Introductie

De afgelopen decennia is er hernieuwde wetenschappelijke interesse ontstaan in klassieke psychedelica, waaronder lyserginezuurdiethylamide (LSD), psilocybine, 2,5-dimethoxy-4-jodoamfetamine (DOI), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) en N,N-dimethyltryptamine (DMT), de psychedelische stof in de Amazone-ayahuasca-brouwsel [1]. Klassieke psychedelica hebben aangetoond dat ze relatief langdurige verbeteringen in de geestelijke gezondheid kunnen veroorzaken na een klein aantal doses, vooral wanneer ze worden gecombineerd met psychotherapie [2]. Bij patiënten die lijden aan depressie, angststoornissen en verslaving, kunnen de voordelen van psychedelica-ondersteunde psychotherapie vele maanden of jaren aanhouden [3,4,5,6,7,8,9,10]. Bovendien melden gezonde proefpersonen een toename van het welzijn tot een jaar na toediening van psychedelica in een veilige en ondersteunende omgeving [11,12,13].

Één toonaangevende theorie over de blijvende effecten van psychedelica classificeert ze als "psychoplastogenen", die snel een periode van verhoogde neuroplasticiteit stimuleren, evenals blijvende neuroplastische veranderingen [14, 15]. Neuroplasticiteit verwijst naar het vermogen van het zenuwstelsel om zijn structuur en functie te reorganiseren en zich aan te passen aan de dynamische omgeving [16]. Gedurende het leven is neuroplasticiteit essentieel voor leren, geheugen en herstel na neurologische beledigingen, evenals aanpassing aan levenservaringen [17]. De theorie dat psychedelica een venster van neuroplasticiteit openen, zou verklaren hoe langetermijneffecten langer aanhouden dan de aanwezigheid van het medicijn in het lichaam, en het is ook aantrekkelijk omdat verstoringen in neuroplasticiteit aanwezig zijn bij stemmingsstoornissen en verslaving [18].

Neuroplasticiteit kan op meerdere niveaus van analyse worden onderzocht. Op moleculair niveau omvat het veranderingen in gen- en eiwitexpressie, evenals post-translationele modificaties [19]. Van bijzonder belang is hersenafgeleide neurotrofe factor (BDNF), een neurotrofine die de groei van neuronen en synaptische plasticiteit reguleert [20]. Veranderingen in gen- en eiwitexpressie leiden tot morfologische veranderingen, waaronder de vorming en aanpassing van synapsen en dendrieten [21]. In bepaalde regio's, met name de hippocampus, omvat neuroplasticiteit ook neurogenese [22]. Deze processen wijzigen neurale circuits en manifesteren zich uiteindelijk in leren, geheugen en veranderingen in adaptief gedrag [19]. Neuroplasticiteit is cruciaal afhankelijk van activiteit op cellulair niveau, wat zich vertaalt naar ervaringsafhankelijkheid op het niveau van cognitie en gedrag: mensen leren zowel passief als actief van hun ervaringen en passen patronen van denken, emotie en gedrag dienovereenkomstig aan [17, 23].

Om het potentieel van psychedelica effectief te benutten, is het essentieel om te begrijpen hoe ze neuroplasticiteit beïnvloeden, evenals de klinische relevantie van deze effecten. In deze review beoordelen we eerst het beschikbare bewijs met betrekking tot de vraag of psychedelica neuroplasticiteit bevorderen. Vervolgens bespreken we waar in de hersenen dit waarschijnlijk gebeurt, welke doses hiertoe in staat zijn, hoelang de effecten kunnen aanhouden, en of ze betekenisvolle gevolgen hebben voor emotie, cognitie en gedrag, evenals therapeutisch gebruik. Ten slotte bespreken we de voordelen en uitdagingen die door psychedelica veroorzaakte neuroplasticiteit met zich meebrengt en identificeren we belangrijke richtingen voor toekomstig onderzoek.


Stimuleren psychedelica neuroplasticiteit?

Klassieke psychedelica worden verondersteld een periode van versnelde neuronale groei te veroorzaken, waardoor de capaciteit van de hersenen voor neuroplastische veranderingen wordt verbeterd. Studies bij dieren hebben aangetoond dat LSD, psilocybine, DMT en DOI de expressie van genen die verband houden met synaptische plasticiteit bevorderen, waaronder onmiddellijke vroege genen (IEGs) en BDNF [24,25,26,27,28,29,30,31,32,27, 35,36,37,38,39,40]. Wat betreft neurogenese zijn de resultaten gemengd: LSD en DOI hadden geen effect op volwassen neurogenese bij ratten, en psilocybine werd getoond om het lichtjes te verminderen bij muizen [41,42,43]. Daarentegen toonden studies bij muizen met zowel DMT als 5-MeO-DMT een toename in neurogenese [44, 45].

Bij mensen hebben studies vaak vertrouwd op perifere BDNF als een marker voor neuroplasticiteit, met wisselende resultaten. Hoewel ayahuasca in één studie de BDNF-niveaus verhoogde bij zowel gezonde als depressieve mensen, werd er in een andere studie geen verandering gevonden [46, 47]. Verschillende studies hebben de effecten van LSD op BDNF gemeten, waarbij sommige een toename vonden [48, 49] en anderen geen verandering [50, 51]. In twee studies bij gezonde proefpersonen verhoogden vergelijkbare doses psilocybine in de ene studie geen plasma BDNF [50], maar wel in de andere [52]. Deze variabiliteit kan gedeeltelijk te wijten zijn aan de beperkingen van perifere BDNF als een biomarker in farmacologische studies. Hoewel is aangetoond dat bloed-BDNF onder normale omstandigheden hersen-BDNF voorspelt, kunnen psychoplastogenen een toename van perifeer BDNF veroorzaken zonder enige toename in hersen-BDNF [53, 54]. Bovendien correleert BDNF mogelijk niet met andere maatregelen van corticale neuroplasticiteit bij mensen, en bloedplaatjes kunnen BDNF opslaan en vrijgeven onafhankelijk van neuronen [55, 56]. Naast het meten van BDNF-niveaus hebben neuroimagingstudies bewijs gevonden van veranderde neurale connectiviteit na behandeling met psilocybine en ayahuasca, wat wordt geïnterpreteerd als bewijs van door medicijnen veroorzaakte neuroplastische veranderingen [57,58,59].

Samengevoegd bieden dierstudies matig sterk bewijs dat psychedelica genen bevorderen die gerelateerd zijn aan neuroplasticiteit, synaptische sterkte en dendritische groei, inclusief BDNF. Analyses van perifeer BDNF-eiwit in menselijke studies zijn echter tot nu toe inconclusief geweest. Toekomstige studies bij mensen zouden baat kunnen hebben bij protocollen die niet alleen vertrouwen op perifere markers, maar ook langdurige veranderingen induceren om neuroplasticiteit te indexeren, zoals paired associative stimulation [60,61,62] of tetanische sensorische stimulatie [63, 64], evenals PET-studies met markers van synaptische dichtheid, zoals SV2A [65].


Hoe stimuleren psychedelica neuroplasticiteit?

