPA ecepto antagonit 88 o agonit Ketamine GABA of mGluR2 an mGluR3 (ReF. 93) aolihe aiou ehaioual effect of NMDA Fgur 1 | Aan na nw an gama a by y. a | Th antagonit in at. Likewie, the ehaioual fgur shows a modl n whh hallunogns, suh as pslon, lysrg ad dthylamd (LSD) and effect of electie NR2b antagonit — uch dmthyltryptamn (DMT), nras xtrallular glutamat lls n th prfrontal ortx through a CP-101,606 (alo (a lo known a Taxopoil), stmulaton of postsynapt srotonn (5-hydroxytryptamn) 2A (5-HT 2A) rptors that ar loatd which pouce oe-epenent pychoon larg glutamatrg pyramdal lls n dp ortal layrs (v ( v and vi) projtng to layr v pyramdal nurons. Ths glutamat rlas lads to an ataton of AMPA (α-amno-3-hydroxy-5-mthyl-4- topic effect imila to thoe of ketamine in 94 soxazol propon ad) and NMDA (N-mthyl-d-aspartat) rptors on ortal pyramdal nurons. in human — can e locke y aminita95 Fina lly,, addton, hallunogns drtly atat 5-HT2A rptors loatd on ortal pyramdal nurons. Ths tion of AMPA ecepto antagonit . Finally lamotigine, which euce peynaptic ataton s thought to ultmatly lad to nrasd xprsson of bran-drd nurotroph fator (BDNF). b | Th fgur shows a modl n whh dssoat NMDA antagonsts, suh as ktamn, blok glutamate eleae, attenuate the ujectie nhbtory GABA (γ-amnobutyr ad)-rg ntrnurons n ortal and subortal bran aras, lad- effect of s-ketamine in human 96. ng to nhand frng of glutamatrg projton nurons and nrasd xtrallular glutamat In aition to haing t hee glutamategic lls n th prfrontal ortx. As ktamn also bloks NMDA rptors on ortal pyramdal nurons, effect, non-competitie NMDA ecepto th nrasd glutamat rlas n th ortx s thought to stmulat ortal AMPA mor than NMDA antagonit antagoni t inceae extacellula pefon pefontal tal rptors. Th nrasd AMPA-rptor-mdatd throughput rlat to NMDA-rptor-mdatd 89,93 an meolimic opamine an pethroughput s thought ultmatly to lad to nrasd xprsson of BDNF. fontal eotonin 89 leel in at, peumaly y timulating coticofugal glutamate 67,85 ehaiou in epone to DOI though aphe ae inole in te epone . eleae in the vTA97 an the oal aphe 89, enitization of 5-HT2 ecepto ignalling in Togethe, thee fining ugget that ownepectiely.. Stuie into the contiution of epectiely 83 the PFC . In human, fonto-limic 5-HT2A egulation of pefontal 5-HT 2A ecepto y thi opaminegic an eotonegic actiaecepto enity i coelate not only with claical hallucinogen might unelie ome tion to the ehaioual ehaioual effect of NMDA anxiety ut alo with an iniiual’ iniiual’ ifficulof the effect of hallucinogen on epeion antagonit antagoni t ae cant an the eult ae tie in coping with te 84. Inee, ecent an anxiety. omewhat contoeial. Specifically, in tuie howe that pefontal 5-HT 2A ecepFinally, with ega to the fining that two tuie in human, ketamine-inuce to locate on ecening pojection that LSD euce anxiety an pain in cance tiatal opamine eleae coelate with 20 contol eotonegic actiity in the oal patient , it i of note that pefontal 5-HT 2A the extent of ketamine-inuce pychotic NATURE REvIEWS | NeuroscieNce
