Exploring the rich landscape of mechanisms that contribute to the therapeutic effects of psychedelics and entactogens will help guide the best use of these substances for different conditions, said Rita Valentino, director of the Division of Neuroscience and Behavior at the National Institute on Drug Abuse (NIDA). The fact that these effects cut across symptom domains suggests that the underlying neurobiological mechanisms probably extend beyond pharmacology to include complex interactions among environmental influences, social factors, and drug actions at the cellular, circuit, and network levels, said Valentino. In addition, their ability to have an enduring effect suggests that acute mechanisms may be very distinct from long-term mechanisms, she said.
Key questions that need to be answered include whether the hallucinogenic effects of psychedelics are essential for their therapeutic effects and whether plasticity, which has been linked to the mechanism of action of psychedelics, occurs at the level of cellular signaling, the synapse, circuit, or structure, said Valentino.
MOLECULAR MECHANISMS
Clinical studies have demonstrated that lysergic acid diethylamide (LSD) improves social behavior, increases empathy, and lessens anxiety and depression, said Gabriella Gobbi, a psychiatrist in the mood disorders program at the McGill University Health Centre and scientist at McGill University (Dolder et al., 2016; Gasser et al., 2015).While these effects are known to reflect modulation of the serotonergic system, Gobbi and colleagues have conducted preclinical research in rats and mice to try to understand at a molecular level LSD’s mechanism of action, including the different receptors and parts of the brain that are affected.
Some of LSD’s mechanisms of action are shared with selective serotonin reuptake inhibitor (SSRI) antidepressant medications such as Prozac, said Gobbi. For example, acute administration of both LSD and SSRIs decreases serotonin-firing activity by stimulating inhibitory autoreceptors (5-HT1A), but repeated dosing results in desensitization of these receptors.
Gobbi has been particularly interested in how LSD enhances sociability in humans and the potential implications in autism and other neuropsychiatric disorders. She and her colleagues have used multiple techniques in mouse models—electrophysiology, optogenetics, behavioral assessments, and molecular biology—to tease apart these effects. They showed that prosocial effects of LSD are mediated by increasing neurotransmission at two particular receptors—5-HT2A and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)—in the medial prefrontal cortex (mPFC), and that this process involves signaling through the mTOR complex in glutamatergic neurons (De Gregorio et al., 2021b). The mPFC is an area of the brain known to be important for social cognition, is implicated in autism spectrum disorder, and is rich with 5-HT2A receptors, said Gobbi (Markopoulos et al., 2022).
She has also been exploring the mechanisms underlying LSD’s ability to decrease anxiety (Gasser et al., 2015). Gobbi and colleagues have shown that in mice, chronic stress exposure causes a decrease in serotonin-firing activity and a loss of dendritic spines, which are restored with LSD treatment. Together these effects result in decreased stress-induced anxiety and increased neuroplasticity (De Gregorio et al., 2022).
One question that particularly intrigued Gobbi was why patients report such different experiences from LSD compared with SSRIs, given that they share similar mechanisms of action in the brain. Patients report that LSD and other psychedelics give new meaning to the experience of suffering, an alteration of consciousness, and a feeling of transcendence, said Gobbi. “We can’t explain these effects only with the serotonin mechanism or the prefrontal cortex effect,” she said. The psychedelics have properties not shared with the SSRIs.
“We can’t study consciousness in mice or rats, but we can study these very important and intriguing nuclei in the brain called the reticular thalamic nuclei (RTN),” said Gobbi. The RTN is a thin sheet of gamma-aminobutyric acid (GABA)-ergic neurons that connects the thalamus to the cortex and is implicated in vigilance, sleep, and neuropsychiatric conditions, such as autism and schizophrenia, she said. More importantly, she said, brain imaging studies in humans have demonstrated that psychedelics alter this thalamocortical connection and may be linked to the experience of ego dissolution. Gobbi and colleagues demonstrated that LSD decreases firing of reticular thalamus neurons, which could explain alterations in consciousness (Inserra et al., 2021). A similar effect has been seen with psilocybin, she said (unpublished data). She added that because of the consciousness-altering effects of psychedelics, they should only be used in association with psychotherapy and in the presence of a trained therapist.