De complexe moleculaire signalering die ten grondslag ligt aan door psychedelica verbeterde neuroplasticiteit is elders uitgebreid besproken [66,67,68,69], maar we zullen kort de belangrijkste aspecten bespreken. Psychedelica lijken neuroplasticiteit te verbeteren via de 5-HT2A-receptor, die ook de meeste van hun subjectieve effecten medieert [70,71,72]. Hoewel relatief lage doses van de selectieve 5-HT2A-receptorantagonist ketanserine psychedelica-geïnduceerde neuroplasticiteit niet volledig blokkeren [37, 73], blokkeren hogere doses ketanserine het volledig [36]. Bovendien voorspelt de affiniteit van verschillende psychedelische drugs voor de 5-HT2A-receptor hun individuele potentie als psychoplastogenen, en muizen zonder 5-HT2A-receptor vertonen geen tekenen van verbeterde neuroplasticiteit na behandeling met psychedelica [24, 27, 36].

Psychedelica stimuleren 5-HT2A-receptoren die zich postsynaptisch bevinden op laag 5 en 6 piramidale neuronen, evenals op GABAerge interneuronen [72]. Het netto-effect lijkt excitatie van laag 5 piramidale neuronen te zijn en verhoogde niveaus van extracellulair glutamaat, resulterend in een grotere stimulatie van AMPA-receptoren [35, 72, 74]. De precieze moleculaire paden die neuroplasticiteit kunnen modificeren na 5-HT2A-receptorstimulatie zijn nog niet volledig begrepen. Echter, een leidende hypothese suggereert dat de eerder genoemde stimulatie van AMPA-receptoren een positieve terugkoppellus activeert: Stimulatie van AMPA-receptoren kan de secretie van BDNF verbeteren, wat op zijn beurt de TrkB-receptoren en mTOR zou stimuleren, wat op zijn beurt verdere productie van BDNF en aanhoudende AMPA-activatie zou stimuleren [36, 38]. Aanhoudende activering van zowel AMPA-receptoren als mTOR lijkt noodzakelijk te zijn voor de verbeterde dendritische groei na stimulatie met psychedelica [35]. Bovendien kan activiteit met zowel 5-HT2A- als glutamaatreceptoren, met name mGlu2, essentieel zijn voor de effecten van psychedelica op neuroplasticiteit [66, 75, 76]. Deze effecten lijken waarschijnlijk specifiek te zijn voor synapsen en circuits die 5-HT2A-receptoren tot expressie brengen, aangezien BDNF lokaal werkt en niet ver na de afgifte diffundeert [20, 77].

Naast 5-HT2A-receptoren kunnen de effecten op neurogenese die worden waargenomen bij DMT en 5-MeO-DMT mogelijk andere receptoren betrekken [42, 43]. DMT heeft een lage maar functioneel significante affiniteit voor de sigma-1-receptor, een weesreceptor die betrokken is bij neuroprotectie en neurogenese [78]. Sigma-1-receptorantagonisten blokkeren de effecten van DMT op hippocampale neurogenese [44, 79], en de activiteit van de sigma-1-receptor is ook aangetoond neurogenese te stimuleren in eerdere studies [80,81,82]. De affiniteit van DMT voor sigma-1-receptoren kan ook niet alleen de effecten op neurogenese verklaren, maar ook de neuroprotectieve effecten van DMT in een rattenmodel van beroerte [83].

Wat betreft 5-MeO-DMT, deze molecule is ongebruikelijk onder psychedelica omdat het bijna 1000 keer hogere affiniteit heeft voor 5-HT1A-receptoren dan voor 5-HT2A-receptoren, en veel van de effecten worden bemiddeld door 5-HT1A-receptoren [79, 84,85,86,87]. Hippocampale 5-HT1A-receptoren kunnen neurogenese bevorderen, wat suggereert dat de effecten van 5-MeO-DMT op neurogenese mogelijk kunnen optreden via krachtige, relatief selectieve activering van 5-HT1A-receptoren [88, 89]. Bovendien zijn 5-HT1A-receptoren over het algemeen remmend en hebben ze meestal tegenovergestelde effecten op downstream signaalroutes dan 5-HT2A-receptoren [90,91,92,93]. Veel psychedelica vertonen affiniteit voor zowel 5-HT2A- als 5-HT1A-receptoren [94]. Bovendien kunnen sommige effecten van psychedelica op aandacht en het visuele systeem worden bemiddeld door het 5-HT1A-receptor [95, 96]. De opwindende en neuroplastische effecten van verschillende psychedelische drugs in een bepaalde hersenregio kunnen mogelijk afhangen van de vraag of die regio rijker is aan 5-HT2A- of 5-HT1A-receptoren [79, 97,98,99,100,101].


Where do psychedelics enhance neuroplasticity?

Because psychedelics promote synapse and dendrite growth in a 5-HT2A receptor-dependent manner, the greatest effects would be expected in regions with high 5-HT2A receptor expression, i.e., the neocortex [72, 91, 102]. Data from animal studies thus far supports this theory, showing relatively robust effects in cortical regions and smaller, less consistent effects on neuroplasticity elsewhere.


Neocortex

Psychedelics have been shown to enhance dendritic growth, including spinogenesis, in cortical neurons [36, 40]. In the frontal lobe specifically, animal studies show that psychedelics upregulate plasticity-related genes and promote the growth of synapses and dendritic spines [25, 27, 36, 37, 103]. In the prefrontal cortex (PFC), several psychedelics have been shown to rapidly upregulate genes related to neuroplasticity [25, 26, 104]. Pigs exposed to a hallucinogenic dose of psilocybin showed increased presynaptic density in the PFC [39]. In humans, PET imaging has shown that psilocybin increases glutamate signaling in the PFC, which is theorized to be important for psychedelic-enhanced plasticity [105].

Other cortical regions likely also show enhanced neuroplasticity as a function of 5-HT2A receptor density. DOI enhanced expression of the plasticity-related Arc gene in the whole cortex, as well as in the parietal cortex specifically [28, 106]. A recent unpublished study in mice examined expression of c-Fos, an early marker of neuroplastic processes, after treatment with psilocybin, revealing strong upregulation in most cortical regions. These included sensory visual, auditory, somatosensory, and gustatory areas, as well as motor and association areas, the anterior cingulate cortex (ACC), and the insula [107].


Hippocampus

Several studies have focused on the hippocampus, but many found modest effects compared to the cortex. In the rodent hippocampus, psilocybin treatment upregulated fewer plasticity-related transcripts in the hippocampus than in the cortex, and LSD failed to upregulate immediate early genes associated with neuroplasticity [24, 25]. Similarly, DOI failed to enhance expression of Arc in the hippocampus [106]. Treatment with DOI may even decrease the expression of BDNF in the dentate gyrus, leaving it unchanged in the rest of the hippocampus [28]. In line with this, the abovementioned PET study in humans found reduced glutamate activity in the hippocampus after psilocybin [105]. However, the cortex and hippocampus do not always show this opposite pattern. Pigs exposed to a hallucinogenic dose of psilocybin showed increased presynaptic density in both the hippocampus and the PFC [39]. Additionally, psilocybin has been shown to strengthen cortico-hippocampal synapses [73].

The reduced tendency toward neuroplastic effects in the hippocampus might be explained by its greater density of 5-HT1A than 5-HT2A receptors [90, 102]. It is possible that LSD, DOI, and psilocybin, and perhaps other psychedelics, have pro-neuroplastic effects in the cortex and other regions richer in 5-HT2A than 5-HT1A receptors, but tend to have modest or even inhibitory effects in 5-HT1A receptor-dominant areas like the hippocampus.


