This cell (in vitro) and animal (in vivo, larvae & rats) study shows the various ways (stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways) through which psychedelics promote/increase plasticity in the brain.
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
Neuropsychiatric disorders such as depression, post-traumatic stress disorder (PTSD), and addiction are highly disabling and often refractory to existing antidepressant treatments, which typically require weeks to produce effects and fail in roughly one-third of patients. Converging evidence from imaging, postmortem and animal studies implicates atrophy of prefrontal cortex (PFC) neurons—manifest as dendritic retraction, loss of spines and synapses—in the pathophysiology of these disorders, and reversing such structural deficits is proposed as a therapeutic strategy. Ketamine, a dissociative anaesthetic, has renewed interest in rapid-acting antidepressant mechanisms because it promotes dendritic spine growth, synaptic protein synthesis and strengthened synaptic responses, and produces fast antidepressant and anxiolytic effects in some treatment-resistant patients. Ly and colleagues set out to test whether classical serotonergic psychedelics and related entactogens from diverse chemical classes (tryptamines, amphetamines, ergolines, and iboga alkaloids) also promote structural and functional plasticity in cortical neurons, potentially via shared downstream signalling with ketamine. The investigators introduce the term "psychoplastogen" for compounds that rapidly induce neuronal plasticity, and aim to characterise neuritogenesis, spinogenesis and synaptogenesis induced by representative psychedelics, to compare potencies with ketamine, and to probe underlying mechanisms including BDNF/TrkB, mTOR and 5-HT2A receptor involvement. The work spans in vitro primary cortical cultures, in vivo rodent experiments and invertebrate/vertebrate developmental models to assess evolutionary conservation of effects.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Bogenschutz, M. P., Pommy, J. A. · Drug Testing and Analysis (2012)
Bouso, J. C., Doblin, R., Farré, M. et al. · Journal of Psychoactive Drugs (2008)
Cameron, L. P., Benson, C. J., Dunlap, L. E. · ACS Chemical Neuroscience (2018)
The study used primary cortical neuronal cultures prepared from embryonic day 18 Sprague-Dawley rats for most in vitro assays. Cells were maintained in Neurobasal-based media with B27 supplement and routine medium changes; plating densities varied by assay (details in supplemental procedures). Compounds for cell experiments were dissolved in DMSO and diluted to a final vehicle concentration of 0.1% DMSO for most drugs. Typical test concentrations were 10 μM for psychedelics and related compounds, with DMT tested up to 90 μM to better approximate brain exposures reported in rodents. For antagonist/inhibitor experiments, neurons were pretreated for 10 min with ANA-12 (TrkB antagonist, 10 μM), rapamycin (mTOR inhibitor, 100 nM) or ketanserin (5-HT2A antagonist, 100 μM) unless otherwise noted; these experiments had a final DMSO concentration of 0.2%. Morphological outcomes were assessed using Sholl analysis to quantify dendritic arbor complexity (area under the Sholl curve and maximum crossings), measures of branch number and total arbor length, and superresolution structured illumination microscopy (SIM) for dendritic spine quantification and morphology. Synaptogenesis was examined by colocalisation of pre- and postsynaptic markers and by counting puncta for VGLUT1 and PSD-95. Dose–response (8-point) studies established relative potencies and efficacies; EC50 values (half-maximal effective concentration) were calculated to compare compounds. In vivo experiments involved intraperitoneal administration of DMT or ketamine to adult Sprague-Dawley rats at 10 mg/kg (1 mL/kg injection volume) and assessment of PFC spine density by Golgi-Cox staining and of functional effects by ex vivo whole-cell voltage-clamp recordings of layer V pyramidal neurons to measure spontaneous excitatory postsynaptic currents (sEPSCs). Developmental and cross-species assays included chronic treatment of zebrafish embryos and dendritic branching measures in Drosophila larvae. Molecular assays included droplet digital PCR (ddPCR) for BDNF transcript and ELISA for BDNF protein. Statistical analyses used one-way ANOVA with Dunnett's post hoc tests for multi-group comparisons and Kolmogorov–Smirnov tests for electrophysiological distribution comparisons; data are reported as mean ± SEM. Cellular experiments were replicated on at least two occasions using neurons derived from multiple wells, and animal procedures were approved by the institutional IACUC.
