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Epigenetics, Neuroplasticity, Stress and the Psychedelic Experience

We are our mind and our minds are not isolated entities confined to our brains. Rather, they are an embodied and relational process that regulates the flow of energy and information within each one of us as sentient beings.  As such, every experience modulates genes by silencing and activating them within the genome of each individual.  In essence, this is epigenetics and its mechanism can be intra and intergenerational.

In developmental psychology, Erik Erikson wrote on an epigenetic principle in his book Identity: Youth and Crisis (1968) on how our environment and surrounding culture influence how we progress through these stages of psychosocial development.  Epigenetic modification is also thought to be intergenerational through a biological mechanism of transgenerational trauma, or intergenerational trauma.  This concept of biologically inherited trauma was first recognized in the mid-1960s by Canadian psychologists who observed a large number of Holocaust survivor descendants seeking mental health care.  Dr. Rachel Yehuda, director of the Traumatic Stress Studies Division at the Icahn School of Medicine at Mount Sinai in New York City, observed that infants born to mothers who were pregnant on 9/11 had low cortisol levels, which were associated with the presence of maternal Post-Traumatic Stress Disorder (PTSD).  Additionally, transgenerational trauma has also been observed in descendants of families separated during the Korean War, Cambodian refugees who fled genocide from the Khmer Rouge, Native American genocide survivors, African-Americans forced into slavery, and so many more.

PTSD is a type of anxiety disorder through which intra and intergenerational trauma is manifested.  However, any type of stress experience, which is a perception of threat, can activate the sympathetic nervous system, causing the flight-fight or freeze response or the reactive response where the ego defends ourselves, where we manipulate situations by being nice or nasty or stubborn, being indifferent or playing the victim—these are all ego-bound modes of behavior.  

Epigenetic mechanisms have also been suggested to have roles in neuroplasticity. Until recently, it was believed that we were born with a ton of neurons, synapse and connections, that our brains were fixed by the end of adolescence and as we got older, the neurons simply died off.   However, current research has shown the opposite to be true—that our brains can actually grow and change throughout our lives.  We can actually make changes to further develop our brains and “rewire” the way we process our experiences and perceive situation, ourselves and others.  This is exciting because those who have experienced trauma have the possibility of being free from its negative repercussions of depression and anxiety that increase morbidity and mortality.  

There are several ways to elevate our neuroplasticity potential—from reading fiction, creating art, getting adequate sleep, enhancing one’s diet, expanding your vocabulary, learning to juggle, doing mnemonic drills to doing exercise or simple tasks with our non-dominant hand.  However, when it comes to trauma experienced in one’s lifetime or transmitted intergenerationally, tactics such as eye movement desensitization and reprocessing (EMDR), cognitive behavioral therapy (CBT) and meditation are specific modalities that can “rewire” the brain through neuroplasticity.  Both CBT and meditation begins with awareness of the mind as an object of awareness.  However, unlike CBT, the goal of meditation practice is to achieve ego death, which is complete transcendence of the self or a complete loss of subjective self-identity.  

An alternative to meditation is the entheogen or psychedelic experience.  The combined mystical and insight experience are the acute psychedelic effects that increase psychological flexibility and can lead to rapid and enduring transformation with greater reduction in trauma, stress, depression and anxiety.  The mystical experience is a spiritual one that consists of positive mood, transcendence of time and space that is difficult to put into words.  The insight experience is of something deeply meaningful to the individual, gaining awareness, realization and discoveries about emotion, behaviors, beliefs, memories and relationships.  Like meditation, the psychedelic experience softens/ceases one’s internal dialogue and expands consciousness and this awareness goes in the direction from the conditioned mind to freedom from it. In one study 2/3 of the patients were found to have transformational changes in the meaning and purpose of life, attitudes about self, life and death, behaviors, mood, well-being and life satisfaction.