Circuit Mechanisms
When psychedelics stimulate various receptors in the brain, they change the activity of neurons, which results in changes in the way the brain processes information and interacts with the environment, said Katrin Preller, a research scientist at Yale University and the University of Zurich. Preller studies these processes at the circuit or network level, working from a model that focuses on the thalamus, a structure in the center of the brain that is responsible for filtering information. “This model suggests that under the influence of a psychedelic, the filtering function is reduced and, as a consequence, the cortex is overloaded with information, which then results in the symptoms that our participants are experiencing,” she said (Preller et al., 2019).
Applying spectral dynamic causal modeling and global brain connectivity to resting-state functional magnetic resonance imaging (fMRI) data, she and her colleagues have shown that LSD and psilocybin change connectivity patterns in the brain, resulting in disintegration of activity in what are normally highly integrated brain regions. More specifically, they observed increased sensory processing in combination with decreased processing capacity in brain areas responsible for making sense of that information and relating it to memories.
“This counterbalance of increased sensory processing and decreased association processing may explain why participants under the influence of psychedelics have visual alterations, but also why they may be able to perceive themselves and the world in a different way, because they are integrating information differently than they usually do,” said Preller. She and Franz Vollenweider of the University of Zurich have hypothesized that psychedelics may be beneficial for people with depression or substance use
disorders because they are able to experience themselves and the world in a different way, which allows them to move past rigid thinking patterns and negative self-impressions (Vollenweider and Preller, 2020). More trials in depression and alcohol use disorder are planned to test this hypothesis, she said.
Preller added that while there are fewer data available on the circuit-level changes under 3,4-Methylenedioxymethamphetamine (MDMA), some studies suggest that in comparison with LSD and psilocybin, MDMA causes similar disintegration of associated brain regions as well as no disintegration of sensory brain networks.
As mentioned earlier, one of the potential benefits of psychedelics for the treatment of psychiatric disorders is the hope that they will introduce long-term changes after minimal drug exposure. However, Preller said that little is known about long-term changes at the network level. One study demonstrated differentiation between sensory and association networks a month after administration of a single dose of psilocybin (Barrett et al., 2020), but another study failed to show significant network changes at 3 months (McCulloch et al., 2022).
Many knowledge gaps remain in understanding the effects of psychedelics at the circuit level and optimizing their use as therapies, said Preller. These include (1) whether circuit-level changes contribute to clinical efficacy; (2) whether there are transdiagnostic circuit-level changes, for example, whether the same changes contribute to clinical efficacy in depression and alcohol use disorder; (3) how much interindividual variability exists; (4) what the optimal dose is for these substances; and (5) how specific the network effects are across different substances.
Psychoplastogenic Effects
Stress-related neuropsychiatric disorders, such as depression, PTSD, and substance use disorder, can be resistant to treatment with currently available drugs that aim to rectify chemical imbalances in the brain, said David Olson, associate professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. Olson and colleagues have pioneered a new approach, which uses small-molecule drugs to selectively modulate neural circuits. This approach targets atrophy of neurons in the prefrontal cortex (PFC)—a hallmark of these illnesses—by changing the structure of the cortical neurons that tend to atrophy in response to chronic stress, said Olson.
Olson calls these molecules psychoplastogens because they induce structural neuroplasticity through the growth of new dendrites and dendritic spines, which are the sites of excitatory synapses in the brain. Unlike the more traditional antidepressants, such as SSRIs, which take weeks or months to show efficacy and are ineffective for about a third of patients,
psychoplastogens should produce long-lasting effects after a single administration, said Olson.
Classic serotonergic psychedelics, such as LSD and dimethyl tryptamine (DMT), were among the first psychoplastogens Olson and his team studied. As shown in Figure 3-1, both of these compounds promote the growth of neuronal dendritic spines and increased complexity of dendritic arbors in comparison with neurons treated with a vehicle control (VEH) (Ly et al., 2018). These effects were eliminated by blocking the serotonin 2A receptor or downstream kinases, including tyrosine protein kinase B (TrkB) and mTOR.
In vivo studies showed similar results, said Olson. In rats, a single injection of DMT produced a profound increase in dendritic spine density
NOTES: DMT = N,N-dimethyl tryptamine; LSD = lysergic acid diethylamide; VEH = vehicle control.