In cultured cortical neurons, several psychedelics from distinct structural classes increased dendritic arbor complexity as measured by Sholl analysis, with effects comparable to ketamine. The morphological changes reflected increases in branch number and total arbor length rather than primary dendrite number or the length of the longest dendrite. Compounds that robustly promoted neuritogenesis included tryptamines (DMT, psilocin), amphetamines (DOI, MDMA), and ergolines (LSD). The flavonoid 7,8-dihydroxyflavone (7,8-DHF) also increased arbor complexity, while serotonin and D-amphetamine produced minimal effects. Dose–response experiments showed that many psychedelics were more potent than ketamine: ketamine's EC50 in the neuritogenesis assay was 132 nM, whereas LSD was especially potent (EC50 = 0.409 nM) and exhibited activity into the low picomolar range. Ibogaine had no effect on neuritogenesis, but its metabolite noribogaine increased dendritic arbor complexity with an EC50 comparable to ketamine. Cross-species and developmental assays found that LSD and DOI increased dendritic branching of class I sensory neurons in Drosophila larvae, though total arbor length was unaffected. Chronic exposure of zebrafish embryos to psychedelics shortly after dechorionation produced no detectable differences in head size or gross locomotor activity. Initiating psychedelic treatment at later Drosophila stages yielded smaller effects, potentially reflecting developmental timing or shorter treatment duration. Psychedelics also promoted spinogenesis and synaptogenesis. A 24 hr treatment of mature cortical cultures with DOI, DMT and LSD increased dendritic spine density measured by SIM, with LSD nearly doubling spine number per 10 μm and shifting spine morphology toward thinner, more immature spine types. Colocalisation of pre- and postsynaptic markers indicated an increase in synapse density but not synapse size; VGLUT1 puncta density increased while PSD-95 puncta did not. In adult rats, a single intraperitoneal dose of DMT (10 mg/kg) produced a significant increase in PFC dendritic spine density 24 hr after dosing, an effect comparable with 10 mg/kg ketamine. Electrophysiological recordings from layer V pyramidal neurons showed increased frequency and amplitude of spontaneous EPSCs after DMT treatment; both 10 mg/kg and 1 mg/kg doses yielded similar electrophysiological responses despite differing predicted hallucinogenic potency. The short half-life of DMT (~15 min) indicates that these structural and functional changes persist well after the drug has been cleared. Mechanistic studies implicate BDNF/TrkB signalling and mTOR. Recombinant BDNF (50 ng/mL) stimulated neuritogenesis to an extent similar to DOI (10 μM), and combining BDNF with DOI provided no additive benefit, suggesting convergent pathways. Psychedelics did not increase BDNF transcript but produced an approximately 2-fold, non-significant increase in BDNF protein. Co-treatment with ANA-12, a TrkB antagonist, completely blocked psychedelic- and BDNF-induced neuritogenesis and spinogenesis. Rapamycin, an mTOR inhibitor, fully abrogated psychedelic-induced neuritogenesis, indicating an mTOR-dependent mechanism. Finally, experiments targeting the 5-HT2A receptor showed that ketanserin blocked the neuritogenic and spinogenic effects of DMT, LSD and DOI; at lower concentrations of LSD (10 nM), ketanserin reduced LSD-induced neuritogenesis by ~50% at equivalent receptor affinity and completely blocked it at 100 nM ketanserin. Concentration–response curves for many psychoplastogens had Hill slopes differing from 1.0, suggesting polypharmacology; DMT uniquely showed a Hill slope greater than 1.0, consistent with positive cooperativity.
