Huberman Lab Podcast #93 Summary and Commentary

Podcast Host: Dr. Andrew Huberman (Stanford Associate Professor - brain development, brain plasticity, and neural regeneration and repair fields)
     - Youtube
     - Lab Website
Podcast Guest: Dr. Nolan Williams (Stanford Assistant Professor - synergistic treatments with TMS and psychedelics for treatment of depression and mood disorders)
     - Lab Website

*Subject Recruitment for Dr. William's Lab's Clinical Trial: A bounty on ResearchHub, paid in ResearchCoin, will be attached to incentivize recruitment for this clinical trial. If you apply to be a participant for the clinical trial for treatment of depression and other mood disorders (here on the right side of the page) and if approved you can post a comment with a screenshot of an approval email under the bounty to receive payment. 
     -Current price of ResearchCoin

Overview and Summary

Transcranial magnetic brain stimulation (TMS), namely to the dorsolateral pre-frontal cortex is a viable option to treat depression and mood disorders. Dr. Williams combines TMS with other more novel psychedelic treatments including ibogaine, psilocybin, cannabis, ketamine and DMT. Dr. Williams and Dr. Huberman discuss studies surrounding the efficacy, safety, and future of psychedelic research, as well as what some early mouse studies are pointing towards which is the ability to remove the psychological effects of the drug treatment but maintain the mental illness treating aspect of it. Additional discussions include, the topic of whether or not SSRI's are efficacious, the misconception of a chemical imbalance, ketamine, cannabis (THC/CBD balances), 

Note: In the ethos of Open Science and transparent publication, this is a living document which will undergo continuous improvement. If you have suggestions, expansions, or corrections please feel free to comment in this thread and we will adjust the document as well as award some RSC for your help.

Key Bounties - Discussion and Direction:

The following are bounties related to the topics of the podcast 

1. Bounty: Is there any evidence that “self-talk” can modulate heart rate, particularly in rapid recovery situations such as those detailed in work by Dr. David Burns (see publications and podcasts, available at https://feelinggood.com)? - JCM
2. Bounty: What is our current understanding of how psychedelic trips induce a change in a person's “self-talk” and how does this relate to the “lack of control over inner states?" For this bounty, we are looking for anecdotal and/or peer-reviewed research statements. - JCM
3. Bounty: As changes in heart rate are not indicative of long-term recovery or chronic changes in mood, what might clinicians use as a physiological marker for reduction in baseline anxiety, panic, or depression? Current treatments use self-assessment strategies which are qualitative in nature. For this bounty, we are looking for a discussion around the design of a quantitative, non-invasive marker of mental health rehabilitation. In addition, is there evidence that the proposed metric is hypothetically sound? Please provide a short description for and against this. - JCM
4. Segment 3 Bounty: How well representative of the population is the human connectome? Is this only valid for healthy adult males? - Tyler Diorio
5. Segment 4 Bounty: Could it be that depressive symptoms line up with decreased heart rate variability because depressed individuals employ a coping mechanism of downplaying emotions and neural queues so much so that they train that specific neural pathways to be less reactive to signaling. Whether that be through physical increases in the resistance of the neural pathways (which would be measurable) or through underlying control mechanisms that are being trained under supervision of the conscious, depressed brain (which would require anecdotal evidence through the experiences of depressed individuals) - Tyler Diorio
6. Segment 9 Bounty: Why is the dose for SSRI's almost an order of magnitude higher when attempting to treat OCD vs Depression? - Tyler Diorio
7. Segment 23 Bounty: Does Space Learning Theory support the need for long time frame experiences (> 2-3 hours) for psychedelic compounds, potentially allowing the individual to approach similar topics spaced over 1-1.5 hour rest periods?

Segment 1: Depression, Risk Factors, Emergency Psychiatric Treatments (00:09:16)

1. Depression - can manifest in various forms including 1. loss of interest 2. anxious and over active 3. no motivation and inactive. Depression is listed as the 4th major risk factor for coronary artery disease as listed by the American Heart Association. TMS is able to decelerate the heart rate to probe the brain heart connection in depression.
2. It is very under appreciated how disabling depression is:

“Moderate depression is about as disabling as having a heart attack, acutely having a heart attack.” 
- Dr. Nolan Williams

“Severe depression is as disabling as having cancer without treatment and dying from a cancer without a treatment” 
- Dr. Nolan Williams

Generally in emergency medicine - increases in symptom severity increase the amount of treatments/procedures attempted; in psychiatric disease, as the disease severity increases, the number of treatments go down on average!

Segment 2: The Brain-Heart Connection, Vagus Nerve, Prefrontal Cortex (00:15:11)

Regions of the brain associated with emotion and the heart are connected.Dr. Williams comments on how heart rate modulation associated with transcranial magnetic brain stimulation (TMS) only explains a small percentage of mood shifts. Rather, there is likely “some parasympathetic process” that causes this to happen as change in mood due to TMS is acute and otherwise healthy persons experience similar reduction in heart rate following TMS. Drs. Huberman and Williams speak on the ability to ‘control’ your autonomic nervous system as a ‘hinge' related to the “lack of control over inner states" associated with depression. Of note, this sense of ‘how do we talk to ourselves’ is a keystone of cognitive behavioral therapy (CBT)--a profoundly powerful tool for persons with compulsive and debilitating depressions.

1. Dorsolateral pre-frontal cortex (DLPFC): governor of the brain
   1. Use of magnet pulse to induce electric current through the brain tissue (not skull, scalp or hair) - causes a depolarization of cortical (surface) neurons. In the scanner, this depolarization is due to induced electrical current physically traveling down the brain anterior cingulate, insula, amygdala, …, nucleus tractus soltarius, and ultimately into the vagus nerve and thus the heart. The heart is the end organ of the DLPFC [2-1].
   2. Stimulation of dorsolateral pre-frontal cortex (2-second train of stimulation) causes a repeatable 10-bpm deceleration for 1 second, breaks for 8 seconds, then goes back down in a sinusoidal fashion. Schematic of the brain-heart connection can be found below

Figure 2-1: Map of spatial connections in the frontal-vegal pathway, demonstrating brain-heart connection. Image obtained from [2-1].