Other subcortical regions

Some preliminary unpublished evidence suggests that psychedelics may enhance neuroplasticity in a few subcortical regions. In the aforementioned study of c-fos, psilocybin increased c-fos expression in the claustrum, locus ceruleus, lateral habenula and some areas of the thalamus, amygdala, and brainstem [107]. The pattern of expression changes correlated with 5-HT2A receptor distribution [107]. Given that c-fos is a relatively unspecific marker, however, these results should be interpreted with caution, and more research is necessary to determine how psychedelics affect neuroplasticity in subcortical regions.

The mesolimbic pathway warrants particular attention due to its role in addiction. Addiction to drugs of abuse is driven by neuroplastic changes in dopaminergic neurons of the mesolimbic pathway [108]. Notably, however, psychedelics do not cause dependence or addiction [108]. Important mesolimbic areas for addiction, including the ventral tegmental area, nucleus accumbens, and striatum, express relatively few 5-HT2A receptors and are therefore unlikely to be much affected by psychedelic-induced plasticity [102, 109]. Additionally, inhibitory neurons projecting from the PFC to areas of the mesolimbic pathway are much richer in 5-HT2A receptors [102, 110], and enhanced dendritic growth in these PFC neurons could conceivably contribute to the anti-addictive effect observed with psychedelics [3, 10, 111].


At what dose do psychedelics enhance neuroplasticity?

Several studies have investigated how different doses of psychedelic drugs affect neuroplasticity. In rats, 0.2 mg/kg LSD promoted neuroplasticity-related changes in gene expression, and the efficacy increased up to a dose of 1 mg/kg, although some genes showed a peak effect at lower doses [31,32,33]. For psilocybin, a dose of 4 mg/kg was required to induce neuroplasticity-related changes in gene expression, and the effect also increased in a dose-dependent manner [25]. DOI also shows a dose-dependent effect on neuroplasticity [28]. Finally, a presumably sub-hallucinogenic dose of 1 mg/kg DMT increased functional plasticity in rat cortical slices, as measured by the frequency and amplitude of excitatory post-synaptic currents [36].

Though these studies suggest that psychedelics probably promote neuroplasticity in a dose-dependent manner, clear dose-response effects on neuroplasticity have not been established in humans. Sub-hallucinogenic doses of between 5 and 20 µg LSD produced significant short-term enhancements in plasma BDNF [48]. However, a similar study using doses of between 25 µg and 200 µg LSD only found significant effects on BDNF at 200 µg [49], and another failed to find significant changes even at this dose [50]. Perhaps using different methods, future research should seek to clarify the minimum and optimal doses for stimulating neuroplasticity with different psychedelics. The prospect of non-hallucinogenic “microdoses” which enhance neuroplasticity is attractive for certain clinical applications, including stroke, brain injury, and neurodegenerative disorders [15].

Particularly regarding microdoses, a discussion of dosing frequency is warranted. While large doses of psychedelics are not taken chronically due to their intense subjective effects, microdoses can be taken regularly and have been hypothesized to enhance neuroplasticity [48, 112]. Chronic dosing with LSD has been associated with enhanced eyeblink conditioning, as well as improved avoidance learning and reversal of stress-induced deficits in synaptogenesis in rodent models of depression [103, 113, 114]. However, chronic dosing with DMT may cause retraction of dendritic spines [115]. Additionally, chronic LSD dosing was associated with upregulation in genes related to neuroplasticity, but also to schizophrenia [104]. Many animal studies investigating chronic dosing have not differentiated between microdoses and hallucinogenic doses, which may be an important distinction. Nevertheless, further studies should investigate whether chronic dosing, particularly chronic microdosing, has different effects on neuroplasticity than single doses.


For how long do psychedelics enhance neuroplasticity?

In order to take advantage of a “window of plasticity,” it is essential to know when this window opens and closes. Evidence of enhanced neuroplasticity appears within several hours after exposure to psychedelics (Fig. 1). The earliest changes involve upregulation of neuroplasticity-related transcripts, which can occur within one hour [24, 34]. In rats, both LSD and psilocybin upregulated genes associated with neuroplasticity after 1.5 hours, particularly in the PFC [25, 33]. BDNF mRNA may become upregulated slightly later: one study found no change 1.5 hours after treatment with psilocybin, but others have found increased expression 2 and 3 hours after treatment with DOI [25, 28, 116].

Fig. 1: Timeline showing the earliest and latest observations of various changes in neuroplasticity following treatment with a single dose of the serotonergic psychedelics LSD, psilocybin/psilocin, DMT, or DOI.
 

One dot represents one study and time point. Human studies are shown in yellow; animal and in vitro studies are shown in purple. BDNF = brain-derived neurotrophic factor, IEGs = immediate early genes. Based on data for synaptic density, it is assumed that rates of dendritogenesis and synaptogenesis also increase at 6 h post-treatment. See Table S1 for citations.

Full size image

Changes in cellular morphology have been observed starting 6 hours after stimulation with psychedelics [35]. One study found no changes in dendritic growth 1 hour after stimulating primary rat neuronal cultures with LSD, but observed significant changes in dendritic growth, synaptogenesis, and spinogenesis at several later time points [35]. In humans, increases in peripheral BDNF levels have earliest been seen 4 hours after oral administration of LSD [48, 49].

Though neuroplasticity may increase within several hours, the peak effect may come some time later. In rat cortical neurons, the observed increase in synaptogenesis was greater at 24 hours than at 6 hours post-stimulation, and in female mice, the rate of dendritic spine formation 3 days after psilocybin treatment is greater than the rate seen just 1 day after treatment [36, 37]. Other work has shown that a significant neuronal growth phase occurs in the 72 hours after initial exposure to psychedelics [35].

Enhanced neuroplasticity may also last for several days. In mice treated with psilocybin, the rate of dendritic spine formation remained elevated for 3 days, returning to baseline by 5 days post-treatment [37]. In humans, both healthy volunteers and depressed patients show elevated peripheral BDNF levels 2 days following treatment with ayahuasca [46]. Finally, a study that treated mice with LSD every other day for 1 month observed long-term upregulated of neuroplasticity-related genes, including BDNF, in the medial PFC 4 weeks after treatment cessation [104]. Additionally, specific markers of neuroplasticity may have different “windows.” Though BDNF mRNA can become upregulated within 2 hours, the effect may already be gone 24 hours later, and it is unclear what this means for BDNF protein expression [36]. Upregulation of other plasticity-related genes follows various time courses, with some genes showing peak expression within a few hours, others at around 48 hours, and still others at 7 days after administration [27, 31, 32].

Crucially, new dendrites and synapses formed during the window of enhanced neuroplasticity can outlast the window itself. Increased synaptic and dendritic density has been observed at 72 hours post-treatment in multiple studies [27, 37, 39]. Furthermore, though mice treated with psilocybin returned to baseline levels of dendritic spine formation within 5 days, new dendrites formed during that period survived for at least 1 month [37]. In humans, research has uncovered changes in brain function which lasted at least 1 month after treatment with psilocybin, suggesting the presence of lasting neuroplastic changes [57].

These data suggest that various signs of enhanced neuroplasticity arise within 1–6 hours, with changes in gene expression appearing earliest and changes in cell morphology and synapse organization arising later. The increased rate of dendritogenesis may taper off within 5 days, however, neuroplastic changes which arise during this period of neural growth may last for at least 1 month. However, important questions about the window of neuroplasticity remain, and future research should aim to define the temporal dynamics of enhanced neuroplasticity in humans, as this may be crucial for the timing of psychotherapeutic interventions.