Ly and colleagues interpret their results as direct evidence that classical serotonergic psychedelics and related entactogens promote both structural and functional plasticity in cortical neurons. The data extend earlier indirect findings by showing that multiple chemical classes of psychedelics increase neurite outgrowth, dendritic spine density and synapse density in vitro, induce comparable structural changes in vivo in rodent PFC and produce functional enhancements in synaptic transmission. The investigators highlight that these effects are not restricted to a single structural class or to monoamine elevation per se, because D-amphetamine did not reproduce the morphological changes seen with psychedelics, and ibogaine lacked activity whereas noribogaine was active. The authors emphasise similarities between psychedelics and ketamine: both produce rapid and lasting increases in cortical spine density and excitability, appear to facilitate fear extinction and antidepressant-like behaviours in animal models, and engage mTOR-dependent pathways known to underlie structural plasticity. Mechanistic experiments presented implicate TrkB, mTOR and 5-HT2A receptors as required signalling hubs for psychedelic-induced plasticity, suggesting these targets may be useful for developing psychoplastogens. The extreme potency of some compounds (notably LSD) is noted and attributed potentially to receptor kinetics. Several limitations and uncertainties are acknowledged. Structural assays in vitro used prolonged exposures to compounds, whereas brain exposure in vivo is often brief due to rapid metabolism; the kinetics of plasticity induction and persistence warrant further study. The authors also recognise safety concerns associated with classical psychedelics because of profound subjective effects and potential for misuse, arguing that non-hallucinogenic analogues that retain psychoplastogenic activity would be valuable both clinically and for resolving whether subjective experiences are necessary for therapeutic benefit. Finally, the investigators suggest that in vitro neuritogenesis/spinogenesis assays, given their consistency with in vivo exposures, could have utility for screening candidate fast-acting antidepressants, and they propose using classical psychedelics as lead structures for medicinal chemistry aimed at safer next-generation neurotherapeutics.
Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2-4 weeks of treatment before they experience any beneficial effects. Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitryand have high comorbidity. A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders and is precipitated and/or exacerbated by stress. These structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity in the PFC, providing a general solution to treating all of these related diseases. However, only a relatively small number of compounds capable of promoting plasticity in the PFC have been identified so far, each with significant drawbacks. Of these, the dissociative anesthetic ketamine has shown the most promise, revitalizing the field of molecular psychiatry in recent years. Ketamine has demonstrated remarkable clinical potential as a fast-acting antidepressant, even exhibiting efficacy in treatment-resistant populations. Additionally, it has shown promise for treating PTSDand heroin addiction. Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses. Like ketamine, serotonergic psychedelics and entactogens have demonstrated rapid and long-lasting antidepressant and anxiolytic effects in the clinic after a single dose, including in treatmentresistant populations. In fact, there have been numerous clinical trials in the past 30 years examining the therapeutic effects of these drugs (Dos, with 3,4methylenedioxymethamphetamine (MDMA) recently receiving the "breakthrough therapy" designation by the Food and Drug Administration for treating PTSD. Furthermore, classical psychedelics and entactogens produce antidepressant and anxiolytic responses in rodent behavioral tests, such as the forced swim testand fear extinction learning, paradigms for which ketamine has also been shown to be effective. Despite the promising antidepressant, anxiolytic, and anti-addictive properties of serotonergic psychedelics, their therapeutic mechanism of action remains poorly understood, and concerns about safety have severely limited their clinical usefulness. Because of the similarities between classical serotonergic psychedelics and ketamine in both preclinical models and clinical studies, we reasoned that their therapeutic effects might result from a shared ability to promote structural and functional neural plasticity in cortical neurons. Here, we report that serotonergic psychedelics and entactogens from a variety of chemical classes (e.g., amphetamine, tryptamine, and ergoline) display plasticity-promoting properties comparable to or greater than ketamine. Like ketamine, these compounds stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR). To classify the growing number of compounds capable of rapidly promoting induced plasticity, we introduce the term "psychoplastogen, " from the Greek roots psych-(mind), -plast (molded), and -gen (producing). Our work strengthens the growing body of literature indicating that psychoplastogens capable of promoting plasticity in the PFC might have value as fast-acting antidepressants and anxiolytics with efficacy in treatment-resistant populations and suggests that it may be possible to use classical psychedelics as lead structures for identifying safer alternatives.