Studies of psychedelics in mental health have been increasing over several decades as research around the world is growing exponentially.  A list of psychedelic clinical trials are listed below:

 

1.     MDMA 

a.    Multidisciplinary Association for Psychedelic Studies (MAPS):
        i.    a multi-site Phase 3 study of MDNA-Assisted Psychotherapy for PTSD with US, Canada and Israel participating, 
       ii.    Evaluation of MDMA on Startle Response at Emory University in Atlanta GA, 
      iii.    MDMA in Subjects with moderate hepatic impairment and subjects with normal hepatic function at the University of California, San Francisco, CA)
      iv.    Psychological Effects of MDMA when administered to Healthy Volunteers (MT-2)
      v.    A Multi-site Study of MDMA-Assisted Psychotherapy for Eating Disorders (MED1)
     vi.    Open-Label Multi-Site Study of Safety and Effects of MDMA-Assisted Psychotherapy for Treatment of PTSD (CA, CO, CT, LA, MA, NY, SC, WI)
    vii.    Study of Safety and Effects of MDMA-assisted Psychotherapy for Treatment of PTSD (British Columbia and Quebec, Canada)

b.    University of Chicago:
      i.    Effects of Drugs on Responses to Brain and Emotion Processes (MAT)
     ii.    Effects of Stimulant Drugs on Social Perception (ESP)
    iii.    Mood Effects of Serotonin Agonists

c.    Yale University
      i.    The Effect of MDMA on Prefrontal and Amygdala Activation in PTSD

d.    University Hospital, Basel, Switzerland
      i.    Effects of MDMA on Fear Extinction
     ii.    Effects of MDMA Co-administration on the Response to LSD in Healthy Subjects (LSD-MDMA)
    iii.    Role of Dopamine, Serotonin, and 5-HT2A Receptors in Emotion Processing

e.    Imperial College of London
     i.    Open-Label Proof of Concept Feasibility Study to Explore the Safety, Tolerability, and Potential Role of MDMA-Assisted Psychotherapy for the Treatment of Detoxified Patients with Alcohol Use Disorder
    ii.    Bristol Imperial MDMA in Alcoholism Study (BIIMA)

f.    MAPS Europe B.V.
     i.    Open Label Multi-Site Study of Safety and Effects of MDMA-assisted Psychotherapy for Treatment of PTSD with Optional fMRI Sub-study (Czechia, Netherlands Norway, Portugal, United Kingdom)

g.    VA Loma Linda Health Care Systems & MAPS
     i.    MDMA-Assisted Psychotherapy in Veterans with Combat-Related, Refractory PTSD (VALLMDMA_001)

h.    Stanford University
    i.    Stanford Reward Circuits of the Brain Study- MDMA (RBRAIN-MDMA)

 

2.    Psilocybin

a.    Johns Hopkins University Center for Psychedelics & Consciousness Research
    i.    Effects of Psilocybin in Anorexia Nervosa
   ii.    Psilocybin for Depression in People with Mild Cognitive Impairment or Early Alzheimer’s Disease
  iii.    Psilocybin-facilitated Smoking Cessation Treatment: A Pilot Study (in collaboration with Berkley Foundation and Heffter Research Institute)
  iv.    The Effects of Psilocybin-Facilitated Experience on the Psychology and Effectiveness of Religious Professionals
   v.    Effects of Psilocybin on Major Depressive Disorder
  vi.    Effects of Psilocybin on Behavior, Psychology and Brain Function in Long-term Mediators
 vii.    Persisting Effects of Psilocybin (in collaboration with NIDA)

b.    Usona Institute, Signat Health, The Emmes Company, LLC
   i.    A Study of Psilocybin for Major Depressive Disorder

c.    Gitte Moos Knudsen 
   i.    Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH)
  ii.    The Neurobiological Effect of 5-HT2AR Modulation