References

[2-1] Iseger et al. 2020. “A frontal-vagal network theory for Major Depressive Disorder: Implications for optimizing neuromodulation techniques”. Brain Stimulation. https://www.sciencedirect.com/science/article/pii/S1935861X19304139

Segment 3: Right vs. Left Brain Hemispheres & Mood Balance, Connectome (00:17:51)

Left DLPFC: Strokes on the brain that cause depression have been shown to interrupt the wiring to the left dorsolateral pre-frontal cortex [3-1].

Figure 3-1: Map of overlaid lesions from Grajny et al. 2016 showing locations of most frequent lesion distribution. Image obtained from [3-1].

1. Lesions that cause mania are all commonly connected to the right DLPFC.
   1. Left and right balance mood spatially across the brain.
   2. Either exciting the left or inhibit the right result in anti-depressant outcomes
   3. Exciting the right DLPFC results in anti-manic outcomes
2. Handedness?
   1. 25% Left-handed people are usually right-brain dominant
   2. 1% right handed people have right-brain dominant

References

[3-1] Grajny et al. 2016. “Depression Symptoms in Chronic Left Hemisphere Stroke Are Related to dorsolateral Prefrontal Cortex Damage”. The Journal of Neuropsychiatry and Clinical Neurosciences. https://neuro.psychiatryonline.org/doi/10.1176/appi.neuropsych.16010004

Segment 4: Heart Rate & Depression, Behavioral Interventions, Transcranial Magnetic Stimulation (TMS) (00:22:34) 

Why does left DLPFC slow the heart rate down and alleviate some symptoms of depression? Brachycardia occurs during fear (slowing down of heart rate) rather than speeding up

Do other ways of slowing the heart rate down alleviate depression?

1. Vagus nerve stimulation: Stimulation of the vagus nerve pervade upward through the same track to alleviate depression from the neck!
2. Mindfulness and Meditation: left DLPFC linked to meditation mindfulness, etc.. suggesting that behavior interventions in mild depression work quite well - volitional threshold for depression where you start losing control over some thoughts. This threshold makes it harder and harder for meditation and mindfulness to work. Catatonia is an extremely far gone categorization of depression, far above the threshold for meditation and mindfulness to work.
3. Exercise: seems to be a great treatment for mild depression. Athletes hold a lower resting heart rate than non-athletes and non-active athletes. Not aware of current studies of left DLPFC and exercise but anecdotal evidence suggests it could correlate. A lot of work with heart rate variability and depression with not all positive results but a lot say that lower heart rate variability is associated with moderate to severe depression.

Can we talk ourselves out of a depressive symptom or talk ourselves into a manic situation? Is this a structural thing or a thought-pattern thing?

1. Highly hypnotizable people have highly functionally connections in the left DLPFC to the dorsal anterior cingulate - not much connection in low hypnotizable [4-1]
   1. This is a smaller subcategorization of the larger system of the left DLPFC important for regulating mood
   2. If you knockout the left DLPFC and have people do the Stroop test (where people are tasked with naming the color of words), people perform poorly. Specifically, there is a greater time delay in poorly functioning left DLPFC which was improved through stimulation

Figure 4-1: Example of the original Stroop Test showing the prompts that participants may be given to analyze language processing and ‘rule switching’. Image obtained from [4-2].

References

[4-1] D. Spiegel. 2013. “Tranceformations: hypnosis in brain and body”. Depression and Anxiety. https://pubmed.ncbi.nlm.nih.gov/23423952/

[4-2] Baghdadi et al. 2021. “Neurocognitive Mechanisms of Attention”. Computational Models, Physiology, and Disease States. https://www.sciencedirect.com/topics/neuroscience/stroop-effect

Segment 5: Belief/Identity “Rules”, Re-scripting, TMS & Talk Therapy (00:39:00)

The Stroop Task, shown in Figure 4-1, is like a rule-switching game which forces participants to suppress responses. Depressed people set ‘rules’ for the context of positivity in their lives such as ‘I dress poorly’ but have a hard time contradicting that rule (i.e. telling themselves they look good in the mirror feels like a lie to them). Something about the DLPFC gives flexibility to rules and this is measured indirectly by the Stroop Task.

1. Journaling allows individuals to do a Stroop Test on their emotions
   1. Cognitive behavioral therapy sessions identify these beliefs and determine how fixed or flexible they are. The therapists then help the individuals find another explanation for them and reintegrate the other explanation into their memory. These types of therapy sessions have been shown to work for mild degrees of depression [5-1, 5-2].
   2. TMS really helps people do their therapy quite a bit better (5 sessions in Dr. Nolan Williams studies) and TMS has been shown to works for moderate degrees of depression [5-3].
2. In depressed individuals the anterior cingulate is temporally ahead of the left DLPFC in the signaling cascade, and in the normal controls (no depression) the left DLPFC is temporally in front of the anterior cingulate - in effective treatment, the left DLPFC is in front of the anterior cingulate [5-4].
   1. The temporal ordering of firing really seems to be coordinated with the depressive symptoms. The cingulate finds and identifies conflict and is overactive in depression. The left DLPFC isn't able to clamp down on that cingulate and reign it in from being too dramatic all the time (this is potentially a bad analogy).

