LSD stimuleert neuroplasticiteit
Abigail E. Calder & Gregor Hasler | Bron: www.nature.com
Klassieke psychedelica, zoals LSD, psilocybine en de DMT-bevattende drank ayahuasca, tonen enig potentieel voor de behandeling van depressie, angst en verslaving. Belangrijk is dat klinische verbeteringen maanden of jaren na de behandeling kunnen aanhouden. Er wordt geopperd dat deze langdurige verbeteringen ontstaan doordat psychedelica snelle en blijvende neuroplasticiteit stimuleren. Het doel van deze review is het beantwoorden van specifieke vragen over de effecten van psychedelica op neuroplasticiteit. Allereerst bekijken we het bewijs dat psychedelica neuroplasticiteit bevorderen en onderzoeken we de cellulaire en moleculaire mechanismen achter de effecten van verschillende psychedelica op verschillende aspecten van neuroplasticiteit, waaronder dendritogenese, synaptogenese, neurogenese en expressie van genen gerelateerd aan plasticiteit (bijv. 'brain-derived neurotrophic factor' en 'immediate early genes'). Vervolgens onderzoeken we in welk deel van de hersenen psychedelica neuroplasticiteit bevorderen, waarbij we met name ingaan op de prefrontale cortex en hippocampus. We onderzoeken ook welke doses nodig zijn om dit effect te bereiken (bijv. hallucinogene doses vs. 'microdoses'), en hoelang vermeende veranderingen in neuroplasticiteit aanhouden. Tot slot bespreken we de waarschijnlijke gevolgen van de effecten van psychedelica op neuroplasticiteit voor zowel patiënten als gezonde personen, en identificeren we belangrijke onderzoeksvragen die het wetenschappelijk begrip van de effecten van psychedelica op neuroplasticiteit en de potentiële klinische toepassingen verder zouden kunnen bevorderen.
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].
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.
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.
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