SOURCES: Presented by David Olson, March 29, 2022; data from Ly et al., 2018.
in the PFC as well as long-lasting functional changes in these neurons. He added that these studies have been replicated and extended by several groups, including one study where a single dose of psilocybin was shown to cause increased spine density that lasted for at least a month (Shao et al., 2021). Using 5-HT2A receptor knockout animals, Olson and colleagues have shown that this functional and structural plasticity is mediated by 5-HT2A receptors.
One of the promising aspects of psychoplastogens is their ability to work across indications, which Olson said reflects the fact that they target the PFC, a critical hub in the brain. PFC circuitry modulates drug-seeking behavior, motivation, mood, the expression of fear, and many other aspects of brain function that underlie depression and related disorders, he said. In animal studies, Olson’s lab has demonstrated profound antidepressant effects of psychoplastogens, which are completely blocked by the 5-HT2A receptor antagonist ketanserin. Another active area of research in Olson’s lab is the potential use of psychoplastogens to restore atrophied neurons in neurodegenerative conditions, such as Alzheimer’s disease. He added that 5-HT2A receptors are expressed not only on cortical neurons but also on the immune cells in the brain, microglia, and astrocytes, raising the possibility that psychedelics may have anti-inflammatory effects on the brain.
“These studies suggest that the 5-HT2A receptor plays a critical role in both the psychoplastogenic effects and the beneficial behavioral effects of psychedelics in preclinical models,” said Olson. However, the 5-HT2A receptor is also known to mediate the hallucinogenic effects of these drugs, he said. To create a safer therapeutic for a larger patient population, he wanted to know if it was possible to decouple the hallucinogenic effects of psychedelics from their effects on structural and functional neuroplasticity and their beneficial behavioral effects. His group has been working with a compound called 6-methoxy-DMT, which is not hallucinogenic, unlike the closely related and highly hallucinogenic compound 5-methoxy-DMT. “What was really exciting to us is that 6-methoxy-DMT is still a potent psychoplastogen, can produce the growth of new neurites, and can promote increased spine density,” said Olson, adding that these effects seem to be mediated by the 5-HT2A receptor.
Olson and colleagues have now engineered a novel compound called tabernanthalog (TBG), a non-toxic analog of ibogaine and 5-methoxy-DMT (Cameron et al., 2021). They showed in mice that TBG has a low hallucinogenic profile but provides a profound increase in spine formation and beneficial effects on neuronal structure and function. They also showed that these effects were blocked in 5-HT2A knockout neurons. “This suggests some type of functional selectivity,” said Olson. “We can engage the 5-HT2A receptor and turn on plasticity or hallucinogenic effects, but we don’t have to turn on both at the same time.”
TBG was also shown to have antidepressant effects in wild type but not 5-HT2A knockout mice, and these therapeutic effects require spinogenesis, which suggests a causal relationship between structural plasticity in the PFC and sustained antidepressant effects, said Olson.
Several unanswered questions remain, including the duration of the therapeutic effects and whether polypharmacology plays a role and could be used to tailor treatment for different indications, said Olson. Finally, he noted the importance of developing translatable biomarkers of the structural changes in the brain that are induced by psychoplastogens.
PSYCHOSOCIAL CONTEXTS AS ESSENTIAL TREATMENT ELEMENTS
As highlighted earlier in Chapter 2 by individuals who have undergone psychedelic treatment, the preparation and integration sessions with therapists are key to a positive therapeutic outcome. Indeed, said clinical psychologist Rosalind Watts, psychosocial contexts (also referred to as set and setting) are essential treatment elements. “You can’t separate the drug from the context,” said Watts, who was the clinical lead for the psilocybin trial at Imperial College London and is the clinical director of the Synthesis Institute.1 “One of the biggest problems in psychedelic therapy at the moment is a widespread overestimating of the importance of the drug and an underestimation of the non-drug elements,” she said.
Watts said that without these elements, psychedelic therapy may be ineffective or even dangerous. Psychedelics do not work like other drugs, she said. “The participant is not a passive recipient and the degree of trust they feel toward themselves, the therapist, and the substance will determine whether the drug works at all and how safe it is.” Lacking this trust, she said, patients may be “unable to surrender to the experience and make the most of it.”