References

[5-1] Cladder-Micus et al. 2018.  “Mindfulness-based cognitive therapy for patients with chronic, treatment-resistant depression: A pragmatic randomized controlled trial”. Depression and Anxiety. https://pubmed.ncbi.nlm.nih.gov/30088834/

[5-2] Zhang et al. 2019. "Cognitive behavioral therapy for primary care depression and anxiety: a secondary meta-analytic review using robust variance estimation in meta-regression". Journal of Behavioral Medicine. https://pubmed.ncbi.nlm.nih.gov/31004323/

[5-3] Cole et al. 2022. “Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial”. American Journal of Psychiatry. https://pubmed.ncbi.nlm.nih.gov/34711062/

[5-4] Bartoli et al. 2018. “Temporal Dynamics of Human Frontal and Cingulate Neural Activity During Conflict and Cognitive Control”. Cerebral Cortex. https://pubmed.ncbi.nlm.nih.gov/29028974/

Segment 6: Dorsolateral Prefrontal Cortex, TMS & Depression Treatment (00:45:49)

Can we say that the left DLPFC is the governor of how we interpret physiological signals and spontaneous thoughts?

1. Yes it places the lens that the rest of the brain sees things through.
2. Experiments where you can make healthy people feel a loss of control and the left DLPFC will go offline.
3. TMS trials with Dr. Williams use a fixed 5-day schedule but a lot of individuals are improved by day 3-4 but request to continue doing the TMS because it's been so beneficial to them.
   1. Anecdotally, Dr. Williams notes an increase in patients being able to “be in the present" following TMS

References

Segment 7: Cingulate Cortex & Emotion, Dissociation & Catatonia (00:48:36)

What is mapped in the anterior cingulate? What things in the body and the mind make the cingulate fire?

1. The Stroop Test elicits activity in the anterior cingulate [7-1].
2. For OCD, certain triggers point to the anterior cingulate; Bokor and Anderson 2014 described OCD as involving several brain regions including orbitofrontal cortex, anterior cingulate gyrus, and the basal ganglia [7-2]. They used to do an anterior cingulotomy to treat OCD, which involved inducing a lesion on the dorsal anterior cingulate cortex [7-3]. Modern therapies such as TMS are being used for non-invasive and effect treatments [7-4].
3. There is a spatial orientation to the degree of conflict tasks' emotional component - the more ventral and sub-genual the activation is.
   1. The dorsal component of the anterior cingulate seems to be a pure cognitive, OCD-type of disorder.
   2. Mood disorders, facial expression conflicts
      1. Stroop test for happy face written above a sad face
      2. Peri-genual, sub-genual areas
   3. There are also heart rate and autonomic components to this as well
4. Akinetic mutism - glioma sitting in the interhemispheric fissure putting pressure on the cingulate puts people in a catatonic space [7-5]. Basically if the cingulate can't function, then people can't connect with reality.
   1. Catatonia is an extreme result of depression [7-6] or schizophrenia [7-7]
   2. Dissociation is an extreme or less extreme outcome of PTSD or trauma [7-8]. It is a phenomenon that occurs in highly hypnotizable people sometimes - like a capacity to dissociate.

Fun fact: Andrew Huberman is super hypnotizable

References

[7-1] Swick and Jovanovic 2002. “Anterior cingulate cortex and the Stroop task: neuropsychological evidence for topographic specificity”. Neuropsychologia. https://pubmed.ncbi.nlm.nih.gov/11931927/

[7-2] Bokor and Anderson 2014. “Obsessive-compulsive disorder”. J. Pharm Pract. https://pubmed.ncbi.nlm.nih.gov/24576790/

[7-3] Diering and Bell 1991. “Functional neurosurgery for psychiatric disorders: a historical perspective”. Stereotact Funct Neurosurg. https://pubmed.ncbi.nlm.nih.gov/1842976/

[7-4] Banks et al. 2015. “Neuroanatomical characteristics associated with response to dorsal anterior cingulotomy for obsessive-compulsive disorder”. JAMA Psychiatry. https://pubmed.ncbi.nlm.nih.gov/25536384/

[7-5] Arnts et al. 2020. “On the pathophysiology and treatment of akinetic mutism”. Neurosci Biobehav Rev. https://pubmed.ncbi.nlm.nih.gov/32044373/

[7-6] Bolgov et al. 2022. "The structure of catatonia in depression and depressive-delusional conditions". Zh Nevrol Psikhiatr Im S S Korsakova. https://pubmed.ncbi.nlm.nih.gov/35797200/

[7-7] Walther and Strik 2016. “Catatonia”. CNS Spectr. https://pubmed.ncbi.nlm.nih.gov/27255726/

[7-8] Choi et al. 2017. “The Dissociative Subtype of Posttraumatic Stress Disorder (PTSD) Among Adolescents: Co-Occurring PTSD, Depersonalization/Derealization, and Other Dissociation Symptoms”. J Am Acad Child Adolesc Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29173740/

Segment 8: Ketamine, the Opioid System & Depression; Psychedelic Experience or Biology? (00:54:27)

Popular treatments for depression include ketamine which is a dissociative anesthetic.

1. People can feel distant from their emotions (third-person themselves)

Others include psilocybin and MDMA that lead to the exact opposite state of highly engaged emotionality, heart rate, and sense of self → leading to alleviation of depression. 

How could a drug that induces dissociative states (ketamine) AND a drug that induces hyper-associative states (MDMA) could lead to relief of the same system?

