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.

FIGURE 3-1

Psychedelics promote dendritic spine growth in vitro. Representative tracings (top) and high-resolution microscopy (bottom) of cortical neurons treated with LSD or DMT show substantially more complex dendritic arbors and increased growth of dendritic (more...)

In vivo studies showed similar results, said Olson. In rats, a single injection of DMT produced a profound increase in dendritic spine density 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-HT_2A receptor knockout animals, Olson and colleagues have shown that this functional and structural plasticity is mediated by 5-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A knockout neurons. “This suggests some type of functional selectivity,” said Olson. “We can engage the 5-HT_2A 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-HT_2A 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.

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-HT_2A 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 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-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A 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 improvement 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