d.    Yale University
   i.    Effects of Psilocybin in Post-Traumatic Headache
  ii.    Efficacy of Psilocybin in OCD: a Double-Blind, Placebo-Controlled Study
 iii.    Psilocybin-Induced Neuroplasticity in the Treatment of Major Depressive Disorder (in collaboration with Heffter Research Institute)
 iv.    Psilocybin for the Treatment of Cluster Headache (in collaboration with Heffter Research Institute and Cluster Headache-Trigeminal Autonomic Cephalalgia LLC
  v.    Repeat Dosing of Psilocybin in Migraine Headache (with Wallace Research Foundation)
 vi.    Psilocybin for the Treatment of Migraine Headache Yale University

e.    University of Wisconsin
   i.    Adjunctive Effects of Psilocybin and Buprenorphine

f.     University Hospital, Basel, Switzerland
   i.    Effects of SERT Inhibition on the Subjective Response to Psilocybin in Healthy Subjects
  ii.    Direct Comparison of Altered States of Consciousness Induced by LAD and Psilocybin in a Random-order Placebo-controlled Cross-over Study in Healthy Subjects
 iii.    Comparative Acute Effects of LSD, Psilocybin and Mescaline (LPM)

g.    University of Zurich
   i.    Characterization of Altered waking States of Consciousness in Healthy Humans
  ii.    Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients—Proof of Concept
 iii.    Clinical and Mechanistic Effects of Psilocybin in Alcohol Addicted Patients
 iv.    Beyond the Self and Back:  Neuropharmacological Mechanisms Underlying the Dissolution of the Self

h.    COMPASS Pathways
   i.    The Safety and Efficacy of Psilocybin in Participants with Treatment Resistant Depression (P-TRD)

i.    NYU Langone Health
   i.    The Effects of Psilocybin-Facilitated Experience on the Psychology and Effectiveness of Religious Professionals
  ii.    Psilocybin Cancer Anxiety Study

j.    University of Arizona
   i.    Psilocybin for Treatment of Obsessive-Compulsive Disorder

k.    University of Alabama at Birmingham
   i.    Psilocybin-facilitated Treatment of Cocaine Use

l.    Helsinki University
   i.    Psilocybin and Depression

m.    Washington University School of Medicine
   i.    Precision Functional Brain Mapping in Psilocybin (Psilocybin PFM)

n.    Imperial College of London
   i.    Psilocybin vs. Escitalopram for Major Depressive Disorder: Comparative Mechanisms in a randomized Controlled Trial

o.    University of California San Francisco
   i.    Psilocybin-assisted Group Therapy for Demoralization in Long-term AIDS Survivors a Study on Distress, Depression, Grief, HIV/AIDS

 

3.    LSD

a.    University Hospital, Basel, Switzerland
   i.    LSD Therapy for Persons Suffering from Major Depression (LAD)
  ii.    Lysergic Acid Diethlamide (LSD) as Treatment for Cluster Headache (LCH)
 iii.    LSD Treatment in Persons Suffering from Anxiety Symptoms in Severe Somatic Disease or in Psychiatric Anxiety Disorders (LSF-assist)
 iv.    Direct Comparison of Altered States of Consciousness Induced by LSD and Psilocybin in a Random-order Placebo-controlled Cross-over Study in Healthy Subjects
  v.    Effects of MDMA CO-administration on the Response to LSD in Healthy Subjects (LSD-MDMA)
 vi.    Role of Dopamine, Serotonin and 5-HT2A Receptors in Emotion Processing
vii.    Role of the Serotonin 5-HT2A Receptor in LAD-induced Altered States of Consciousness (LDR-Study)

b.    University of Chicago
   i.    Mood Effects of Serotonin Agonists
  ii.    Mood Effects of Serotonin Agonists Extended (MESA-E)

4.    Ketamine
Too many to list! Search: https://clinicaltrials.gov/ct2/results?cond=&term=ketamine&cntry=&state=&city=&dist=

 

 

Author
Yung Park, M.D.

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