Because atrophy of cortical neurons is believed to be a contributing factor to the development of mood and anxiety disorders, we first treated cultured cortical neurons with psychedelics from a variety of structural classes (Figuresand) and measured the resulting changes in various morphological features. Using Sholl analysis, we observed that several psychedelics increased dendritic arbor complexity comparably to ketamine, as measured by the area under the curve of the Sholl plots as well as the maximum number of crossings . This increase in arbor complexity appeared to result from large changes in both the number of dendritic branches and the total length of the arbors. Psychedelics had a limited effect on the number of primary dendrites and did not alter the length of the longest dendrite. Nearly all psychedelic compounds tested were capable of robustly promoting neuritogenesis, with comparable effects being produced by tryptamines (N,N-dimethyltryptamine [DMT] and psilocin), amphetamines (2,5-dimethoxy-4-iodoamphetamine [DOI] and MDMA), and ergolines (lysergic acid diethylamide). As a positive control, we treated cells with 7,8-dihydroxyflavone (DHF), a psychoplastogen structurally dissimilar to classical psychedelics, and found that it also increased dendritic arbor complexity (Figure). This neurite outgrowth structural phenotype seems to only be induced by select compounds because serotonin and D-amphetamine, molecules that are chemically related to classical psychedelics and entactogens, exerted minimal to no effects on neuritogenesis (Figure). To establish the relative potencies and efficacies of hallucinogens and entactogens for promoting neurite outgrowth, we conducted 8-point dose-response studies (Figure). We defined 100% and 0% efficacy as the maximum number of crossings induced by ketamine (10 μM) and vehicle (0.1% DMSO), respectively. We chose the 10 μM concentration of ketamine as the upper limit because this concentration of ketamine is reached in the brain following intraperitoneal administration of an antidepressant dose in rats. For consistency, we used this same concentration when testing the effects of psychedelics and entactogens, with DMT being the only exception. We used a maximum 90 μM concentration of DMT in our studies to more closely mimic the brain concentration of DMT in rats treated with an antidepressant dose. In this neuritogenesis assay, ketamine's half maximal effective concentration (EC 50 ) value was 132 nM. Surprisingly, the majority of the psychedelics and entactogens we tested exhibited significantly greater potency than ketamine, with LSD being particularly potent (EC 50 = 0.409 nM). In fact, LSD exhibited activity across 8 orders of magnitude into the low picomolar range (Figure). Notably, the anti-addictive alkaloid ibogainewas the only psychedelic tested that had absolutely no effect (Figure). This was a surprising result because we hypothesized that ibogaine's long-lasting anti-addictive properties might result from its psychoplastogenic properties. Previous work byclearly demonstrated that ibogaine increases the expression of glial cell line-derived neurotrophic factor (GDNF) and that this plasticity-promoting protein is critical to ibogaine's antiaddictive mechanism of action. Because several reports have suggested that noribogaine, a metabolite of ibogaine, might actually be the active compound in vivo, we decided to test its ability to promote neuritogenesis in cultured cortical neurons. Gratifyingly, noribogaine robustly increased dendritic arbor complexity with an EC 50 value comparable to ketamine (Figure), providing additional evidence suggesting that it may be the active compound in vivo. To assess the in vivo effects of classical psychedelics on neuritogenesis, we started treating Drosophila larvae during the first instar with LSD and DOI. As observed in rodent cortical cultures, both LSD and DOI significantly increased dendritic branching of class I sensory neurons; however, they did not increase the total length of the dendritic arbors (Figures). Because of the striking effects of psychedelics on the structures of immature neurons, we hypothesized that they might influence neurodevelopment. To test this, we chronically treated zebrafish embryos with compounds for 6 days immediately following dechorionation and assessed gross morphological changes and behavior. We did not observe any differences in head sizes between the treatment groups, nor did we detect any statistically significant differences in activity levels (Figure). Next we assessed the ability of psychedelics to promote neuritogenesis in more mature neurons by starting to treat Drosophila larvae during the late second instar. Again, psychedelics increased the branching of class I neurons, although the effect was less dramatic than that observed when treatment was started during the first instar (Figure). Although different developmental stages might be more or less susceptible to the effects of psychedelics, it is also possible that the smaller effect size observed after administering compounds starting at the later time point was simply the result of treating the larvae for a shorter period of time. Regardless, it was quite surprising to observe compound-induced changes in neuronal structure after initiating treatment during the late second instar because class I neurons are stereotyped and typically possess relatively few higher-order branches. Moreover, our results demonstrate that psychedelics can promote changes in neuronal structure across vertebrate (rats) and invertebrate (Drosophila) species, suggesting that they act through an evolutionarily conserved mechanism.