1. Ketamine - The level of dissociation is associated with the therapeutic effect. Necessary but not sufficient to produce a therapeutic effect [8-1]. No psychological change typically means they have less potent anti--depressant benefits.
   1. Study Dr. Williams conducted -  naltrexone (opiate antagonist) [8-2]
      1. 1 pill of 50mg (high dose) naltrexone or 1 pill of placebo (blinded) or typical ketamine therapeutic dose. Participants ultimately received the other type of dose after they relapsed in depression in order to evaluate what effect of blocking the opioid receptor on the antidepressant effect.
      2. If ketamine works on the glutamate system, this would have no effect by naltrexone because naltrexone only works on the opiate system. Ketamine works over multiple areas including the opiate system and the MDMA receptor antagonism in glutamate. If glutamate is driving the anti-depressive effect there should be no effects between the two regions. If the opioid properties of ketamine are necessary for the anti-depressive effect then loss of anti-depressive effect in + naltrexone as opposed to + placebo effect. Dramatic block of anti-depressive effect when naltrexone was given in people who had an anti-depressive effect with ketamine + placebo alone.
      3. TMS study + pain -→ TMS of left DLPFC + naloxone (basically the same function as naltrexone) and they were able to block the anti-pain effects of TMS with an opiate blocker. Therefore the opiate receptor may have a role in mood regulation.
         1. In a study of people with total knee replacement (super painful surgery), people that are depressed have triple the opioid dose around day 4 required to treat the pain.
            1. It could be treating emotional pain as well as physical pain, hence requiring more dosage.
         2. No effect on dissociation in the ketamine trial which challenges the idea that the psychological experience of the psychedelic effect may be all that's necessary to produce an effect. The pharmacology probably does matter since Dr. Williams shows the underlying pharmacology and the state have a role. It is unclear whether you can remove the psychedelic effect and still treat the disease state. There is some animal data to suggest the psychedelic effect may be removable to maintain the same therapeutic effect. [8-3]. This is not to say that the psychedelic effect is useless, but rather it is to identify the degree to which the long term therapeutic shift in disease modulation is attributable to the underlying pharmacological or neural circuitry changes. It is important to separate the variables individually to evaluate the effect of all.

References

[8-1] Corriger and Pickering 2019. “Ketamine and depression: a narrative review” Drug Des Devel Ther. https://pubmed.ncbi.nlm.nih.gov/31695324/

[8-2] Williams et al. 2018. "Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry 175:12. https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2018.18020138

[8-3] Cameron et al. 2020. “A non-hallucinogenic psychadelic analogue with therapeutic potential”. Nature 589, 474-479. https://www.nature.com/articles/s41586-020-3008-z

Segment 9: SSRIs, Serotonin & Depression; Childhood, Chemical Imbalance or Circuit? (01:03:42)

Selective serotonin re-uptake inhibitors. These are powerfully effective in OCD and depression but potentially not in the way we're thinking they're working. There seems to be data that suggest there is no correlation between serotonin levels and depression. 

What could be happening that explains the therapeutic benefit of SSRI's given their potential lack of correlation to serotonin?

1. SSRI's clearly work and are greatly beneficial for depression, OCD, and generalized anxiety/panic. SSRI's cause serotonin to remain in the cleft between neurons which allows for the accumulation of serotonin over time.
2. Brain-derived neurotrophic factors are upregulated by chronic anti-depressive usage and are associated with brain plasticity. The idea is that these drugs work but it just might not be in the way we think. It's not a deficit of serotonin or a chemical imbalance.
3. TMS works really well over 1-5 days but it doesn't induce an upregulation in serotonin [9-1]. This pushes back against the serotonin related hypothesis that posits people have “chemical imbalances”. Psychiatry 3.0 posits that perturbations in brain regions cause circuit level changes that provide therapeutic effect, rather than the ‘chemical imbalances’ that psychiatry 2.0 thought.
4. TMS act on the same brain regions (subgenual default mode network) that psilocybin and ketamine act on. This is highly correctable electrophysiology which means it is highly treatable. Early life experiences do not dictate the cascade of brain circuitry for the rest of life, it is correctable.
   1. It is possible to relapse but the patients never seem to have the terminal life-ending thoughts because they realize the ‘chemical imbalance’ or childhood trauma are treatable. They feel in-control and optimistic still.

References

[9-1] Williams et al. 2021. "Accelerated Neuromodulation Therapy for Obsessive-Compulsive Disorder. Brain Stimulation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114181/

Segment 10: Memories & “Rule” Creation; Psilocybin & “Rule” Resolution (01:13:58)

Synesthesia could be like a Stroop test of sorts where your brain interprets colors, sounds, sights, using alternate areas of perception. In the psychedelic experience, this could be important for affecting the ability of the depressed individuals to change the “Rule” creation laws that govern their thought.

Why would the brain hold on to rules that don't serve use well? We hold onto these memories from an evolutionary perspective in that they allow us to perform in similarly negatively valanced situations. But in the modern world, this doesn't serve us as well.

1. For example: Veterans and PTSD symptoms (i.e. Loud noise triggering hiding and running).

What about psilocybin and related molecules (in terms of their neurochemistry) that allow this novel rule consideration phenomenon? Reconsolidation of a memory in the neuroplastic state of psychedelics could help the memory to rest in one's mind.

References

Segment 11: MDMA & Post-Traumatic Stress Disorder (PTSD) Treatment, Psilocybin & Depression Treatment (01:21:00)

What do these trials show? Are they effective after 1 or 2 sessions? Psilocybin and MDMA

1. MDMA: 1-2 sessions have an anti-PTSD effect outside of the standard assumed ability to recover in individuals with this level of PTSD [11-1, 11-2]. 
   1. 150-175mg is the standard dose repeated once or twice.
   2. ⅔ of people had a clinically significant change in their PTSD. These changes lasted in the range of years for some people, showing long-term changes not just acute alleviations.
   3. Ketamine comparatively only lasts 1.5 weeks.
2. Psilocybin: Relief from depression in ½ to ⅔ of people, depending on their level of treatment resistance as demonstrated from press releases, not from fully published results as of time of video. Very promising when separated from placebo. There was a single-dose (25mg) psilocybin study for treatment-resistant major depression published in Nov. 2022 in New England Journal of Medicine that showed significantly reduced depression scores over a period of 3 weeks [11-3]. Notably, there were adverse events reported in 77% of patients which including headache, nausea, and dizziness; the authors also note explicitly that "suicidal ideation or behavior or self-injury occurred in all dose groups" [11-3].