Consequences of enhanced neuroplasticity

Is enhanced neuroplasticity simply something we can measure, or does it also have meaningful consequences? Answering this question is essential for understanding the basis of psychedelics’ long-term effects, however, few studies have related changes in neuroplasticity directly to behavioral outcomes. In chronically stressed mice, psilocybin both strengthened cortico-hippocampal synapses and reduced anhedonia, which may be the result of improved synaptic strength in reward circuits [73]. Additionally, DMT has been seen to enhance both neurogenesis and memory performance [44]. Other studies have reported improvements in fear extinction learning and reductions in anxious behaviors and learned helplessness following exposure to psychedelics, while also observing increased dendritic spine density in separate cohorts of animals [27, 37, 103]. Finally, the enhanced spinogenesis induced by ketamine, which is also a psychoplastogen, has been associated with reductions in depression-related behaviors [117, 118]. More research is needed to determine whether the same could be true for classic psychedelics, and to confirm or deny the associations between neuroplastic and behavioral effects suggested in the literature thus far.

In humans, one study found that depressed patients treated with ayahuasca had elevated BDNF levels which correlated with their clinical improvements [46]. In another study, psilocybin lastingly increased connectivity between the PFC and other brain areas, including limbic and subcortical regions, and these increases occurred alongside decreases in negative affect and anxiety [57]. However, one limitation of many of these studies is the lack of causal inference: though changes in neuroplasticity and changes in cognition or behavior may occur simultaneously, whether neuroplasticity mediated those changes remains an open question for future studies to address.


Further outcomes possibly explained by enhanced neuroplasticity

Changes in neuroplasticity may also partially explain some other long-term effects of psychedelics. Psychedelics, combined with psychotherapy, have shown clinical efficacy in trials for mood disorders and addiction, and healthy participants also report improved mood after taking psychedelics [3,4,5,6, 10, 119,120,121,122,123]. Enhanced dendritic and synaptic growth in PFC neurons may be a plausible explanation for this: the PFC is essential for emotional regulation via its connections with the amygdala and other subcortical regions [124, 125]. Depression in particular is characterized by reduced cortical neuroplasticity [56, 126,127,128], synapse atrophy in the PFC [18, 129,130,131], and a reduced ability of the PFC to regulate limbic areas [132, 133]. Additionally, PTSD, social anxiety disorder, and generalized anxiety have been associated with fewer synaptic connections between the medial PFC and the amygdala, compromising the PFC’s ability to regulate fear responses [134,135,136]. In addiction, neuroplasticity in the circuits between the PFC and the nucleus accumbens, striatum, and limbic system becomes impaired, reducing PFC modulation of these regions [137]. Relatively selective dendritic growth on neurons originating in the PFC may help reverse these deficits, restoring signaling balance and top-down control over the limbic system.

Other modest cognitive improvements found after treatment with psychedelics may also be explained by enhanced neuroplasticity in cortical regions. In animal studies, chronic LSD treatment has been associated with improvements in learning [113, 114, 138]. In humans, LSD has improved frontal-dependent memory retrieval, and unpublished data suggests that it may also improve reinforcement learning, possibly by enhancing reward sensitivity [139, 140]. Cognitive flexibility also involves several circuits originating in the PFC [141, 142], and ayahuasca and psilocybin have been shown to promote certain aspects of cognitive flexibility [143,144,145,146,147]. Regular ayahuasca users additionally perform better on tests of behavioral inhibition, cognitive flexibility, working memory, and executive functioning [147]. Ayahuasca and psilocybin have also been shown to increase mindfulness, one form of attentional regulation for which the PFC, but also the ACC is essential [13, 58, 143, 148,149,150]. It is possible that dendritic growth in PFC and ACC neurons is responsible for these effects [59].

Finally, neuroplasticity may not only play a role in positive long-term effects of psychedelics, but also undesirable ones. Drug-induced neuroplastic changes in sensory regions could conceivably be a factor in psychedelic-induced flashbacks, as well as the rarer and more severe hallucinogen persisting perceptual disorder (HPPD), in which some drug effects, including hallucinations and psychological distress, persist after the drug has been metabolized [108, 151].


Experience-dependent neuroplasticity

Neuroplastic changes occur in an activity- and experience-dependent manner [16]. This is an important consideration when discussing psychedelic-enhanced neuroplasticity, because psychedelics themselves can catalyze intense experiences [2]. The beginning of the window of plasticity falls within the timeline of many psychedelic drugs’ subjective effects, meaning that at least some of the psychedelic experience takes place within a highly plastic brain [1, 152].

Because of this, the experiences people have under psychedelics may have more power to re-shape neural circuitry than everyday occurrences. This possibility comes with opportunities and challenges. In a safe and supportive setting, psychedelic drugs can cause personally meaningful, emotionally salient experiences which can lead to lasting improvements in well-being [11]. Both patients and healthy volunteers report insights into personal problems, emotional breakthroughs, reprocessing of traumatic memories, and feelings of connectedness and empathy for oneself and others [7, 12, 123, 153,154,155,156]. Sometimes this can take the form of a “helioscope effect” in which people seem to perceive their experiences in more detail, but are also able to work through difficult material without becoming overwhelmed [157]. These effects are commonly described in terms of learning experiences [154, 158]. Furthermore, mystical experiences, emotional breakthroughs, and insights correlate significantly with positive long-term effects, independently from the overall intensity of drug effects [155, 159]. There may be a synergy between enhanced neuroplasticity and these positive, therapeutic experiences.

However, especially in unsafe settings, psychedelics can also cause “bad trips” involving intense physical and psychological distress [160]. Negative psychedelic experiences, in particular longer ones, are sometimes associated with subsequent negative changes in well-being, and feelings of anxiety during a psychedelic experience correlate negatively with therapeutic effects [12, 160,161,162]. Along these lines, most people who develop HPPD report that distressing symptoms appeared after a frightening acute psychedelic experience [163]. Crucially, not all negative experiences lead to decreases in well-being; in fact, most do not, and long-term negative effects are rare [12, 161]. In a survey of people who had had a challenging experience while on psilocybin, the duration of the challenging experience was significantly and negatively correlated with changes in well-being [161]. This suggests that challenging experiences which resolve relatively quickly are less likely to cause undesirable neuroplastic changes, perhaps because overcoming difficult feelings becomes a positive learning experience. However, prolonged experiences of anxiety and distress during a state of heightened plasticity have the potential to be damaging.

Finally, the psychedelic experience itself is not the only important experience in psychedelic therapy. Enhanced neuroplasticity may also make people more responsive to other therapeutic interventions, including psychotherapy, but potentially also neurorehabilitation after stroke or brain injury [14]. Therapeutic interventions combined with antidepressants, which also modestly promote neuroplasticity, have been shown to be more effective than either intervention alone, and the same is likely true of psychedelics [164, 165]. Enhanced neuroplasticity, coupled with a psychedelic experience in a safe setting and accompanying psychotherapy, could ultimately generate a therapeutic effect that is more than the sum of its parts.


Conclusions

Significant progress has been made toward understanding how psychedelics affect neuroplasticity. Data thus far supports the theory that psychedelics stimulate dendritogenesis, synaptogenesis, and the upregulation of plasticity-related genes in a 5-HT2A receptor-dependent manner, affecting the cortex in particular. The window of neuroplasticity appears to open within a few hours and may last a few days, although neuroplastic changes occurring during this time may survive for at least a month. Because neuroplastic changes occur in an experience-dependent manner, experiences people have during this time may have a greater psychological impact than they otherwise would. Future research should attempt to confirm preclinical findings in humans, clarify optimal doses and specific neuroplastic effects for different psychedelic compounds, and further explore the consequences of psychedelic-enhanced neuroplasticity for both patient groups and healthy people.