In addition to dendritic atrophy, loss of dendritic spines is a hallmark of depression and other neuropsychiatric disorders, so we next assessed the effects of psychedelics on spinogenesis. We treated mature rat cortical cultures for 24 hr with DOI, DMT, and LSD as representative compounds from the amphetamine, tryptamine, and ergoline classes of psychedelics, respectively. All three compounds increased the number of dendritic spines per unit length, as measured by superresolution structured illumination microscopy (SIM) (Figures, and S6), with LSD nearly doubling the number of spines per 10 μm. Additionally, treatment caused a shift in spine morphology, favoring immature (thin and filopodium) over more mature (mushroom) spine types (Figure). Colocalization of pre-and postsynaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses (Figure). This increase in synapse density was accompanied by an increase in the density of VGLUT1 puncta, but not PSD-95 puncta, following compound administration (Figuresand). Encouraged by our in vitro results, we next assessed the effects of a single intraperitoneal dose of DMT on spinogenesis in the PFC of adult rats using Golgi-Cox staining. We chose to administer a 10 mg/kg dose of DMT for three reasons. First, all available data suggested that this dose would produce hallucinogenic effects in rats with minimal safety risks. Second, we have previously shown that a 10 mg/kg dose of DMT produces positive effects in rat behavioral tests relevant to depression and PTSD. Finally, we wanted to directly compare the effects of DMT with ketamine, and seminal studies conducted byhad previously demonstrated that a 10 mg/kg dose of ketamine produced a robust increase in dendritic spine density in the PFC of rats. We observed a significant increase in the density of dendritic spines on cortical pyramidal neurons 24 hr after dosing with DMT (Figuresand). This effect was comparable with that produced by ketamine at the same dose (Figure). Importantly, this DMT-induced increase in dendritic spine density was accompanied by functional effects. Ex vivo slice recordings revealed that both the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) were increased following DMT treatment (Figures). Interestingly, 10 mg/kg and 1 mg/kg doses produced similar responses despite the fact that they are predicted to be hallucinogenic and subhallucinogenic, respectively. Because the half-life of DMT is exceedingly short (~15 min), these results confirm that structural and functional changes induced by DMT persist for hours after the compound has been cleared from the body. Moreover, they demonstrate that DMT produces functional effects on pyramidal neurons of the PFC that mirror those produced by ketamine. Because the PFC is a key brain region involved in extinction learning, and both ketamine and DMT have been shown to facilitate fear extinction, our results suggest a link between the plasticitypromoting and behavioral effects of these drugs. Because fear extinction can be enhanced by increasing levels of brain-derived neurotrophic factor (BDNF) in the PFC, and ketamine's behavioral effects have been shown to be BDNF-dependent, we next sought to determine the role of BDNF signaling in the plasticitypromoting effects of classical psychedelics.
