1. Manifesting the Potential of Psychedelic Treatments

              Psychedelics provide something psychiatry has rarely been able to produce pharmacologically: an opportunity to modify deeply entrenched patterns of learning. They can bring about rapid changes in the brain that a multitude of mental health treatments have yet to achieve. We are on the brink of new era of therapeutic interventions  that could save thousands of lives from suicide, cut public health costs associated with depression, anxiety, substance abuse disorders, personality disorders, eating disorders, PTSD, ADHD, sex addiction, gambling addiction psychiatric hospitalizations, psychiatric hospitalizations, incarcerations, and homelessness. It could decrease family estrangements, divorces and improve quality of life. Neurobiological research and potential solutions exist to advance our ability to help people and those with mental disorders as long as we are open to change and collaboration.

               The significance of psychedelic treatment is its ability to create neuroplasticity, providing an opportunity to change the brain in short periods of time. Robin Carhart Harris found that psychedelics open the brain for new learning. In a 2019 Nature study, Neuroscientist Gul Dölen’s research on the effects of MDMA on mice found that the brain opened for a critical period in which it becomes unusually receptive to social and environmental learning. The drug itself does not teach a person rather it creates a state in which the brain becomes unusually responsive to subsequent experiences and context. This demonstrated that psychedelics may have a major shared therapeutic property in their capacity to induce meta plasticity, changing the brain's capacity to undergo subsequent plastic change. This involves oxytocin-dependent synaptic plasticity in the nucleus accumbens, a brain region central to reward processing. Gul Dolen’s findings demonstrated that various psychedelics reopened a critical period for social reward learning in the adult mice brain.

2. GUL DOLENS findings: Critical Periods, Meta Plasticity, and Social Reward Learning

             Does the brain’s reopening of critical periods for social learning indicate that there is a need within the brain for corrective experiences in social learning? Can providing social learning during this critical period create lasting therapeutic change? We must now ask a more precise question: If psychedelic drugs create a temporary state of enhanced plasticity, what specific means of therapeutic learning should occur during that state to enhance social learning and connection? The scientific question should therefore no longer be limited to: What does the drug do to the brain? It should also include: What does the brain learn while the drug-induced window of change is open? Of note, this creates rapid changes in contrast to lengthy psychotherapy however reinforcement of the new learning is essential. The components of the learning experience is crucial. It is not the psychedelic alone creating change, it is the drug plus the specific therapeutic treatment implemented in a trusting and compassionate environment. The question is, what does the brain need to learn when the drug-induced window of change is open, and what is the most effective method to accomplish new learning? Gul Dolen Talk click here

            Can the nature of psychotherapy implemented at this crucial time determine what changes therapeutically and the sustainability of these changes? Integrating what has happened during the actual drug session should not be the primary objective. Current Psychedelic treatment has emphasized set and setting: the patient’s psychological state, the physical environment, preparation, interpersonal reassurance, and the presence of trained personnel during drug administration. These factors are important for safety. But safety is not the same as a therapeutic mechanism to  induce positive change, new learning. We must ask a more precise question: If psychedelic drugs create a temporary state of enhanced plasticity, what therapeutic learning should occur during that state to enhance social learning and connection? The scientific question should therefore no longer be limited to: What does the drug do to the brain? It should also include: What does the brain learn while the drug-induced window of change is open? The goal should now be how to provide opportunities for reinforcing the new learning  so that it is sustainable.

3.  Mental illness, Psychedelic Treatment and the Promise of Neuro Plasticity

            Many of the speakers at the FDA Public Hearing described people who sought out psychedelic therapy as having problems with anxiety, depression, insecurities, and, what they're calling, post-traumatic stress. What their descriptions had in common was their negativity, people who see situations negatively, are rejection sensitive, anxious, hypervigilant and who do not feel safe. These are descriptions of people who feel they do not fit in or belong. Many people diagnosed with various mental illnesses share these same feelings. They are related to impaired social reward learning and results in negativity, misunderstanding of intentions of other people, rejection sensitivity, inability to experience the positive feelings of social connection. These seem to be transdiagnostic characteristics or underlying symptoms of many mental health disorders. (PTSD, addictive disorders, personality disorders, eating disorders, ADHD, autism, etc).

4. THE IMPORTANCE OF SOCIAL LEARNING  AND SOCIAL CONNECTION

           Can psychedelic-induced plasticity, paired with targeted psychotherapy involving corrective learning, capitalize on the “open critical period plasticity” to modify dysfunctional neurobehavioral systems that cut across multiple psychiatric diagnoses? Would specific treatment focusing on social learning and social connection break a patient out of isolation, reduce egocentric anxiety, build trust, social connection and  deep relational empathy?

What is social learning? Social learning helps people function effectively in relationships and groups. It allows them to learn from other people, interpret social information accurately, and form and continually revise their understanding of other people based on social experience.