Watts acknowledged that there is little research teasing out the benefits and mechanisms of these non-drug elements, in part because it would be unethical to provide psychedelics without them. Brain imaging combined with qualitative research has indicated, however, that an overarching mechanism that contributes to treatment efficacy is psychological flexibility, said Watts.
Watts has proposed a simplified model informed by six psychological flexibility concepts as well as a thematic analysis of the qualitative experiences of participants in psychedelic therapy trials (see Figure 3-2). She calls this model “Accept, Connect, Embody,” or ACE (Watts and Luoma, 2020).
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1 To learn more about the Synthesis Institute, see https://www.synthesisinstitute.com (accessed May 14, 2022).
NOTE: To learn more about the six core process of ACT, see https://contextualscience.org/the_six_core_processes_of_act (accessed May 14, 2022).
SOURCES: Presented by Rosalind Watts, March 29, 2022; Hayes, 1999.
From being a guide in so many psilocybin therapy sessions, Watts said she has come to believe that these three elements determine the effectiveness of psilocybin treatment for depression.
She simplified the model into its three main elements: acceptance, connection, and embodiment. “Acceptance is the most important aspect for avoiding a bad trip” said Watts, “it is all about being able to let go and feel whatever comes up in the session.” The preparation and integration sessions reassure patients that even uncomfortable or frightening experiences during the treatment sessions provide the potential for learning and change and that they will be safe. Connectedness focuses on an individual’s ability to
stay with the emotional content of what they are experiencing. Connecting these experiences to new insights at the time of treatment and in integrative sessions after the treatment sessions helps patients derive meaning from the experience. “The most common insight from people is they realize everything is interconnected, rather than being separate,” said Watts. Embodiment refers to the experience as it is felt in the body, said Watts. “Often people experience some kind of insight into their difficulties through for example a tight feeling in their chest. . . . There is the sense that we hold our traumas in our bodies, and people are able to really access those pockets of held trauma that have crystalized and are able to explore and release [them],” she added.
The preparation sessions are about building trust, which takes time, said Watts. Visualization exercises are often used to prepare patients for the psilocybin experience. For example, Watts might offer the analogy of a pearl dive. “They imagine they’re swimming out to sea, and they dive under the surface and down to the bottom of the sea and look around. It’s all about going toward the spikey oyster shells at the bottom of the sea rather than swimming away from them; opening the oysters up and looking for pearls, and then swimming up to the surface with this new outlook on life.”
Embodiment also requires extensive preparation, said Watts, adding that having two guides is important and that the sessions should be videotaped. Setting boundaries with regard to touch should be done in advance. Music is another critical part of the psilocybin experience and can be thought of as the “third therapist,” she said. “It’s really important to have a good playlist.” It can help people be in their bodies and can open them up to emotions that might otherwise be resisted.
The integration sessions are about finding meaning in the experience, said Watts. Some patients have clear insights, but for others, very careful and sensitive non-directed therapeutic support can help patients make a narrative of what they learned through the experience, which helps them to continue benefiting from the treatment even after the “afterglow” ends, she said.
Watts described a psilocybin trial at the Imperial College London, which was a randomized trial comparing two groups that both had two guides and music mediation, preparation, and integration sessions. One group received 25 milligrams of psilocybin while the other group received 1 milligram of psilocybin (as placebo) plus a course of the SSRI antidepressant escitalopram (Carhart-Harris et al., 2021). No significant differences were found between the two groups on the primary outcome measure, measuring symptoms of depression. However, as the leader of the clinical team, Watts spoke with all participants. Among those in the antidepressant group, many told her that the antidepressants were not responsible for the benefits they experienced. “What they described as profound was the expe-
rience of having two therapists, two days of sitting with music, and having space for the emergence of what is referred to in psychedelic therapy as the inner healer that we all have within us,” said Watts. “So I would say that we mustn’t underestimate the importance of the care and the connectedness that psychedelic therapy offers people, and how much of an impact that has on the outcomes.”
Beyond this trial, Watts cited several research studies that have demonstrated the importance of context (Carhart-Harris et al., 2018), emotional breakthrough (Roseman et al., 2019), and the quality of the acute psychedelic experience (Roseman et al., 2018) in achieving therapeutic efficacy, as well as the potential benefits of providing psychedelics in group settings, known as psychedelic communitas (Kettner et al., 2021). While there has been little research to prove that the drug and the psychosocial context are inseparable, she highlighted the fact that many people take psychedelics recreationally but describe no therapeutic benefits. Watts said she views psychedelics as compounds that can amplify psychedelic-assisted therapy, but that without the psychological flexibility framework, the benefits are lost very quickly.