The role of BDNF in both neuritogenesis and spinogenesis is well known, and several reports suggest that psychedelics are capable of increasing levels of neurotrophic factors. Therefore, we treated cortical neurons with BDNF, DOI, and a combination of the two to see whether they had any additive or synergistic effects. Doseresponse studies using recombinant BDNF (Figures) revealed that a 50 ng/mL treatment increased neuritogenesis to a comparable extent as DOI (10 μM). Moreover, a combination of the two did not confer any added benefit, suggesting that they operate through a related mechanism (Figures). Next, we treated cortical neurons with DOI, DMT, and LSD for 24 hr before measuring BDNF gene and protein expression using droplet digital PCR (ddPCR) and ELISA, respectively. Although psychedelics did not increase the expression of BDNF transcript (Figure), they did result in a 2-fold increase in BDNF protein levels, although this effect was not statistically significant (Figure). When cortical cultures were co-treated with ANA-12, a selective antagonist of BDNF's high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked (Figure). Activation of TrkB is known to promote signaling through mTOR, which plays a key role in structural plasticity, the production of proteins necessary for synaptogenesis, and the effects of ketamine. Treatment with rapamycin, an mTOR inhibitor, completely blocked psychedelic-induced neuritogenesis (Figure), thus confirming that mTOR activation plays a role in the plasticity-promoting effects of classical serotonergic psychedelics.
Finally, we sought to determine whether the 5-HT2A receptor played any role in the plasticity-promoting effects of DOI, DMT, and LSD because this receptor is known to be primarily responsible for the hallucinogenic effects of classical psychedelics. Furthermore, the psychoplastogenic potencies of these and related compounds correlate well with their 5-HT2A receptor affinities (Figure) (i.e., a higher 5-HT2A binding affinity generally predicts more potent psychoplastogenic effects). Control experiments demonstrated that 5-HT2A receptors were expressed on cultured rat cortical neurons at both 6 days in vitro (DIV6) and DIV19 (Figure). Next we found that cotreatment with ketanserin, a selective 5-HT2A antagonist, completely abrogated the ability of DMT, LSD, and DOI to promote both neuritogenesis and spinogenesis (Figures). Ketanserin was also able to block the effects of psilocin as well as the non-classical psychedelic noribogaine and enactogen MDMA (Figure). These initial experiments were performed using doses of psychoplastogens that produced maximal effects on structural plasticity (circa 10 μM) in combination with a 10-fold excess of ketanserin (100 μM). At these concentrations, we could not rule out the possibility of other receptors contributing to the antagonistic effects of ketanserin. Therefore, we treated cultured cortical neurons with a significantly lower dose of LSD (10 nM) and attempted to block its ability to promote neurite outgrowth using increasing doses of ketanserin (Figure). We found that ketanserin blocks the psychoplastogenic effects of LSD by ~50% when treated at 10 nM. This is consistent with the fact that the binding affinities of ketanserin and LSD for the 5-HT2A receptor are roughly equivalent (low nanomolar). Increasing the concentration of ketanserin to 100 nM, 10-fold higher than the concentration of LSD used in this experiment, completely prevented LSD-induced neuritogenesis. At 100 nM, ketanserin is relatively selective for the 5-HT2A receptor, although, at this concentration, we cannot rule out the possible involvement of 5-HT2C, adrenergic, or histamine receptors. As a final note, the concentration responses of most psychoplastogens had Hill slopes that deviated from 1.0 (Figure), implying polypharmacology. Because psychedelics have relatively high affinities for 5-HT2A receptors, it is likely that the effects of psychedelics are mediated primarily through 5-HT2A receptors at low concentrations and modulated by other targets at high concentrations. Interestingly, the concentration response of DMT was the only one to exhibit a Hill slope greater than 1.0, indicating some form of cooperativity.