Bronnen

  1. Nichols DE. Psychedelics. Pharm Rev. 2016;68:264–355.

    CAS PubMed Central PubMed Google Scholar 

  2. Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177:391–410.

    PubMed Google Scholar 

  3. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29:289–99.

    CAS PubMed Google Scholar 

  4. Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacol (Berl). 2018;235:399–408.

    CAS Google Scholar 

  5. Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30:1165–80.

    CAS PubMed Central PubMed Google Scholar 

  6. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30:1181–97.

    CAS PubMed Central PubMed Google Scholar 

  7. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 2015;29:57–68.

    PubMed Google Scholar 

  8. Ross S, Agin-Liebes G, Lo S, Zeifman RJ, Ghazal L, Benville J, et al. Acute and sustained reductions in loss of meaning and suicidal ideation following psilocybin-assisted psychotherapy for psychiatric and existential distress in life-threatening cancer. ACS Pharm Transl Sci. 2021;4:553–62.

    CAS Google Scholar 

  9. Agin-Liebes GI, Malone T, Yalch MM, Mennenga SE, Ponte KL, Guss J, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020;34:155–66.

    PubMed Google Scholar 

  10. Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abus. 2017;43:55–60.

    Google Scholar 

  11. Schmid Y, Liechti ME. Long-lasting subjective effects of LSD in normal subjects. Psychopharmacol (Berl). 2018;235:535–45.

    CAS Google Scholar 

  12. Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011;25:1434–52.

    CAS PubMed Google Scholar 

  13. Uthaug MV, van Oorsouw K, Kuypers KPC, van Boxtel M, Broers NJ, Mason NL, et al. Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution. Psychopharmacol (Berl). 2018;235:2979–89.

    CAS Google Scholar 

  14. Hasler G. Toward specific ways to combine ketamine and psychotherapy in treating depression. CNS Spectr. 2020;25:445–7.

    PubMed Google Scholar 

  15. Olson DE. Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics. J Exp Neurosci. 2018;12:1179069518800508.

    PubMed Central PubMed Google Scholar 

  16. Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski JQ, et al. Harnessing neuroplasticity for clinical applications. Brain. 2011;134:1591–609.

    PubMed Central PubMed Google Scholar 

  17. Ismail FY, Fatemi A, Johnston MV. Cerebral plasticity: Windows of opportunity in the developing brain. Eur J Paediatr Neurol. 2017;21:23–48.

    PubMed Google Scholar 

  18. Ray MT, Shannon Weickert C, Webster MJ. Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry. 2014;4:e389.

    CAS PubMed Central PubMed Google Scholar 

  19. Gulyaeva NV. Molecular mechanisms of neuroplasticity: an expanding universe. Biochem (Mosc). 2017;82:237–42.

    CAS Google Scholar 

  20. Song M, Martinowich K, Lee FS. BDNF at the synapse: why location matters. Mol Psychiatry. 2017;22:1370–75.

    CAS PubMed Central PubMed Google Scholar 

  21. Ribak CE, Shapiro LA. Dendritic development of newly generated neurons in the adult brain. Brain Res Rev. 2007;55:390–4.

    PubMed Google Scholar 

  22. Gage F. Adult neurogenesis in mammals. Science. 2019;364:827–8.

    CAS PubMed Google Scholar 

  23. Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res. 2008;51:S225–39.

    PubMed Google Scholar 

  24. Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–52.

    CAS PubMed Google Scholar 

  25. Jefsen OH, Elfving B, Wegener G, Muller HK. Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. J Psychopharmacol. 2020;35:269881120959614.

  26. Kelley DP, Venable K, Destouni A, Billac G, Ebenezer P, Stadler K, et al. Pharmahuasca and DMT rescue ROS production and differentially expressed genes observed after predator and psychosocial stress: relevance to human PTSD. ACS Chem Neurosci. 2022;13:257–74.

  27. de la Fuente Revenga M, Zhu B, Guevara CA, Naler LB, Saunders JM, Zhou Z, et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Reports. 2021;37:109836.

  28. Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci. 1997;17:2785–95.

    CAS PubMed Central PubMed Google Scholar 

  29. Gewirtz JCC AC, Terwilliger R, Duman RC, Marek GJ. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacol, Biochem Behav. 2002;73:317–26.

    Google Scholar 

  30. Desouza LA, Benekareddy M, Fanibunda SE, Mohammad F, Janakiraman B, Ghai U, et al. The hallucinogenic serotonin2A receptor agonist, 2,5-Dimethoxy-4-Iodoamphetamine, Promotes cAMP response element binding protein-dependent gene expression of specific plasticity-associated genes in the rodent neocortex. Front Mol Neurosci. 2021;14:790213.

  31. Nichols CD, Sanders-Bush E. Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase-1, C/EBP-beta and ILAD-1, a novel gene with homology to arrestins. J Neurochem. 2004;90:576–84.

    CAS PubMed Google Scholar 

  32. Nichols CD, Garcia EE, Sanders-Bush E. Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration. Mol Brain Res. 2003;111:182–8.

    CAS PubMed Google Scholar 

  33. Nichols CD, Sanders-Bush E. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology. 2002;26:634–42.

    CAS PubMed Google Scholar 

  34. González-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, et al. Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-Hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 2003;23:8836–43.

    PubMed Central PubMed Google Scholar 

  35. Ly C, Greb AC, Vargas MV, Duim WC, Grodzki ACG, Lein PJ, et al. Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth. ACS Pharmacol Transl Sci. 2020;4:452–60.

  36. Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23:3170–82.

    CAS PubMed Central PubMed Google Scholar 

  37. Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021;109:2535–44.e4.

    CAS PubMed Central PubMed Google Scholar 

  38. De Gregorio D, Popic J, Enns JP, Inserra A, Skalecka A, Markopoulos A, et al. Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proc Natl Acad Sci. 2021;118:1–9.

    Google Scholar 

  39. Raval NR, Johansen A, Donovan LL, Ros NF, Ozenne B, Hansen HD, et al. A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci. 2021;22:85.

  40. Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021;589:474–9.

    CAS PubMed Google Scholar 

  41. Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res. 2013;228:481–91.

    CAS PubMed Google Scholar 

  42. Jha S, Rajendran R, Fernandes KA, Vaidya VA. 5-HT2A/2C receptor blockade regulates progenitor cell proliferation in the adult rat hippocampus. Neurosci Lett. 2008;441:210–4.

    CAS PubMed Google Scholar 

  43. Banasr M, Hery M, Printemps R, Daszuta A. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology. 2004;29:450–60.

    CAS PubMed Google Scholar 

  44. Morales-Garcia JA, Calleja-Conde J, Lopez-Moreno JA, Alonso-Gil S, Sanz-SanCristobal M, Riba J, et al. N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Transl Psychiatry. 2020;10:331.

    PubMed Central PubMed Google Scholar 

  45. Lima da Cruz RV, Moulin TC, Petiz LL, Leao RN. A single dose of 5-MeO-DMT stimulates cell proliferation, neuronal survivability, morphological and functional changes in adult mice ventral dentate gyrus. Front Mol Neurosci. 2018;11:312.