Impaired Social Learning.  Deficits in Social learning characterize many of the major social and mental problems facing society today, such as addiction, ADHD, PTSD, conduct disorder, gambling, domestic violence. A social-learning deficit does not necessarily mean that someone lacks intelligence or does not want relationships. It means that some part of acquiring, interpreting, updating, or using social information is less effective. This can lead to inaccurate expectations about others, impaired trust and cooperation, repeated interpersonal misunderstandings, and difficulty forming stable social relationships. Depending on which processes are affected, consequences of problems with Social learning can include:

Difficulty interpreting other people's intentions, predicting how other people will respond
Difficulty learning from social feedback, changing an impression after receiving new information Unable to revise an impression of someone or a situation when new evidence appears.
Difficulty repairing relationships after conflict, Repeated interpersonal misunderstandings, Difficulty repairing relationships after conflict, Repeated interpersonal misunderstandings,
Misreading neutral or ambiguous behavior as hostile, rejecting, or threatening Difficulty recognizing when another person is trustworthy or untrustworthy Problems with perspective-taking or understanding what another person knows or believes Problems developing or maintaining reciprocal relationships, Excessive mistrust or excessive trust Reduced enjoyment or withdrawal from opportunities for social reward from social interaction Social withdrawal or avoidance, Increased loneliness and social isolation, never feeling safe

What is Social Connection?

This is the subjective and biological experience of being meaningfully related to other people---.feeling that one belongs, is accepted, can trust others, and can give and receive care, support, compassion.  It is the experience of feeling safe, understood, accepted, valued, and meaningfully connected to other people. Social connection involves the brain registering another person as socially meaningful, potentially rewarding, and sufficiently safe to approach and engage with., It is not the same as simply being around others.  A person can have many social contacts and still feel disconnected. it depends on trust, reciprocity, belonging, and the expectation that relationships can be rewarding rather than threatening. It is based on Theory of mind, the ability to mentalize another person.

Impaired Social Connection Social connection depends on social learning. Deficits can lead to inaccurate expectations about others, impaired trust and cooperation, repeated interpersonal misunderstandings, and difficulty forming stable social relationships. The inability to experience positive feelings with social connection can be interpreted as feeling abandoned. Social connection is the state produced when the brain perceives another person as socially meaningful, sufficiently safe, and rewarding, allowing attachment, trust, affiliation, and sustained interpersonal engagement to develop. Biologically, there is no single “social connection system.” It emerges from several interacting systems.

Social connection is based on Biology : Oxytocin helps regulate social recognition, attachment, affiliation, and the salience of social cues. Its effects are context-dependent; it should not be thought of simply as a “bonding hormone.” Human oxytocin findings are more complex than what popular description suggests.

Dopamine contributes to motivation and reward. Mesolimbic dopamine circuits help make interaction with another person rewarding enough that we want to approach them, maintain contact, and repeat affiliative experiences. Oxytocin and dopamine interact within these circuits.

Endogenous opioids, especially the mu-opioid system, contribute to the pleasure, comfort, and soothing qualities of affiliation. Human evidence increasingly implicates this system in the rewarding experience of social connection.

Vasopressin participates in social recognition, attachment, territorial, and affiliative behaviors, although its functions differ by species, sex, brain region, and context.

Stress-regulation systems, particularly the HPA axis and cortisol, interact strongly with social relationships. Perceived rejection, isolation, or interpersonal threat can engage physiological threat responses, (HYPERVIGILANCE) whereas social support and perceived safety can dampen aspects of those responses. The autonomic nervous system, including sympathetic activity and parasympathetic/vagal regulation, helps determine whether the body is prepared for defense or is sufficiently regulated for calm social engagement.

Brain networks :  The amygdala helps evaluate emotional significance and possible social threat. Reward structures including the ventral tegmental area and nucleus accumbens/ventral striatum help assign reward value to social experiences. Prefrontal and temporal regions help interpret facial expressions, intentions, beliefs, and social context. Networks involved in mentalizing, empathy, and social cognition enable us to represent what another person may be thinking or feeling. Biologically, successful social connection requires at least four processes working together: TRUST is essential—- recognize another person → interpret their signals → determine whether interaction is safe → experience interaction as sufficiently rewarding to approach and maintain it.

Social connection is partly a reward-learning phenomenon. Humans are biologically equipped so that social interaction acquires positive value. Dopamine, oxytocin, endogenous opioids, threat-regulation systems, and social-cognitive brain circuits interact so that particular people can become associated with safety, pleasure, comfort, trust, attachment, and belonging.

5. Treatments Focusing on Social Connection

Psychedelics may open the window. Our responsibility now is to determine what kind of psychotherapy helps patients learn while this window is open. The potential goal is larger than symptom reduction: to help people relearn the value, safety, and reward of social connection. There are specific therapies that focus on connection and trust. They are generally  based on Theory of Mind. Examples include Compassion Focused Therapy by Paul GIlbert and Mentalization Based Therapy developed by Bateman and Fonegy. Reopening plasticity may create an opportunity to relearn the value, safety, and reward of social connection.