References

[11-1] Krystal et al. 2021. "Psychotherapy-supported MDMA treatment for PTSD”. Cell Rep Med. https://pubmed.ncbi.nlm.nih.gov/34467253/

[11-2] Mitchell et al. 2021. “MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study”. Nature Med. https://pubmed.ncbi.nlm.nih.gov/33972795/

[11-3] Goodwin et al. 2022. “Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression”. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/36322843/

Segment 12: Is MDMA Neurotoxic?, Drug Purity, Dopamine Surges, Post-MDMA Prolactin (01:24:12)

The study group that first identified that MDMA may be neurotoxic in a study on monkeys later published a follow-up that determined that the first set of studies actually utilized methamphetamine (which is known to be neurotoxic) to the monkeys and not MDMA. Therefore, it was not true that the initial study showed a neurotoxic effect of MDMA. The correction did not make as big of a splash in popular press.

• Attention: I was unable to find the reference for the groups mentioned for the MDMA neurotoxicity study and follow-up publication. The first study showing MDMA neurotoxicity in primates seems to be Ricuarte et al. 1988, published in JAMA, with authors from Johns Hopkins [12-1]. If anyone is able to find the specific references being mentioned, please comment them and I will adjust the document.

Group of individuals that only took MDMA and group of individuals that did not take MDMA. There was no neurocognitive profile differences which proved that MDMA is not damaging. Although this didn't have a pre-post MDMA exposure, it showed a comparative study which is pretty good.

Purity of MDMA substances is guaranteed in clinical studies, but maybe not so much in other settings (raves). There is a reported drop in energy for a few days after using MDMA. Very likely this could have to do with a surge in prolactin subsequent to the big surge of dopamine in MDMA [12-2]. Huge lifts in dopamine also cause huge increases in prolactin which has an effect on libido, energy, and fatigue [12-3].

MDMA is an amphetamine and thus has effects on the dopaminergic system but psilocybin is very much a neutral or lightly dopamine, much more of a serotonergic drug [12-4].

References

[12-1] Ricuarte et al. 1988. “(+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates”. JAMA. https://pubmed.ncbi.nlm.nih.gov/2454332/

[12-2] Hysek et al. 2013. “MDMA enhances emotional empathy and prosocial behavior”. Soc Cogn Affect Neurosci. https://pubmed.ncbi.nlm.nih.gov/24097374/

[12-3] Fitzgerald and Dinan 2008. “Prolactin and dopamine: what is the connection? A review article”. J Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/18477617/

[12-4] Carhart-Harris et al. 2016. “Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study”. Lancet Psychiatry. https://pubmed.ncbi.nlm.nih.gov/27210031/

Segment 13: Psilocybin, Brain Connectivity & Depression Treatment (01:30:38)

Psilocybin being a serotonergic drug operates on the 5HT serotonin 2A receptors [13-1]. What is psilocybin doing in the brain over time? 

1. Psilocybin has been shown to increase global functional connectivity in a double-blind, randomized, counter-balanced, crossover study with 23 healthy participants [13-2]. These healthy participants were given either placebo or 0.2 mg/kg of psilocybin (orally) over 2 test days then underwent MRI scans at 3 time points (20, 40, 70 min post-administration) to view brain connectivity during peak and non-peak effects. The results of Preller et al. 2020 showed that psilocybin reduced associative but increased sensory, brain-wide, and baseline connectivity. Additionally, the psilocybin-associated changes were “correlated in a time-dependent manner with spatial gene expression patterns of the 5-HT_2A (5-hydroxytryptamine 2A) and 5-HT_1A (5-hydroxytryptamine 1A) receptors”.
2. The anti-depressant effects of psilocybin have a specific connectivity change similar to the TMS treatment which is in the connection between the subgenual anterior cingulate and the default mode network [13-3]. Downregulation of connectivity in the negatively valenced, self-representation part of the brain and this same downregulation occurs after psilocybin dose.

References

[13-1] Castro Santos and Gama Marques 2021. “What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review”. Porto Biomed J. https://pubmed.ncbi.nlm.nih.gov/33884324/

[13-2] Preller et al. 2020. “Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity”. Biol Psychiatry. https://pubmed.ncbi.nlm.nih.gov/32111343/

[13-3] Cole et al. 2021. “Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial”. The American Journal of Psychiatry. https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2021.20101429

Segment 14: Exposure Response Prevention: “Letting Go” & Depression Treatment (01:34:53)

Is the untethering from the autonomic system important? i.e. letting go of physical control and leaving the medical professionals in charge of keeping you safe.

1. Exposure and response prevention therapy [14-1]: This is a “letting go” therapy where the individual is exposed to something that triggers the compulsion. It is important to keep the anxiety level to the exposure tolerable, such as leaving the lights on in the car for an hour to show that you don't need to worry about your battery dying all the time if you forget.
2. Studies with psilocybin and MDMA to treat OCD with the same idea of “letting go” runs along the same lines of thinking.
   1. Although I couldn't immediately find a publication on psilocybin/OCD explicitly talking about “letting go” - there was one regarding ketamine (in enantiomer form “esketamine”) by Breeksema et al. 2022 [14-2].