Classical serotonergic psychedelics are known to cause changes in moodand brain functionthat persist long after the acute effects of the drugs have subsided. Moreover, several psychedelics elevate glutamate levels in the cortexand increase gene expression in vivo of the neurotrophin BDNF as well as immediate-early genes associated with plasticity. This indirect evidence has led to the reasonable hypothesis that psychedelics promote structural and functional neural plasticity, although this assumption had never been rigorously tested. The data presented here provide direct evidence for this hypothesis, demonstrating that psychedelics cause both structural and functional changes in cortical neurons. Prior to this study, two reports suggested that psychedelics might be able to produce changes in neuronal structure.demonstrated that DOI was capable of transiently increasing the size of dendritic spines on cortical neurons, but no change in spine density was observed. The second study showed that DOI promoted neurite extension in a cell line of neuronal lineage. Both of these reports utilized DOI, a psychedelic of the amphetamine class. Here we demonstrate that the ability to change neuronal structure is not a unique property of amphetamines like DOI because psychedelics from the ergo-line, tryptamine, and iboga classes of compounds also promote structural plasticity. Additionally, D-amphetamine does not increase the complexity of cortical dendritic arbors in culture, and therefore, these morphological changes cannot be simply attributed to an increase in monoamine neurotransmission. The identification of psychoplastogens belonging to distinct chemical families is an important aspect of this work because it suggests that ketamine is not unique in its ability to promote structural and functional plasticity. In addition to ketamine, the prototypical psychoplastogen, only a relatively small number of plasticity-promoting small molecules have been identified previously. Such compounds include the N-methyl-D-aspartate (NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3 antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic receptor antagonist scopolamine. We observe that hallucinogens from four distinct structural classes (i.e., tryptamine, amphetamine, ergoline, and iboga) are also potent psychoplastogens, providing additional lead scaffolds for medicinal chemistry efforts aimed at identifying neurotherapeutics. Furthermore, our cellular assays revealed that several of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting properties of psychedelics and entactogens rivaled that of BDNF (Figuresand). The extreme potency of LSD in particular might be due to slow off kinetics, as recently proposed following the disclosure of the LSD-bound 5-HT2B crystal structure. Importantly, the psychoplastogenic effects of psychedelics in cortical cultures were also observed in vivo using both vertebrate and invertebrate models, demonstrating that they act through an evolutionarily conserved mechanism. Furthermore, the concentrations of psychedelics utilized in our in vitro cell culture assays were consistent with those reached in the brain following systemic administration of therapeutic doses in rodents. This suggests that neuritogenesis, spinogenesis, and/or synaptogenesis assays performed using cortical cultures might have value for identifying psychoplastogens and fast-acting antidepressants. It should be noted that our structural plasticity studies performed in vitro utilized neurons exposed to psychedelics for extended periods of time. Because brain exposure to these compounds is often of short duration due to rapid metabolism, it will be interesting to assess the kinetics of psychedelic-induced plasticity. A key question in the field of psychedelic medicine has been whether or not psychedelics promote changes in the density of dendritic spines. Using superresolution SIM, we clearly demonstrate that psychedelics do, in fact, increase the density of dendritic spines on cortical neurons, an effect that is not restricted to a particular structural class of compounds. Using DMT, we verified that cortical neuron spine density increases in vivo and that these changes in structural plasticity are accompanied by functional effects such as increased amplitude and frequency of spontaneous EPSCs. We specifically designed these experiments to mimic previous studies of ketamine) so that we might directly compare these two compounds, and, to a first approximation, they appear to be remarkably similar. Not only do they both increase spine density and neuronal excitability in the cortex, they seem to have similar behavioral effects. We have shown previously that, like ketamine, DMT promotes fear extinction learning and has antidepressant effects in the forced swim test. These results, coupled with the fact that ayahuasca, a DMT-containing concoction, has potent antidepressant effects in humans, suggests that classical psychedelics and ketamine might share a related therapeutic mechanism. Although the molecular targets of ketamine and psychedelics are different (NMDA and 5-HT2A receptors, respectively), they appear to cause similar downstream effects on structural plasticity by activating mTOR. This finding is significant because ketamine is known to be addictive whereas many classical psychedelics are not. The exact mechanisms by which these compounds stimulate mTOR is still not entirely understood, but our data suggest that, at least for classical psychedelics, TrkB and 5-HT2A receptors are involved. Although most classical psychedelics are not considered to be addictive, there are still significant safety concerns with their use in medicine because they cause profound perceptual disturbances and still have the potential to be abused. Therefore, the identification of non-hallucinogenic analogs capable of promoting plasticity in the PFC could facilitate a paradigm shift in our approach to treating neuropsychiatric diseases. Moreover, such compounds could be critical to resolving the long-standing debate in the field concerning whether the subjective effects of psychedelics are necessary for their therapeutic effects. Although our group is actively investigating the psychoplastogenic properties of non-hallucinogenic analogs of psychedelics, others have reported the therapeutic potential of safer structural and functional analogs of ketamine. Our data demonstrate that classical psychedelics from several distinct chemical classes are capable of robustly promoting the growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities between the effects of ketamine and those of classical serotonergic psychedelics, supporting the hypothesis that the clinical antidepressant and anxiolytic effects of these molecules might result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. We have demonstrated that the plasticity-promoting properties of psychedelics require TrkB, mTOR, and 5-HT2A signaling, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. Taken together, our results suggest that psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.