LINKING BIOLOGICAL, PSYCHOLOGICAL, AND CLINICAL EFFECTS OF PSYCHEDELICS: RESEARCH GAPS AND OPPORTUNITIES
Although evidence has been accumulating to support the therapeutic use of psychedelics and entactogens, critical research gaps remain, said John Krystal, chair of the department of psychiatry at Yale University. To further develop these agents for the treatment of psychiatric disorders, Krystal said further research is needed in three critical areas: (1) translating molecular and circuit effects of psychedelics into clinical benefits; (2) identifying the critical psychological and psychosocial treatment elements that underlie clinical benefits; and (3) understanding the therapeutic importance of psychedelic effects.
The serotonin 2A receptor is known to be the main molecular target of classic psychedelics, but Robert Malenka, Pritzker Professor of Psychiatry and Behavioral Sciences at Stanford University, suggested that while necessary, it may not be sufficient. “It may be much more complicated than activating serotonin 2A receptors to get therapeutic benefits,” he said Another still open question is whether post-acute effects of psychedelics are mediated by this receptor, said Javier González-Maeso, professor of physiology and biophysics at the Virginia Commonwealth University School of Medicine. If the mechanisms of the acute and postacute effects are different, it may be possible to achieve therapeutic effects without hallucinations, he said.
Is the Subjective Experience Necessary?
Related to this question and also unanswered is whether the psychedelic effects are necessary to achieve therapeutic effects, said González-Maeso. Roland Griffiths, professor of psychiatry and neurosciences at the Johns Hopkins University School of Medicine, asserted that the subjective effects reflect the underlying neurobiology and are necessary for full and enduring therapeutic effects. Historical, anecdotal, and qualitative data support this view, he said. As was pointed out by Watts and described by Nora Osowski and Lori Tipton in Chapter 2, clinical studies have shown that participants attach deep meaning and significance to their psychedelic experiences, including a sense of connectedness and unity, said Griffiths. He suggested that something about these experiences is integral to meaning making2 and the construction of a changed narrative. In addition, he said it has been shown experimentally that features of the mystical-type experience are predictive of enduring positive changes going forward.
Malenka said while he also believes the subjective experience is critically important for therapeutic benefits, much of the evidence is correlative. Griffiths suggested one approach that would disprove the importance of subjective effects experimentally: administration of psychedelics to individuals rendered fully unconscious. If participants in such a study had no memory of the psychedelic experience yet had full and lasting therapeutic efficacy, subjective effects would seem irrelevant. Although such an experiment could be difficult, Malenka said, “If there is an experiment to be done that disproves your hypothesis, you should do it. In fact, you are morally bound to do it.”
Malenka suggested that another experiment that could help tease out the importance of hallucinogenic or mystical experiences would be to compare treatment of depression using lisuride, the non-hallucinogenic analog of LSD, versus psilocybin or LSD in combination with adjunctive psychotherapy. An even more difficult experiment would be to block the subjective experience by administering the 5-HT2A antagonist ketanserin before psilocybin or LSD. If under that pharmacologic condition LSD or psilocybin still showed a therapeutic benefit, “that would be a very powerful result that would actually change the game enormously,” said Malenka.
Whether the therapeutic benefits result from the drug’s interaction at the receptor or from the whole therapeutic session is a “strange dichotomy,” said Gitte Moos Knudsen, professor of neurology and chair of the Neurobiology Research unit at the University of Copenhagen and Rigshospitalet, Denmark. “What we experience makes us who we are and we are our
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2 Meaning making is the “process by which people interpret situations, events, objects, or discourses, in the light of their previous knowledge and experience” (Zittoun and Brinkmann, 2012).
brains,” she said. She noted that there are large individual differences in how people react to these substances and suggested that there may be an epigenetic explanation that ties together an individual’s experience with the pharmacological effects at the 5-HT2A receptor site.