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PersPectives ymptom 98,99, ut in anothe tuy ytemic aminitation of the opamine D2 ecepto antagonit halopeiol i not attenua attenuate te ketamine-inuce pychotic ymptom in healthy oluntee100. Although 5-HT2A ecepto antagonit antagonit eee the iuptie effect of NMDA antagonit on enoimoto gating 101 an on oject ecognition 102 in animal, no compaale tuie of the ole of eotonin in the mechanim of action of NMDA antagonit hae een conucte in human. The enhance glutamate eleae that eult fom NMDA ecepto lockae y ketamine lea to an inceae actiation of AMPA ecepto elatie to NMDA ecepto95. The antiepeant-like effect of ketamine an the electie NR2b antagonit CP-101,606 in animal can e locke y aminitation of the AMPA ecepto antagonit 2,3-ihyoxy-6-nito-7-ulphamoyl-enzo[f]quinoxalin phamo yl-enzo[f]quinoxaline-2,3-ione e-2,3-ione 95 (NbQX) , uggeting that enhance AMPA actiation in cotical cicuit i cucial fo the theapeutic effect of NMDA ecepto antagonit 34,95. a
A common mechanism? Thee i accumulating eience that, epite thei iffeent pimay moe of action, claical hallucinogen an iociatie anaethetic oth moulate glutamategic neuotanmiion in the pefontal–limic cicuity that i implicate in the pathophyiology of moo ioe. Thi moulation i eience y the oeation in at that hallucinogen 103,104 an iociatie anaethetic88,89 hae a imila effect in enhancing extacellula glutamate eleae in the PFC, leaing to inceae actiation of pyamial cell 63,65,105,106. Futhemoe, an conguent with thee fining, human neuoimaging tuie hae hown that oth pilocyin an ketamine makely actiate pefontal cotical aea, incluing the ACC an inula an, to a lee extent, tempoal an paieto-occipital egion 107–111 (FiG. 2). Accoing to cuent moel of emotion egulation the PFC, incluing the ACC, exet ‘cognitie’, top-own contol oe emotion an te epone though it connection to the amygala an oal aphe 47,85. Reuce pefontal glutamate leel that ae aociate with attenuate PFC actiation b
s-Ketamine
Psilocybin
Fgur 2 | Ban ay an n y-n a nn. a | Bran magng studs usng 18fluorodoxygluos [18FDG] postron msson tomography (PeT) rald that modrat doss of s-ktamn (top) and psloybn (bottom) n halthy oluntrs nrasd nuronal atty. Ths s shown by hangs n th rbral mtabol rat for gluos (cMRglu) n th prfrontal ortx and assoatd lmb rgons and n subortal struturs, nludng th thalamus107,109 . Ths smlar prfrontal–lmb ataton pattrn supports th w that both lasss of drugs ha onrgng ffts on a fnal pathway or nurotransmttr systm. b | Rnt [18FDG] PeT bran magng studs ha dmonstratd that th dgr to whh ah of th psyhdl-ndud ky dmnsons of altrd stats of onsousnss (BOX 2) s manfstd and orrlatd wth funtonal altratons n ortal and lmb rgons and subortal struturs, nludng th basal gangla and thalamus. For xampl, th ntnsty of xprn of th ky dmnson ‘oan boundlssnss’ orrlatd wth th s-ktamn- and psloybn-ndud ataton (rd) of a prfrontal–partal ntwork and th dataton (blu) of a strato–lmb amygdalontr amygdalontr ntwork149.