    PubMed Central PubMed Google Scholar 

  46. de Almeida RN, Galvao ACM, da Silva FS, Silva E, Palhano-Fontes F, Maia-de-Oliveira JP, et al. Modulation of serum brain-derived neurotrophic factor by a single dose of ayahuasca: observation from a randomized controlled trial. Front Psychol. 2019;10:1234.

    PubMed Central PubMed Google Scholar 

  47. Rocha JM, Rossi GN, de Lima Osório F, Bouso JC, de Oliveira Silveira G, Yonamine M, et al. Effects of ayahuasca on the recognition of facial expressions of emotions in naive healthy volunteers: a pilot, proof-of-concept, randomized controlled trial. J Clin Psychopharmacol. 2021;41:267–74.

    PubMed Google Scholar 

  48. Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, et al. Low doses of LSD acutely increase bdnf blood plasma levels in healthy volunteers. ACS Pharmacol Transl Sci. 2020;4:461–6.

  49. Holze F, Vizeli P, Ley L, Muller F, Dolder P, Stocker M, et al. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2021;46:537–44.

    CAS PubMed Google Scholar 

  50. Holze F, Ley L, Muller F, Becker AM, Straumann I, Vizeli P, et al. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2022;47:1180–7.

  51. Holze F, Vizeli P, Muller F, Ley L, Duerig R, Varghese N, et al. Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacology. 2019;45:462–71.

    PubMed Central PubMed Google Scholar 

  52. Becker AM, Holze F, Grandinetti T, Klaiber A, Toedtli VE, Kolaczynska KE, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther. 2021;111:886–95.

  53. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol. 2011;14:347–53.

    CAS PubMed Google Scholar 

  54. Le Nedelec M, Glue P, Winter H, Goulton C, Broughton L, Medlicott N. Acute low-dose ketamine produces a rapid and robust increase in plasma BDNF without altering brain BDNF concentrations. Drug Deliv Transl Res. 2018;8:780–6.

    PubMed Google Scholar 

  55. Le Blanc J, Fleury S, Boukhatem I, Belanger JC, Welman M, Lordkipanidze M. Platelets selectively regulate the release of BDNF, but not that of its precursor protein, proBDNF. Front Immunol. 2020;11:575607.

    PubMed Central PubMed Google Scholar 

  56. Player MJ, Taylor JL, Weickert CS, Alonzo A, Sachdev P, Martin D, et al. Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology. 2013;38:2101–8.

    PubMed Central PubMed Google Scholar 

  57. Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep. 2020;10:2214.

    CAS PubMed Central PubMed Google Scholar 

  58. McCulloch DE, Madsen MK, Stenbaek DS, Kristiansen S, Ozenne B, Jensen PS, et al. Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals. J Psychopharmacol. 2021;36:2698811211026454.

  59. Sampedro F, de la Fuente Revenga M, Valle M, Roberto N, Dominguez-Clave E, Elices M, et al. Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Int J Neuropsychopharmacol. 2017;20:698–711.

    PubMed Central PubMed Google Scholar 

  60. Galvez V, Nikolin S, Ho KA, Alonzo A, Somogyi AA, Loo CK. Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial. Compr Psychiatry. 2017;73:31–4.

    PubMed Google Scholar 

  61. Rajji TK, Sun Y, Zomorrodi-Moghaddam R, Farzan F, Blumberger DM, Mulsant BH, et al. PAS-induced potentiation of cortical-evoked activity in the dorsolateral prefrontal cortex. Neuropsychopharmacology. 2013;38:2545–52.

    PubMed Central PubMed Google Scholar 

  62. Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 2000;123:572–84.

    PubMed Google Scholar 

  63. Spriggs MJ, Sumner RL, McMillan RL, Moran RJ, Kirk IJ, Muthukumaraswamy SD. Indexing sensory plasticity: Evidence for distinct Predictive Coding and Hebbian learning mechanisms in the cerebral cortex. Neuroimage. 2018;176:290–300.

    CAS PubMed Google Scholar 

  64. Sanders PJ, Thompson B, Corballis PM, Maslin M, Searchfield GD. A review of plasticity induced by auditory and visual tetanic stimulation in humans. Eur J Neurosci. 2018;48:2084–97.

    PubMed Google Scholar 

  65. Cai Z, Li S, Matuskey D, Nabulsi N, Huang Y. PET imaging of synaptic density: A new tool for investigation of neuropsychiatric diseases. Neurosci Lett. 2019;691:44–50.

    CAS PubMed Google Scholar 

  66. Banks MI, Zahid Z, Jones NT, Sultan ZW, Wenthur CJ. Catalysts for change: the cellular neurobiology of psychedelics. Mol Biol Cell. 2021;32:1135–44.

    CAS PubMed Central PubMed Google Scholar 

  67. Inserra A, De Gregoria D, Gobbi G. Psychedelics in psychiatry: neuroplastic, immunomodulatory, and neurotransmitter mechanisms. Pharm Rev. 2018;73:202–77.

    Google Scholar 

  68. Olson DE. Biochemical mechanisms underlying psychedelic-induced neuroplasticity. Biochemistry. 2022;61:127–36.

    CAS PubMed Google Scholar 

  69. Aleksandrova LR, Phillips AG. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol Sci. 2021;42:929–42.

  70. Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Stampfli P, et al. The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Curr Biol. 2017;27:451–7.

    CAS PubMed Google Scholar 

  71. Stenbaek DS, Madsen MK, Ozenne B, Kristiansen S, Burmester D, Erritzoe D, et al. Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. J Psychopharmacol. 2020;35:269881120959609.

  72. Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 2020;21:611–24.

    CAS PubMed Google Scholar 

  73. Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci USA. 2021;118:e2022489118.

  74. Muschamp JW, Regina MJ, Hull EM, Winter JC, Rabin RA. Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res. 2004;1023:134–40.

    CAS PubMed Google Scholar 

  75. Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett. 2011;493:76–9.

    CAS PubMed Central PubMed Google Scholar 

  76. Delille HK, Mezler M, Marek GJ. The two faces of the pharmacological interaction of mGlu2 and 5-HT(2)A - relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology. 2013;70:296–305.

    CAS PubMed Google Scholar 

  77. Horch HW, Katz LC. BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci. 2002;5:1177–84.

    CAS PubMed Google Scholar 

  78. Crouzier L, Couly S, Roques C, Peter C, Belkhiter R, Arguel Jacquemin M, et al. Sigma-1 (sigma1) receptor activity is necessary for physiological brain plasticity in mice. Eur Neuropsychopharmacol. 2020;39:29–45.

    CAS PubMed Google Scholar 

  79. Ray TS. Psychedelics and the human receptorome. PLoS One. 2010;5:e9019.

    PubMed Central PubMed Google Scholar 

  80. Moriguchi S, Shinoda Y, Yamamoto Y, Sasaki Y, Miyajima K, Tagashira H, et al. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice. PLoS One. 2013;8:e60863.

    CAS PubMed Central PubMed Google Scholar 

  81. Meunier J, Maurice T. Beneficial effects of the sigma1 receptor agonists igmesine and dehydroepiandrosterone against learning impairments in rats prenatally exposed to cocaine. Neurotoxicol Teratol. 2004;26:783–97.

    CAS PubMed Google Scholar 

  82. Fukunaga K, Moriguchi S. Stimulation of the sigma-1 receptor and the effects on neurogenesis and depressive behaviors in mice. In: Smith, S., Su, TP. (eds) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Springer: Cham; 2017. p. 201–11.