Particularly intriguing, she said, is the observation that many people who have mystical experiences with their first exposure to psychedelics have a similar experience on a second occasion months later, whereas those who do not have a mystical experience the first time usually do not have one the second time either. Griffiths agreed that there appear to be real individual differences but said there are also considerable within-subject differences.
Griffiths added that people who are less open to the psychedelic experience seem to struggle more with it, which results in a strong selection bias with respect to the people who decide to participate in these studies. Krystal said he saw similar struggles among participants in ketamine trials, which may be related to temperament. “People who were very frightened by losing control were more likely to be frightened and have a difficult experience during ketamine [treatment] than people who found the ketamine experience interesting, engaging, or even exciting,” he said. Knudsen pointed to the known relationship between personality and cerebral 5-HT2A receptor density, noting that studies have shown a correlation between the receptor density and both neuroticism and openness. Knudsen suggested that there may be observable traits that could be used to predict who would benefit from the treatment.
Understanding the Linkage Between Mechanism and Effect
A disconnect exists between basic science and clinical work, in part because there are no good animal models for neuropsychiatric disease, said Olson. “These are uniquely human conditions,” he said. Animal studies can, however, be used to look at specific behavioral readouts of certain circuitry activation and to assess the effects of environmental changes, he said.
Krystal added that “there is a tendency to think about the effects of these drugs as either working through their molecular or synaptic plasticity or through cognitive mechanisms.” But there may also be both component benefits and component risks associated with each of these mechanisms, and these effects may be additive, he said. Griffiths noted that serious toxicities are associated with psychedelics. Yet, he nonetheless questioned the ethics of withholding the possibility of a life-changing experience from someone who would otherwise not have such an experience.
Also with regard to plasticity, Malenka said that differentiating drug-induced from psychotherapy-induced plasticity is a false dichotomy. “I believe that certain forms of psychotherapy are powerful therapeutic agents of change that work by modifying spines, synapses, and circuits in the
brain, just in very complex ways that are much harder to understand than giving a single drug that has one or multiple molecular targets that we can manipulate,” he said.
Tristan McClure-Begley, program manager at the Defense Advanced Research Projects Agency (DARPA), proposed diversifying the chemical space around psychedelics as an alternative approach toward understanding the mechanisms underlying their therapeutic effects. “We’ve been tossing around concepts that can really be broken down into two separate questions,” he said. One is whether subjective effects are necessary for therapeutic effects of psychedelics; the other is whether the targets engaged by psychedelics represent “therapeutic gateways in their own right that may share some, but not all, of the mechanistic aspects of classic psychedelics for therapeutic use.”
To answer this second question will require the synthesis of novel chemical compounds, said McClure-Begley. Most known chemotypes engage neurotransmitter receptors in an unbiased fashion and are indiscriminate with respect to the downstream signaling pathways they activate, he said. By contrast, he proposed designing and testing novel chemical matter with predictable and reliable pharmacokinetics that selectively engage downstream signaling with minimal off-target effects. For example, a drug that engages 5-HT2A but does not cause the psychedelic experience might not be useful taken a few times in guided therapy sessions. However, it could be useful as a more traditional psychopharmacologic agent, said McClure-Begley.
He noted that there are known non-psychedelic analogues of some hallucinogens, such as LSD. Adding to our toolbox in terms of molecular diversity could allow us to see, for example, to what degree signaling bias is necessary or sufficient to engage mechanisms that cause certain behavioral effects, he said. “We could also, at the same time, be talking about a completely different therapeutic mechanism of action compared to what is possible with classic psychedelics,” said McClure-Begley.
Griffiths added that “our understanding of the differences among these different existing psychedelic compounds is embarrassingly primitive.” A few preclinical studies have provided clues, said Krystal. For example, the spines produced during psilocybin treatment last longer than those created during ketamine infusions, he said, although the mechanisms underlying these differences are unclear. González-Maeso added that studies with 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a psychedelic structurally similar to but more potent than mescaline affects gene expression and chromatic organization after a single dose, which does not happen with ketamine. He suggested that the longer duration of effects from psilocybin and other classic psychedelics may be related to gene expression and plasticity.