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in epone to emotional timuli 34,112,113 hae een epote in patient with epeion. Futhe,, epee iniiual 46 an uject Futhe with high tait anxiety 114 how euce PFC actiity when executie contol i engage, an might uffe fom eceae topown inhiition of amygala actiity 115,116 . Coneely, chonic teatment with scv sroo rupak hbors (SSRI) inceae the functional connectiity etween the amygala an the PFC117, an attenuate the amygala epone to the peentation of image howing a face in patient with epeion118,119. Thi ugget that the nomalization of thi yegulate netwok might e impotant in the ecoey fom epeion 46. Gien that oth pilocyin an ketamine inceae extacellula glutamate leel in the pefontal–limic cicuity in at an that the antiepeant effect of oth ug outlat thei acute pychotopic effect in epee patient, we popoe that a nomalization of thi netwok though a glutamate-epenent neuoplatic aaptation i the common theapeutic mechanim of thee ug. Specifically, we poit that pycheelic enhance neuoplaticity y inceaing AMPA-type glutamate ecepto tafficking an y aiing the leel of aineie neuotopic facto (bDNF). Deficit in thee neuoplatic mechanim hae een implicate in the pathophyiology of epeion34,120. Nomalization of thee neuoplatic eficit might contiute not only to the elatiely utaine antiepeant effect of ketamine121,122 ut alo to thoe of pilocyin. In line with thi iew, oth clae of ug hae een emontate to timulate t imulate AMPA ecepto y inceaing extacellula glutamate leel6,95 an to inceae bDNF leel in pefontal an limic ain aea in at 123–125. A ecent tuy in patient with epeion, howee, faile to emontate an inceae in bDNF plama leel in the fit 4 h afte ketamine infuion 122. Whethe ketamine teatment lea to an inceae in bDNF leel at a late time an whethe uch an inceae i aociate with utaine antiepeant effect waant futhe inetigation. Coclusos ad future drectos
The clinical fining an cuent unetaning of the mechanim of action of claical hallucinogen an iociatie anaethetic conege on the iea that pycheelic pycheel ic might e ueful in the teatment of majo epeion, anxiety ioe an OCD. Thee ae eiou, eilitating, life-hotening illnee, an a the cuently aailale teatment hae high failue ate, pycheelic might offe altenatie
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PersPectives teatment tategie that coul impoe the well-eing of patient an the aociate economic uen on patient an ociety. Accumulating eience how a cucial ole fo the glutamate ytem in the egulation of neuonal platicity, an inicate that anomalitie in neuoplaticity contiute to the pathophyiology of moo ioe. Thu, ug that taget neuonal platicity may offe a noel appoach to thei teatment. Thi Pepectie popoe that claical Gay Cluster period A prod of durg whch cusr hadach aacks occur rguary.
Enantiomers two srosorc ocus ha ar rror ags of ach ohr ad ar o suprposab.
Existentially oriented psychotherapy A for of hrapy ha phaszs h dvop of a ss of sf-drco hrough choc ad of awarss rsovg xsa cofcs (such as h vaby of dah, soao ad agsss agssss). s).
Neurosis A forr r for a cagory of a dsordrs characrzd by axy ad a ss of dsrss. ths cagory cuds dsordrs ow cassfd as ood dsordrs, axy dsordrs, dssocav dsordrs, sxua dsordrs ad soaofor dsordrs.
Psychoanalytically oriented psychotherapy A hrapy basd o Fruda psychoaayss whch ucoscous cofcs ha ar hough o caus h pa’s sypos ar brough o coscousss o cra sgh for h rsouo of h probs.
Regression i Fruda psychoaayc hory hs r dscrbs a psychoogca sragy o cop wh ray by as of a porary rvrso of h go o a arr sag of dvop.
Riluzole A drug usd o ra ayorophc ara scross ad ha has nmDA (N -hy-hy-d-aspara) rcpor bockg proprs sar o hos of ka.
Schedule 1 A gsav cagory coag corod drugs ha hav a hgh poa for abus, a ack of accpd safy ad o curry accpd dca us ras.
Selective serotonin reuptake inhibitors A cass of copouds ypcay usd as adprssas.
Self-actualization th ovao o raz a of o’s poa.
Structure–activity relationship (Of abbrvad o SAR.) ths s h raoshp bw h chca srucur of a ocu ad s boogca acvy.
Transference A phoo psychoaayss characrzd by ucoscous rdrco of fgs or dsrs fro o prso o aohr.