References

[14-1] “Exposure and Response Prevention”. Psychology Today. https://www.psychologytoday.com/us/therapy-types/exposure-and-response-prevention

[14-2] Breeksema et al. 2022. “Holding on or letting go? Patient experiences of control, context, and care in oral esketamine treatment for treatment-resistant depression: A qualitative study”. Front Psychiatry. https://pubmed.ncbi.nlm.nih.gov/36506427/

Segment 15: Normal Spectrums for Mental Health Disorders (01:41:23)

Normal scores for depression is not zero, with some sadness being considered as absolutely normal. The Montgomery-Asberg Depression Rating Scale (MADRS) is clinically user in adults 18-years or older [15-1]. The cutoff points for the scale are, as curated by [15-2]:

• 0 to 6 – normal [15-4] /symptom absent [15-3]
• 7 to 19 – mild depression [15-3, 15-4]
• 20 to 34 – moderate depression [15-4]
• >34 – severe depression [15-4]

Anecdotally from Dr. Williams, the MADRS scores of 0-10 is the normal range and same on the OCD scale, with mildly abnormal around the 10. Psychiatric diagnosis is when it severely impacts your ability to function. It really is a range of the disease spectrum where some degree of OCD, depression, etc. is within the normal range if it doesn't impair your life but when it starts to affect life and the ability to function then it gets diagnosed.

References

[15-1] “Montgomery-Asberg Depression Rating Scale (MADRS)”. MDCalc. https://www.mdcalc.com/calc/4058/montgomery-asberg-depression-rating-scale-madrs#why-use

[15-2] “Montgomery–Åsberg Depression Rating Scale”. Wikipedia. 17 October 2022. https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale

[15-3] Muller-Thomsen et al. 2005. “Detecting depression in Alzheimer's disease: evaluation of four different scales”. Archives of Clinical Neuropsychology. https://academic.oup.com/acn/article/20/2/271/2760?login=false

[15-4] Herrman et al. 1998. “The Sunnybrook Stroke Study: A Prospective Study of Depressive Symptoms and Functional Outcome”. Stroke. https://www.ahajournals.org/doi/10.1161/01.STR.29.3.618

Segment 16: Ibogaine & “Life Review”; PTSD, Depression & Clinical Trials (01:45:35)

What is ibogaine? 

1. Ibogaine is an alkyloid that you can extract from an Iboga tree root bark which typically grows in Gaban, Africa [16-2]. Bwiti religious/sacramental group uses Iboga root bark as part of their scarement.
2. Psilocybin/LSD cause visual hallucinations but ibogaine doesn't do this. Open eyes they don't see anything but closed eyes they can see previous memories in a place of empathy (detached from self), like a third-party viewing.
3. Ibogaine is not a recreational substance even if you want it to be. It is like 10-years of psychotherapy in a night - like a whole life review.
4. Duration can be 24-36 hours. Super long time, longest lasting psychadelic substance that Dr. Williams knows.
5. Seems to be the most powerful and potent psychadelic, but also the most dangerous one because of the cardiac effect that it has. There is no recreational use of ibogaine. People describe it as relieving but hard work.
   1. The 2016 case study by Meisner et al. describes an ibogaine-associated cardiac arrest and death [16-3].

What does this have to do with the Toad? 

1. People were taking ibogaine then 5-MEO DMT (which is the association with the Frog), which produces a psychadelic effect. 5-MEO lasts longer than traditional DMT. These were two completely seperate sessions where ibogaine was first, then they would return later for the 5-MEO DMT trip. This is supportive psychotherapy where there are sessions before and after. During the trip, there is little interaction but there is a sitter with them providing any help that's needed, but the internal reconsolidation of the drug seems important. I was able to find two studies that seemed to follow the description provided in the Podcast but not directly cited, e.g. Barsuglia et al. 2018 and Davis et al. 2020:
   1. Barsuglia et al. 2018 did a case report on sequential administration of Ibogaine and 5-MEO DMT [16-4]. Results showed that the patient reported “improvement in mood, cessation of alcohol use and reduced cravings at 5-days post-treatment” with effects sustained around 1-month and “partial return to mild alcohol use at 2-months". 
   2. Additionally, Davis et al. 2020 demonstrated reductions of cognitive impairment, symptoms of PTSD, depression, and anxiety, in a study of 51 U.S Special Operations Forces Veterans [16-5]. This study was conducted in Mexico and appeared to be quite thorough, so I will describe the methodology as follows: The study involved 2 screening protocols to confirm no contraindicated substances were present (urine toxicology and alcohol tests). On day 1, participants were administered a single dose of ibogaine hydrochloride (10 mg/kg)  in a group setting of 4-5 participants. Following administration, participants laid supine and received continuous cardiac monitoring, IV fluids, and medical attention for the duration of the ibogaine session. On day 2, participants were encouraged to process their experience and speak with others, including psychological support staff. On day 3, participants were individually prepared then individually administered 5-MEI DMT in at least three doses: 5mg, 15mg, and 30mg (total=50mg). If participants did not reach observed effects of altered consciousness or emotional catharsis then a fourth dose of 30mg was administered and potentially a fifth dose up to 45 mg.

Note: The book by Daniel Pinchbeck mentioned by Dr. Huberman has been linked below in [16-1].

References

[16-1] Pinchbeck, Daniel. 2002. Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism. Broadway Books. ISBN 0-7679-0742-6.

[16-2] Wasko et al. 2018. “DARK Classics in Chemical Neuroscience: Ibogaine”. ACS Chem Neurosci. https://pubmed.ncbi.nlm.nih.gov/30216039/

[16-3] Meisner et al. 2016. “Ibogaine-associated cardiac arrest and death: case report and review of the literature”. Ther Adv Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/27141291/

[16-4] Barsuglia et al. 2018. “A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder”. Prog Brain Res. https://pubmed.ncbi.nlm.nih.gov/30471678/

[16-5] Davis et al. 2020. “Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans”. Chronic Stress. https://pubmed.ncbi.nlm.nih.gov/32704581/

Segment 17: Clinical Use of Psychedelics (01:57:16)

What is it used for clinically? 