For in vitro studies, all compounds were dissolved in DMSO and diluted 1:1,000, with the exception that BDNF was dissolved in water. Cells were treated with DMT at a final concentration of 90 μM (0.1% DMSO), whereas all other compounds were used at 10 μM (0.1% DMSO) unless noted otherwise. For in vivo studies, DMT or ketamine was dissolved in sterile 0.9% saline and administered intraperitoneally at a dose of 10 mg/kg and an injection volume of 1 mL/kg.
Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA, USA). The age and sex of the animals used are noted under each individual experimental subheading. All experimental procedures involving animals were approved by the University of California, Davis Institutional Animal Care and Use Committee (IACUC) and adhered to the principles described in the NIH Guide for the Care and Use of Laboratory Animals. The University of California, Davis is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) and has an Animal Welfare Assurance number (A3433-01) on file with the Office of Laboratory Animal Welfare (OLAW).
Primary cortical cultures were prepared using tissue from embryonic day 18 (E18) Sprague-Dawley rats. Cells were plated at various densities on poly-D-lysine-coated plates depending on the specific experiment (Supplemental Experimental Procedures). Plating medium consisted of 10% heat-inactivated fetal bovine serum (FBS) (Life Technologies), 1% penicillin-streptomycin (Life Technologies), and 0.5 mM glutamine (Life Technologies) in Neurobasal (Life Technologies). After 15-24 hr, the medium was removed and exchanged for replacement medium containing 1 × B27 supplement (Life Technologies), 1% penicillinstreptomycin, 0.5 mM glutamine, 12.5 μM glutamate, and Neuro-basal. After 96 hr, 50% of the medium was removed and replaced with feed medium containing 1 × B27 supplement, 1% penicillin-streptomycin, and 0.5 mM glutamine. Once per week, until the cultures had reached sufficient maturity for experiments, 50% of the culture medium was removed and replaced with feed medium, with an additional 20% by volume being added to account for evaporation. For experiments using antagonists or inhibitors, cells were pretreated with ANA-12 (10 μM), rapamycin (100 nM), and ketanserin (100 μM) for 10 min prior to addition of test compounds unless otherwise noted. The final DMSO concentration of these experiments was 0.2%. The neurons used in each cellular experiment were taken from at least two different treatment wells, and the wells were randomized to account for plate effects. All of the cellular experiments were replicated on at least two occasions by two or more experimenters.
Appropriate samples sizes were estimated based on our previous experiences performing similar experiments. Data are represented as mean ± SEM. Statistical analyses were performed using GraphPad Prism (version 7.0a). For analyses involving comparison of three or more groups, a one-way analysis of variance (Dunnett's post hoc test) was utilized. No statistics were calculated for the individual points of the Sholl plots. Instead, statistical analyses were performed on the aggregate data (i.e., the area under the curve of the Sholl plot). Probability distributions from electrophysiology experiments were compared using a Kolmogorov-Smirnov test. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 compared with vehicle control or vehicle + antagonist. (K and L) Whole-cell voltage-clamp recordings of layer V pyramidal neurons from slices obtained 24 hr after DMT treatment (10 mg/kg and 1 mg/kg) demonstrate that DMT increases both spontaneous excitatory postsynaptic current (sEPSC) frequency (K) and amplitude (L) (n = 11-38 neurons from 3 animals). (M) Representative traces for the 10 mg/kg experiments quantified in (K) and (L). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, as compared to vehicle control (VEH). Data are represented as mean ± SEM. See also Figure.
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