  83. Szabo I, Varga VE, Dvoracsko S, Farkas AE, Kormoczi T, Berkecz R, et al. N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain. Neuropharmacology. 2021;192:108612.

    CAS PubMed Google Scholar 

  84. Winter JC, Filipink RA, Timineri D, Helsley SE, Rabin RA. The paradox of 5-methoxy-N, N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors. Pharmacol Biochem Behav. 2000;65:75–82.

    CAS PubMed Google Scholar 

  85. Riga MS, Llado-Pelfort L, Artigas F, Celada P. The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors. Neuropharmacology. 2018;142:219–30.

    CAS PubMed Google Scholar 

  86. Riga MS, Bortolozzi A, Campa L, Artigas F, Celada P. The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors. Neuropharmacology. 2016;101:370–8.

    CAS PubMed Google Scholar 

  87. Krebs-Thomson K, Ruiz EM, Masten V, Buell M, Geyer MA. The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats. Psychopharmacol (Berl). 2006;189:319–29.

    CAS Google Scholar 

  88. Islam MR, Moriguchi S, Tagashira H, Fukunaga K. Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice. Neuroscience. 2014;272:116–30.

    CAS PubMed Google Scholar 

  89. Grabiec M, Turlejski K, Djavadian RL. The partial 5-HT1A receptor agonist buspirone enhances neurogenesis in the opossum (Monodelphis domestica). Eur Neuropsychopharmacol. 2009;19:431–9.

    CAS PubMed Google Scholar 

  90. Mengod G, Palacios JM, Cortes R. Cartography of 5-HT1A and 5-HT2A receptor subtypes in prefrontal cortex and its projections. ACS Chem Neurosci. 2015;6:1089–98.

    CAS PubMed Google Scholar 

  91. Lopez-Gimenez JF, Gonzalez-Maeso J. Hallucinogens and serotonin 5-HT2A receptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018;36:45–73.

    CAS PubMed Central PubMed Google Scholar 

  92. Celada P, Puig MV, Amargós-Bosch M, Adell A, Artigas F. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci. 2004;29:252–65.

  93. Reissig CJ, Eckler JR, Rabin RA, Winter JC. The 5-HT 1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology. 2005;182:197–204.

    CAS PubMed Central PubMed Google Scholar 

  94. Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26:1327–37.

    CAS PubMed Google Scholar 

  95. Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cogn Neurosci. 2005;17:1497–508.

    PubMed Google Scholar 

  96. Pokorny T, Preller KH, Kraehenmann R, Vollenweider FX. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience. Eur Neuropsychopharmacol. 2016;26:756–66.

    CAS PubMed Google Scholar 

  97. Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM. Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N, N-diethyllysergamide (LSD). J Medicinal Chem. 2002;45:4344–49.

    CAS Google Scholar 

  98. Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME. Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology. 2015;99:546–53.

    CAS PubMed Google Scholar 

  99. Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, et al. Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. Psychopharmacol (Berl). 2014;231:2771–83.

    CAS Google Scholar 

  100. Savalia NK, Shao LX, Kwan AC. A dendrite-focused framework for understanding the actions of ketamine and psychedelics. Trends Neurosci. 2020;44:260–75.

  101. Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017;31:1091–120.

    CAS PubMed Central PubMed Google Scholar 

  102. Beliveau V, Ganz M, Feng L, Ozenne B, Hojgaard L, Fisher PM, et al. A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci. 2017;37:120–28.

    CAS PubMed Central PubMed Google Scholar 

  103. De Gregorio D, Inserra A, Enns JP, Markopoulos A, Pileggi M, El Rahimy Y, et al. Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline. Neuropsychopharmacology. 2022;47:1188–98.

  104. Martin DA, Marona-Lewicka D, Nichols DE, Nichols CD. Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology. 2014;83:1–8.

    CAS PubMed Central PubMed Google Scholar 

  105. Mason NL, Kuypers KPC, Muller F, Reckweg J, Tse DHY, Toennes SW, et al. Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology. 2020;45:2003–11.

    CAS PubMed Central PubMed Google Scholar 

  106. Benekareddy M, Nair AR, Dias BG, Suri D, Autry AE, Monteggia LM, et al. Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol. 2013;16:405–15.

    CAS PubMed Google Scholar 

  107. Davoudian PA, Shao L-X, Kwan AC. Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin. bioRxiv, Preprint. 2022. https://doi.org/10.1101/2022.03.18.484437.

  108. Korpi ER, den Hollander B, Farooq U, Vashchinkina E, Rajkumar R, Nutt DJ, et al. Mechanisms of action and persistent neuroplasticity by drugs of abuse. Pharm Rev. 2015;67:872–1004.

    CAS PubMed Google Scholar 

  109. Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med. 1998;39:208–14.

    CAS PubMed Google Scholar 

  110. Kalivas PW. Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res. 2008;14:185–9.

    PubMed Google Scholar 

  111. Morgan C, McAndrew A, Stevens T, Nutt D, Lawn W. Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use. Curr Opin Behav Sci. 2017;13:71–6.

    Google Scholar 

  112. Fadiman J, Korb S. Might microdosing psychedelics be safe and beneficial? An initial exploration. J Psychoact Drugs. 2019;51:118–22.

    Google Scholar 

  113. Romano AG, Quinn JL, Li L, Dave KD, Schindler EA, Aloyo VJ, et al. Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et al. Psychopharmacol (Berl). 2010;212:441–8.

    CAS Google Scholar 

  114. Buchborn T, Schroder H, Hollt V, Grecksch G. Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J Psychopharmacol. 2014;28:545–52.

    PubMed Google Scholar 

  115. Cameron LP, Benson CJ, DeFelice BC, Fiehn O, Olson DE. Chronic, intermittent microdoses of the psychedelic N,N-Dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS Chem Neurosci. 2019;10:3261–70.

    CAS PubMed Google Scholar 

  116. Gewirtz JC, Chen AC, Terwilliger R, Duman RC, Marek GJ. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacol, Biochem Behav. 2002;73:317–26.

    CAS PubMed Google Scholar 

  117. Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078.

  118. Wu M, Minkowicz S, Dumrongprechachan V, Hamilton P, Kozorovitskiy Y. Ketamine rapidly enhances glutamate-evoked dendritic spinogenesis in medial prefrontal cortex through dopaminergic mechanisms. Biol Psychiatry. 2021;89:1096–105.

    CAS PubMed Central PubMed Google Scholar 

  119. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of psilocybin versus escitalopram for depression. N. Engl J Med. 2021;384:1402–11.

    CAS PubMed Google Scholar 

  120. Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78:481–9.

    PubMed Google Scholar 

  121. Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014;202:513–20.

    PubMed Central PubMed Google Scholar 

  122. Schimmel N, Breeksema JJ, Smith-Apeldoorn SY, Veraart J, van den Brink W, Schoevers RA. Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review. Psychopharmacology (Berl). 2021;239:15–33.

  123. Majic T, Schmidt TT, Gallinat J. Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences? J Psychopharmacol. 2015;29:241–53.

    CAS PubMed Google Scholar 

  124. Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL. Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci. 2007;2:303–12.

    PubMed Central PubMed Google Scholar 

  125. Dixon ML, Thiruchselvam R, Todd R, Christoff K. Emotion and the prefrontal cortex: An integrative review. Psychol Bull. 2017;143:1033–81.