1. Reconsolidation of memories.
2. First clinical study of Ibogaine happening right now under Dr. Williams which appears to be investigating the effects on a population exposed to previous traumatic brain injury, according to the Clinical Trial summary [17-1]. Anecdotally, Dr. Williams has not seen any cardiac issue so far in his cohort at the time of the Podcast. The study is estimated to conclude in August 2023 with a total of 30 participants.

Should ibogaine be recreational?

1. In the experience of Dr. Williams and others in the field, Ibogaine should not be used recreationally because they are too powerful for recreational use. They put you in these states of serious retrospection that should be clinically maintained and under medical supervision.

References

[17-1] “An Observational Pre-post Study Evaluating the Safety of Tabernanthe Iboga Exposure”. U.S. National Library of Medicine: ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT04313712?term=Nolan+Williams&draw=2

Segment 18: Ayahuasca, Brazilian Prisoner Study (02:01:59)

Ayahuasca is a sacramental psychadelic in Brazil, Peru, Ecuador, and other South American countries. It is a two plant combination, whose individual parts do little without the combination. Out of 20,000 plants in the forest, these two specifically being combined results in a potent psychadelic. Cooking it for 5-10 hours removes the DMT from one of the plants and the reversible monoamine oxidase inhibitor from the other plant - such that the reversible monoamine oxidase inhibitor prevents the GI breakdown of DMT and thus allows it to make it to the brain. Therefore, without the reversible monoamine oxidase inhibitor, it would never cross the blood brain barrier and cause a hallucinogenic effect. If it wasn't a reversible inhibitor, then it would throw you into a serotonin syndrome [18-1]. Dr. Williams describes ayahuasca as very safe, and describes small children who have been exposed to small doses in tribal settings have no neurocognitive deficit as assessed by a psychiatrist from UCLA Harbor. There have also been some studies that have evaluated ayahuasca as an antidepressant agent [18-2, 18-3].

Brazilian Prisoner Study

The Brazilian Prisoner study, as described by Dr. Williams and Dr. Huberman, seems to have began around 2015 although I had trouble locating good sources for the study. From what they said, it appears that half of the prisoners were given inert substance and half were given ayahuasca. They describe that the study found statistically significantly lower recidivism rate for prisoners given ayahuasca than those given inert substance. Here are two potential references I found that may describe the study they're referring to: [18-4] [18-5].

References

[18-1] “Serotonin syndrome”. Mayo Clinic. January 22 2022. https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758

[18-2] Palhano-Fontes et al. 2019. “Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial”. Psychol Med. https://pubmed.ncbi.nlm.nih.gov/29903051/

[18-3] Faria Sanches et al. 2016. “Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study”. J Clin Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/26650973/

[18-4] “In Brazil, Some Inmates Get Therapy with Hallucinogenic Tea”. New York Times. March 2015: https://www.nytimes.com/2015/03/29/world/americas/a-hallucinogenic-tea-time-for-some-brazilian-prisoners.html?smid=tw-share

[18-5] Aaron, Kase.“Brazil Offers Ayahuasca To Violent crime Inmates on Their Path to Redemption”. https://reset.me/story/brazil-offers-ayahuasca-to-violent-crime-inmates-on-their-path-to-redemption/

Segment 19: Cannabis: THC, CBD & Psychosis, Clinical Uses (02:06:55)

Dr. Williams and Dr. Huberman mentioned a Lancet psychology report on 18-20 yr old subjects' use of cannabis that demonstrated the exacerbation of psychosis in later life by cannabis use. There were counter points regarding the tendency of those users to seek pharmacologically-mediated help however the effect size was large as pointed out by Dr. Huberman. Although I was unable to determine exactly which report they were referring to, I've gathered two potential reports from Lancet including [19-1] Di Forti et al. 2015 which found that high potency cannabis in South London might have resulted in greater numbers of first onset psychosis in 18-65 year olds than previous studies; and [19-2] Crow 2015, which found that in a 15-year follow-up of 45,570 conscripts in the Swedish army there were 21 cases of schizophrenia among the 752 who had taken cannabis >50 times; this represented a 6x increased relative risk and the authors note that the schizophrenia was not found at age 21 but the individuals were 3x more at risk of other psychiatric diagnosis.

For more information on cannabis and psychosis, there was a thorough review article published in 2018 by Bettina Ortiz-Medina et al. that assessed 66 papers (23 cohort trials and 43 reviews) and concluded that Cannabis roughly doubles the risk of developing psychosis in vulnerable people [19-3]

The two primary chemicals involved in Cannabis are Tetrahydrocannabinol (THC) and Cannabidiol (CBD). There is a THC-free cannabis strain (Charlotte's Web). CBD at high doses is anti-psychotic and anti-schizophrenic. CBD has been bred out of cannabis over time for THC content, but THC is pro-psychotic and pro-schizophrenic. High doses of THC has driven some individuals to psychosis for short periods of time, and once the THC clears from their system the psychosis resolves. The balance of THC and CBD matters critically in the balance of psychotic and schizophrenic downstream effects. CBD was given to children who have severe, seizures and was shown to help with symptoms when other treatments (barbiturates, bromide) were ineffective. However, high THC load in adolescents before pre-frontal maturation (approx. < 25 years) may have some role of developing psychosis. Adolescents and children who have not experienced pre-frontal maturation should not be exposed to THC-containing substances including cannabis for the potential to develop psychosis in adult life. 