pycheelic, uch a pilocyin, an iociatie anaethetic, uch a ketamine, alte glutamategic neuotanmiion in pefontal–limic cicuitie, an that thi lea to neuoplatic aaptation, peumaly though enhancement of AMP AM PA ecepto function. Thee aaptation may explain ome of the hae an elatiely utaine antiepeant effect that ae oee in clinical tuie with ketamine an pilocyin. To futhe aliate thi glutamate-inuce neuoplaticity hypothei the elationhip etween meaue of glutamategic actiity an clinical outcome nee to e etalihe. Moeoe,, the fining that claical halluciMoeoe nogen (unlike iociatie anaethetic) alo moulate 5-HT2A ecepto ignalling ugget that they may impoe utype of anxiety an te-elate ioe. ioe. Stuie that t hat ue iomake fo genotype o that ue expeion leel of 5-HT2A ecepto in paallel with clinical en point woul e eential not only fo claifying the ole of 5-HT 2A ecepto in the theapeutic mechanim of claical hallucinogen ut alo fo the eelopmen eelopmentt of peonalize meicine in the teatment of anxiety an te-elate ioe. In aition, to optimize the clinical enefit of pycheelic an to euce thei unwante ie effect, a eepe unetaning of aiou facto i neceay. nec eay. Thee inclue srucur–acvy raoshps, oe– epone elationhip an the influence of pychotheapeutic appoache on the effect of pycheelic. In thi context, it i inteeting to note that thee wa no inication of polonge pychoi, peiting peception ioe o uequent ug aue afte pilocyin126 o ketamine127 aminitation in a lage ample of pychotheapeutically wellpepae healthy uject in a uppotie eeach etting. Simila oeation wee epote in mall ample of patient with epeion29 an OCD37. Nonethele, it i often claime that the iociatie effect of, fo example, ketamine may limit clinical ue, epite it epote efficacy 24,94. In thi ene, unetaning the molecula mechanim of action coul infom the eelopment of noel ligan fo 5-HT 2A o NMDA ecepto that iplay antiepeant popetie ut hae fewe iociatie effect than pilocyin an ketamine. Futhe ealuation of the oe–epone elationhip may e anothe appoach to minimize unwante ie effect. Fo example, low to moeate oal oe of pilocyin (<0.215 mg pe kg) wee foun to only aely pouce anxiou iociatie ymptom in contolle etting 126 (BOX 1) ut to euce anxiety, epeion an OCD ymptom in patient22,37. Similaly, a low
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oe of the NR2b antagonit CP-101,606 (in comination with an SSRI) ha tanient antiepeant effect in a mall ample of patient with epeion an only aely inuce iociatie ymptom 94. To take the oppoite pepectie, it i notewothy that initial clinical application of pycheelic in pycheelic an pycholytic theapy wee ae on the pemie that the ug-inuce pychological expeience ha an eential, facilitatoy effect on the pychotheapeutic poce — that i, it wa a fom of phamacology-aite pychotheapy pychotheapy.. Inee, it ha een hown that the tancenent peak (mytical-type) expeience, which ha a key ole in the theapeutic outcome in pycheelic theapy 128–130 an wa ate a among the mot peonally meaningful expeience 131,132 , occu in mot cae only in uppotie etting an afte high-oe aminitation of pycheelic. One might intepet thi concept a an ealy example of the neuoplaticity hypothei in which the ug-inuce expeience an it integation in the pychotheapeutic poce i the cucial mechanim that enale neuoplaticity an ehaioual change. by contat, cuent phamacological tategie often aume that meication alone pouce neuoplatic aaptation. Howee, Howee, ug that inceae neuoplaticity,, uch a pycheelic, neuoplaticity pycheelic , might e paticulaly clinically efficient in comination with pychotheapeutic inteention121. In uppot of thi notion, cognitie ehaioual theapy wa hown to nomalize pefontal–limic functioning in epee patient46, an coul theefoe enhance the popoe neuoplatic effect of pycheelic in pefontal–limic tuctue a icue hee. Thu, futhe lin, contolle tuie ae oiouly now neee to tet thee altenatie an oppoing hypothee. The potential of ug to taget glutamategic neuotanmiion in pefontal– limic cicuitie an to facilitate neuoplatic aaptation may tanlate into pomiing new teatment appoache fo affectie ioe. The noel hypothee peente hee now nee to e inetigate uing wellcontolle clinical tuie, keeping in min the contoeial hitoy of thi cla of ug. Franz X. Vollenweider Vollenweider and Michael Kometer are at the Neuropsychopharmacology and Brain Imaging Research Unit, University Hospital of Psychiatry, Zurich, Switzerland. Franz X. Vollenweider is also at the School of Medicine, University Univers ity of Zurich, Switzerland. Correspondence to F.X.V. e‑mail:
[email protected] do:10.1038/r2884 Pubshd o 18 Augus 2010
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Acknowledgements The authors would like to acknowledge the financial support of the Sw iss Neuromatrix Foundation (to F.X.V. and M.K.), and of the Heffter Research Institute (to F.X.V.). The authors thank D. Nichols for critical comments on the manuscript.
Competing interests statement The authors declare no competing financial interests.
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