    PubMed Google Scholar 

  126. Kuhn M, Mainberger F, Feige B, Maier JG, Wirminghaus M, Limbach L, et al. State-dependent partial occlusion of cortical LTP-like plasticity in major depression. Neuropsychopharmacology. 2016;41:1521–9.

    CAS PubMed Google Scholar 

  127. Normann C, Schmitz D, Furmaier A, Doing C, Bach M. Long-term plasticity of visually evoked potentials in humans is altered in major depression. Biol Psychiatry. 2007;62:373–80.

    PubMed Google Scholar 

  128. Noda Y, Zomorrodi R, Vila-Rodriguez F, Downar J, Farzan F, Cash RFH, et al. Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation. Depress Anxiety. 2018;35:448–56.

    CAS PubMed Google Scholar 

  129. Smith R, Chen K, Baxter L, Fort C, Lane RD. Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. J Affect Disord. 2013;146:414–9.

    CAS PubMed Google Scholar 

  130. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7.

    CAS PubMed Central PubMed Google Scholar 

  131. Schmaal L, Hibar DP, Samann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–09.

    CAS PubMed Google Scholar 

  132. Hare BD, Duman RS. Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry. 2020;25:2742–58.

    PubMed Central PubMed Google Scholar 

  133. Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry. 2020;25:530–43.

    PubMed Google Scholar 

  134. Kim MJ, Loucks RA, Palmer AL, Brown AC, Solomon KM, Marchante AN, et al. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav Brain Res. 2011;223:403–10.

    PubMed Central PubMed Google Scholar 

  135. Liu WZ, Zhang WH, Zheng ZH, Zou JX, Liu XX, Huang SH, et al. Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety. Nat Commun. 2020;11:2221.

    CAS PubMed Central PubMed Google Scholar 

  136. Yabuki Y, Fukunaga K. Clinical therapeutic strategy and neuronal mechanism underlying post-traumatic stress disorder (PTSD). Int J Mol Sci. 2019;20:3614.

  137. Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10:561–72.

    CAS PubMed Google Scholar 

  138. Gimpl MP, Gormezano I, Harvey JA. Effects of LSD on learning as measured by classical conditioning of the rabbit nictitating membrane response. J Pharmacol Exp Therapeutics. 1979;208:330–4.

    CAS Google Scholar 

  139. Kanen JW, Luo Q, Kandroodi MR, Cardinal RN, Robbins TW, Carhart-Harris RL, et al. Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans. bioRxiv, Preprint. 2021: https://doi.org/10.1101/2020.12.04.412189.

  140. Wiessner I, Olivieri R, Falchi M, Palhano-Fontes F, Oliveira Maia L, Feilding A, et al. LSD, afterglow and hangover: Increased episodic memory and verbal fluency, decreased cognitive flexibility. Eur Neuropsychopharmacol. 2022;58:7–19.

    CAS PubMed Google Scholar 

  141. Waltz JA. The neural underpinnings of cognitive flexibility and their disruption in psychotic illness. Neuroscience. 2017;345:203–17.

    CAS PubMed Google Scholar 

  142. Lange F, Seer C, Kopp B. Cognitive flexibility in neurological disorders: Cognitive components and event-related potentials. Neurosci Biobehav Rev. 2017;83:496–507.

    PubMed Google Scholar 

  143. Murphy-Beiner A, Soar K. Ayahuasca’s ‘afterglow’: improved mindfulness and cognitive flexibility in ayahuasca drinkers. Psychopharmacol (Berl). 2020;237:1161–9.

    CAS Google Scholar 

  144. Doss MK, Povazan M, Rosenberg MD, Sepeda ND, Davis AK, Finan PH, et al. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Transl Psychiatry. 2021;11:574.

    CAS PubMed Central PubMed Google Scholar 

  145. Davis AK, Barrett FS, Griffiths RR. Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. J Contextual. Behav Sci. 2020;15:39–45.

    Google Scholar 

  146. Magaraggia I, Kuiperes Z, Schreiber R. Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach. Neurobiol Learn Mem. 2021;183:107467.

    CAS PubMed Google Scholar 

  147. Bouso JC, Gonzalez D, Fondevila S, Cutchet M, Fernandez X, Ribeiro Barbosa PC, et al. Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One. 2012;7:e42421.

    CAS PubMed Central PubMed Google Scholar 

  148. van Oorsouw K, Toennes SW, Ramaekers JG. Therapeutic effect of an ayahuasca analogue in clinically depressed patients: a longitudinal observational study. Psychopharmacology (Berl). 2022;239:1839–52.

  149. Dominguez-Clave E, Soler J, Elices M, Franquesa A, Alvarez E, Pascual JC. Ayahuasca may help to improve self-compassion and self-criticism capacities. Hum Psychopharmacology: Clinical and Experimental. 2021;37:e2807.

  150. Madsen MK, Fisher PM, Stenbaek DS, Kristiansen S, Burmester D, Lehel S, et al. A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. Eur Neuropsychopharmacol. 2020;33:71–80.

    CAS PubMed Google Scholar 

  151. Müller F, Kraus E, Holze F, Becker A, Ley L, Schmid Y, et al. Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants. Psychopharmacology (Berl). 2022;239:1933–43.

  152. Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78:544–53.

    CAS PubMed Google Scholar 

  153. Kometer M, Pokorny T, Seifritz E, Volleinweider FX. Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacol (Berl). 2015;232:3663–76.

    CAS Google Scholar 

  154. Breeksema JJ, Niemeijer AR, Krediet E, Vermetten E, Schoevers RA. Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS Drugs. 2020;34:925–46.

    CAS PubMed Central PubMed Google Scholar 

  155. Yaden DB, Griffiths RR. The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharm Transl Sci. 2021;4:568–72.

    CAS Google Scholar 

  156. Watts R, Day C, Krzanowski J, Nutt D, Carhart-Harris R. Patients’ accounts of increased “connectedness” and “acceptance” after psilocybin for treatment-resistant depression. J Humanist Psychol. 2017;57:520–64.

    Google Scholar 

  157. Hasler G. Toward the “helioscope” hypothesis of psychedelic therapy. Eur Neuropsychopharmacol. 2022;57:118–9.

    CAS PubMed Google Scholar 

  158. Brouwer A, Carhart-Harris RL. Pivotal mental states. J Psychopharmacol. 2020;35:269881120959637.

  159. Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008;22:621–32.

    CAS PubMed Central PubMed Google Scholar 

  160. Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016;30:1279–95.

    PubMed Central PubMed Google Scholar 

  161. Carbonaro TM, Bradstreet MP, Barrett FS, MacLean KA, Jesse R, Johnson MW, et al. Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. J Psychopharmacol. 2016;30:1268–78.

    PubMed Central PubMed Google Scholar 

  162. Roseman L, Nutt DJ, Carhart-Harris RL. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharm. 2018;8:974.

    Google Scholar 

  163. Halpern JH, Lerner AG, Passie T. A review of hallucinogen persisting perception disorder (HPPD) and an exploratory study of subjects claiming symptoms of HPPD. Curr Top Behav Neurosci. 2018;36:333–60.

    CAS PubMed Google Scholar 

  164. de Jonghe F, Kool S, van Aalst G, Dekker J, Peen J. Combining psychotherapy and antidepressants in the treatment of depression. J Affect Disord. 2001;64:217–29.

    PubMed Google Scholar 

  165. Areán PA, Cook BL. Psychotherapy, Antidepressants, and Their Combination for Chronic Major Depressive Disorder: A Systematic Review. Biol Psychiatry. 2013;52:293–303.

    Google Scholar