References

[19-1] Di Forti et al. 2015. “Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study”. Lancet Psychiatry. https://pubmed.ncbi.nlm.nih.gov/26359901/

[19-2] Crow 2015. “Cannabis and Psychosis”. Lancet Psychiatry. https://pubmed.ncbi.nlm.nih.gov/26360274/

[19-3] Bettina Ortiz-Medina et al. 2018. “Cannabis consumption and psychosis or schizophrenia development." Int J Soc Psychiatry. https://pubmed.ncbi.nlm.nih.gov/30442059/

Segment 20: Personal Relative Drug Risk & Alcohol (02:14:52)

Alcohol is ranked number one as the most dangerous drug in the world, ahead of cocaine, heroine, and other drugs in it's harm to others [20-1]. Dr. Williams thinks there is a chance that alcohol follows a similar path to smoking, where a threshold moment will allow prompt universities and hospitals to remove/prohibit alcohol consumption due to it's highly negative effects on human health as well as it's danger ranking. 

References

[20-1] Nutt et al. 2010. “Drug harms in the UK: a multicriteria decision analysis”. The Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61462-6/fulltext

Segment 21: Circadian Reset for Depression, Sleep Deprivation, Light (02:20:42)

The foundation of mental health, physical health, and high performance is to try to get enough quality deep sleep for 80% of the nights of your life, just like exercise and good social behavior. 

Triple Therapy:

Dr. Greg Sahlem, who is a professor at Stanford, has done a lot of work with sleep, particularly sleep deprivation. One night of sleep deprivation will have an anti-depressant effect but after the following night of sleep, they come into the same level of initial depression. Insomnia is highly related to depression, with symptoms of depression having a range of sleep disruptive effects. The triple therapy involves sleep depriving an individual, then shifting their phase of sleep, and simultaneously exposing them to bright light in an attempt to re-entrain their circadian rhythm [21-1]. From the Triple Therapy trials, there was a fairly durable and profound anti-depressant effect. This should not be done at home due to the complexities involved, as noted by Dr. Williams. Sleep deprivation is a profound anxiety agent and thus should be done under medical supervision. 

References

[21-1] Sahlem et al. 2014. “Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study”. Journal of Psychiatric Research. https://www.sciencedirect.com/science/article/pii/S0022395614002519?via%3Dihub

Segment 22: Stanford Neuromodulation Therapy (SNT) Study (02:28:43)

TMS studies for treating depression have been done since around 1995 [22-1] and FDA clearance has been granted for TMS treatments around 2008 [22-2]. Before precision instruments, researchers were using rulers to approximate left DLPFC and ice to keep the coil at low temperatures but still able to engineer the stimulation. 

The Stanford Neuromodulation Therapy (SNT) study uses TMS as a device to deliver a treatment [22-3]. The treatment is the protocol of stimulation parameter set in a specific brain region for each specific condition. This means that different conditions can be treated by using the same TMS device to deliver a different treatment, i.e. different parameters to a different brain region. Condition-specific and patient-specific treatment regimens are the future of TMS, and are actively discussed in literature such as Cash et al. 2020 which describe the identification of a target for use in all patients as well as a personalized target for each individual patient [22-4]. 

References

[22-1] George et al. 1995. “Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression”. Neuroreport. https://pubmed.ncbi.nlm.nih.gov/8547583/

[22-2] Horvath et al. 2010. “The NeuroStar TMS device: conducting the FDA approved protocol for treatment of depression”. J vis Exp. https://pubmed.ncbi.nlm.nih.gov/21189465/

[22-3] Cole et al. 2022. “Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial”. American Journal of Psychiatry. https://pubmed.ncbi.nlm.nih.gov/34711062/

[22-4] Cash et al. 2020. “Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression”. Biol Psychiatry. https://pubmed.ncbi.nlm.nih.gov/32800379/

Segment 23: Space Learning Theory & TMS Stimulation (02:34:25)

The stimulation protocol can be modified but run through the same TMS device. In 2005 a group published a paper in Neuron to demonstrate that if you stimulate with the Hippocampal rhythms through a TMS coil, you can excite the brain with memory rhythms and it lasts an hour. Although I'm not certain this is the exact publication mentioned by Dr. Williams, Huang et al. 2005 published on a related topic in Neuron [23-1] and Paulus 2005 [23-2] also published a commentary on the results of Huang et al. 2005, pointing at it's impact. Other groups next looked to implement 6-week schedules for repeated TMS programs. Interestingly, groups are working on optimizing and reorganizing the time-course of the treatment approach by using Space Learning Theory. 

Space Learning Theory is a psychological nuance best explained by the following example:

• If I am cramming for a text, I write out 60 note cards, each for a minute until I get back to the first notecard - about 1 hour later. We do this because writing 1 note card and looking at it over and over again, doesn't work. This is because Space Learning theory posits that you need to see something about once every hour in order to learn it effectively.

Space Learning Theory has been applied to TMS by altering the time-course of stimulation to align with our psychological nuances. To put it more clearly, by theta-burst stimulating a hippocampal slice (from a mouse in the example study), you will induce some enlarged dendritic spines and some primed dendritic spines. Interestingly, if you re-stimulate immediately after you will see very little if any change, but if you wait 1-1.5 hours you get even more enlarged and even more primed dendritic spines. Dr. Williams used this Space Learning Theory to reorganize 6-weeks of TMS to properly fit into 1-day and 9-months of TMS in 5-days, where each day is roughly 10-hours of temporally spaced 9-minute sessions and it abides by the 1-1.5 rest time.  60-90% of the time, patients will go into total remission quantified as a normal mood by the end of session. Some remission ranges as verbalized by Dr. Williams range from 1-year to 4-years.

Fun Fact: Ketamine also causes the same enlargement and increased priming of dendritic spines as theta stimulation by Space Learning Theory spacing in time.

References

[23-1] Huang et al. 2005. “Theta burst stimulation of the human motor cortex”. Neuron. https://pubmed.ncbi.nlm.nih.gov/15664172/

[23-2] Paulus 2005. “Toward establishing a therapeutic window for rTMS by theta burst stimulation”. Neuron. https://pubmed.ncbi.nlm.nih.gov/15664167/