Setting may also be the social-learning environment presented to a highly plastic brain. Psychedelic drug development has appropriately focused on pharmacology, safety, dose, patient selection, integration and “set and setting.” Considerably less attention has been given to what specific psychotherapy should accompany a psychedelic drug, and does the nature of that psychotherapy determine whether therapeutic change becomes sustainable? Nor it seems has data been collected that could clarify usage and efficacy. The Psychotherapy components may not be an undefined supportive background condition, but may be an essential component of the psychedelic experience (treatment).

What is a Critical Period?A critical period is a time during development when the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for accelerated brain plasticity during early development and for developing constraints that are imposed on these mechanisms as the brain matures. Social impairments in some disorders may be responses to experiences resulting in actual or perceived “social injury.” This makes psychotherapy potentially part of the mechanism rather than simply part of the infrastructure surrounding drug administration. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identifying how  to reopen critical periods has long been a priority for translational neuroscience. 

6. What is needed for FDA Approval of Psychedelic Drug Treatment?  

Psychedelic treatment development has appropriately focused on pharmacology, safety, dose, patient selection, integration and “set and setting.” Less attention has been given to what specific psychotherapy should accompany psychedelic drug. Consider the following:

1  Is the therapy addressing the underlying neurologically based problem in the patients? 2  Does the nature of the psychotherapy accompanying psychedelic treatment determine or influence change or the sustainability of change? 3  If appropriate treatment is not received during “critical periods” does the brain return to its prior state? 4  Is DATA available on the reasons people seek out Psychedelic therapy?? Are people receiving psychedelic therapy as participants or patients? Are they seeking the psychedelic experience or are they hoping to relieve feelings of depression, anxiety or painful feelings of social isolation? 5  Is DATA available to determine differences in outcome and duration of change? 6  Is DATA required or available on diagnosis of participants? 7  Are there criteria for participation or exclusion criteria for psychedelic treatment? 8  Pre and post data is needed regarding specific diagnoses of participants, Outcomes: specific changes aftertreatment; Longitudional data to determine sustainability of changes; . 9 expectations for participating in psychedelic treatment? 10 Comparison of outcomes based on orientation of therapist (CBT, psychoanalytic, DBT, etc) 11 Is treatment addressing the specific underlying problem of the person?

Can the Psychedelic Community answer the following questions:

What should we be teaching? What is the significance of which part of the brain opens during critical periods? What is the relevance of the opening of a critical period for social reward learning? What is the relevance of the ability to experience social reward and social connection? How would social reward learning and social connection help these people?  Is psychedelic drug treatment providing an opportunity for corrective experiences through learning? Is “psychedelic integration” reinforcing the learning that can take place when the brain is open? Has a specific method for enhancing social reward learning been implemented for psychedelic treatment?

The Psychotherapy components is not an undefined supportive background condition. It is an essential and crucial component of the psychedelic experience (treatment),just as essential as the psychedelic drug.

7. AVOID Repeating Past Public Health Errors

Although we believe strongly that psychedelic treatment has enormous potential, we are concerned that legalizing treatment without appropriate scientific research can lead to similar outcomes as has occurred with cannabis.  Cannabis may have been legalized because of social pressure before the rigorous scientific studies to evaluate its use were completed. There is no doubt that it is used and approved across the United States. Unfortunately, esteemed neuroscientists such as Yasmin Hurd have demonstrated that cannabis is not as harmless as we were led to believe. (EG An Update on the Behavioral and Neurobiological Effects of Cannabis Use in Adolescents: A Translational Perspective by Yasmin Hurd) She has studied its effect on pregnant women and their babies as well as on adolescents. Psychedelic Treatment is now facing similar pressures. The scientific responsibility now is to determine what kind of psychotherapy helps patients learn while the brain is open and how to reinforce and integrate these changes into the patient’s life. The potential goal is larger than symptom reduction: it is to help people relearn the value, safety, and reward of social connection,  to live a more connected and fulfilling life.

Future Directions  
I urge FDA, NIH, and the broader psychedelic research community to require greater scientific attention to the psychotherapeutic component of psychedelic treatment.Future research should: 1.      specify what therapists are actually doing before, during, and after drug administration. 2.      identify the proposed therapeutic mechanism of those interventions. 3.      compare specific psychotherapy models experimentally. 4.      examine social-learning and outcomes alongside traditional symptom measures. 5.      investigate the duration of the post-drug therapeutic learning window. 6.      test whether corrective social learning improves durability of treatment effects.

   We at TARA strongly believe that psychedelic treatment has enormous potential. We support legalizing psychedelic research and treatment only if accompanied by targeted rigorous scientific research. If problems arise before this is achieved, it might deter further advances in our understanding and application of this promising new method that we feel can ultimately lead to cures for many mental illnesses. Go ahead. The potential goal is larger than symptom reduction. It is to help people relearn the value, safety, and rewards of social connection, to live a more connected and fulfilling life.

 Respectfully submitted, Valerie Porr, M.A.