While psychedelics are known to induce changes in brain connectivity, how long these changes last remains an important unanswered question,
said Preller. She suggested that studies comparing the effects of classic psychedelics with ketamine could be valuable to increase understanding of trans-drug mechanisms. Olson mentioned that all of these drugs produce similar effects on corticostructural plasticity, but they have distinct targets, and their effects persist for different periods of time. “What that really suggests is that they can engage a similar biochemical pathway,” he said. For example, TrkB and mTOR activation seems to be critical for all of these agents, which suggests new therapeutic targets distinct from 5-HT2A receptor activation, he said.
Another important question to be answered is where in the brain these drugs are active, said Malenka. “I don’t believe the whole story is the PFC, and in the PFC it’s going to depend on which class of neurons are being modified and what they are connected to,” he said. Moreover, the signaling bias you want in a therapeutic agent will not be uniform throughout the brain,” said Malenka. Figuring out which circuits are being modified in which brain areas could help bridge the gap between preclinical and clinical research using human brain imaging and resting state functional connectivity studies, he said.
Valentino added that some LSD users report flashbacks of hallucinogenic experiences many years later. The molecular mechanisms underlying these flashbacks are unclear, said Gobbi, but may involve the thalamus, as well as the hippocampus and entorhinal cortex, which are important for autobiographical memory.
Predicting Responsiveness to Psychedelic Treatment
Knudsen pointed to the emerging evidence from animal studies that psychedelics induce neuroplasticity that may be associated with the beneficial treatment effects. To investigate this further in humans, possible markers of neuroplasticity could include levels of serum brain derived neurotrophic factor (BDNF), hippocampal volume assessed with magnetic resonance imaging (MRI), assessment of glutamate levels using mass spectroscopy, molecular neuroimaging of the synaptic vesicle protein 2A (SV2A) using positron emission tomography (PET), or electroencephalogram-based visual potentials, she said. She also urged the development of other novel PET tracers to identify the optimal molecular target.
With respect to SV2A imaging, Krystal cited a recent pilot study that, in a secondary analysis, showed that in depressed patients with reduced synaptic density, but not in those with normal synaptic density, a single dose of ketamine increased SV2A binding, and these increases were correlated with reduced depression severity (Holmes et al., 2022). While ketamine produced dissociative symptoms in patients with and without evidence of synaptic deficits, dissociative symptoms correlated with clinical improve-
ment and synaptic increases only in those patients who had initial synaptic deficits. While ketamine is not a psychedelic drug, these results suggest that dissociative symptoms do not mediate clinical benefits, but rather serve as a marker of changes in circuit function that are permissive of adaptive plasticity in subgroups of patients, said Krystal.
Griffiths also suggested investigating genetic markers for sensitivity to transcendent experiences, noting that data to address this question are currently insufficient.
Studies by Alex Kwan and colleagues at Yale have demonstrated profound sex differences in the increase in spine density following a single dose of psilocybin, and similar sex differences have been seen in preclinical studies of ketamine and other psychedelics, said Olson (Shao et al., 2021). In small human studies, however, Preller and colleagues have not observed sex differences in the response to psychedelics.
Standardizing Nomenclature
As was alluded to in Chapter 1, questions remain about nomenclature, said Malenka. He said that addressing this issue and developing a more sophisticated language among researchers, government agencies, and philanthropic organizations will grow in importance as the field develops. The term “psychedelic” itself is problematic when used to encompass the different classes of compounds that were discussed at this workshop, said Malenka. For example, he argued that classic serotonin 2A hallucinogenic ligands, such as LSD and psilocybin, are mechanistically and subjectively quite different from entactogens such as MDMA. In addition, the dissociative anesthetic ketamine, which is often lumped together with classic hallucinogens, most likely works through different mechanisms, he said.
Malenka said more rigorous and sophisticated language is also needed when discussing concepts such as plasticity. There are maladaptive forms of plasticity that involve spine changes and changes in the dendritic tree and in circuit dynamics, as well as decades of research showing that drugs of abuse can cause structural changes in different parts of the brain. Knudsen agreed on the need for more rigorous nomenclature when it comes to definitions of the term “psychedelics” and suggested the neuroscience-based nomenclature introduced by the European College of Neuropsychopharmacology.3
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3 To learn more about the neuroscience-based nomenclature published by the European College of Neuropsychopharmacology, see https://www.ecnp.eu/research-innovation/nomenclature (accessed May 25, 2022).
