The New Frontiers of Mental Health — Brain Stimulation, Rapid-Acting Tools for Depression, and More

How SAINT helped Deirdre Lehman

• Deirdre, a bipolar patient, experienced severe depression and was treated with rapid-acting neurostimulation approach (SAINT).
• Initially in very bad shape, she was treated within 24 hours and showed no depression or suicidality.

Typical vs. atypical sequences of activation

• Resting state functional connectivity MRI reveals the timing and sequence of brain region activation.
• In depressed patients, the sequence is atypical, with the singulate cortex temporally preceding the dorsolateral prefrontal cortex in 70% of cases.
• Patients who responded to SAINT had biomarker and brain changes, indicating potential for predictive testing.

Psychiatry paradigms

• Historical eras of psychiatry identified as Psychiatry 1.0, 2.0, and 3.0
• Psychiatry 1.0 focused on life experiences and psychotherapy
• Psychiatry 2.0 introduced the use of antipsychotics and antidepressants, leading to a shift away from the belief in a purely chemical imbalance for psychiatric disorders
• Psychiatry 3.0 focuses on the concept of mental disorders as circuit problems, providing a shift towards addressing miswiring and misfiring issues

The development of SAINT

• SAINT (Stanford Accelerated Intelligent Neuromodulation Therapy) was developed as a form of neuromodulation therapy
• SAINT reorganized conventional Transcranial Magnetic Stimulation (TMS) in time and space
• Conventional TMS used average skull positions to stimulate, which was less efficient and utilized a less effective approach
• SAINT utilized a higher efficiency signal and more targeted stimulation, aiming to influence brain activity more effectively

Empowerment through rapid-acting neuromodulation

• Rapid-acting neuromodulation provides an alternative option for individuals struggling with suicidal ideation and depression
• The quick and durable relief provided by rapid-acting neuromodulation therapy empowers individuals by offering a plan B and a sense of hope
• Patients feel empowered and in control of their mental health, reducing the feeling of hopelessness and offering a way out of depression

TMS vs. ECT

• TMS (Transcranial Magnetic Stimulation) and ECT (Electroconvulsive Therapy) are different treatments.
• ECT aims to produce a therapeutic seizure, while TMS does not.
• TMS is non-invasive and does not require anesthesia, making it suitable for outpatient settings.

Rewards and risks of shortening treatment timeframe

• Conventional TMS treatment is slow and not suitable for psychiatric emergencies.
• Shortening the treatment timeframe by compressing sessions into a single day has been explored successfully.
• This approach has shown the potential to achieve remission in a shorter timeframe and allow people to return to work or regular activities sooner.

Numbers treated and common side-effects

• More than 400 to 500 people have undergone accelerated TMS treatment.
• Common side-effects include headaches, fatigue, and facial muscle activation, which can lead to an anti-pain effect in the long term.
• TMS may also have potential in addressing chronic pain through the release of endogenous opioids.

Patient demographics

• Participants in the trial had an average of 9 years of current depressive episode
• They had 5+/-2 medication failures and a lifetime load of depression of about 25 years
• The study observed a correlation between flipping of the signal and higher depression scores
• The intervention was more effective for those with a more advanced stage of depression
• The treatment was found to be more effective for those with impaired attention

Observed benefits of SAINT over more conventional treatments

• In the original pilot study, 90% of participants experienced remission
• In the randomized control trial, 79% of people experienced remission at some point in the four-week follow-up
• There is a subpopulation of patients that has a slower time to remission, especially in older adults
• TMS is a probe of the system and can provide insights into neuroanatomy and condition-specific responses
• There is a need to identify a subgroup of patients with different neuroanatomy similar to Parkinson's disease

Adapting treatment when symptoms prove misleading

• There is an ongoing effort in psychiatry to parse depression into different categories or biotypes
• Clinically identifying different biotypes can aid in prescribing more tailored treatment
• This approach can potentially reduce the time, risk, and cost associated with diagnosis and treatment
• In bipolar depression, it takes an average of years to diagnose the condition, leading to prolonged uncertainty and treatment search

Where to find current open trials

• Trials are ongoing at the Stanford brain stimulation lab for various conditions, such as anodic depression, obsessive-compulsive disorder, bipolar depression, and addiction
• Interested individuals can find more information and enroll through the lab's website
• Participation in the trials is free and funded through the research studies
• The trials typically require a commitment of a couple of weeks

SAINT remission numbers versus those of alternative therapies

• STARD D study suggests low remission rates for conventional treatments
• Conventional TMS shows higher remission rates than oral antidepressants and other therapies
• Conventional TMS efficacy decreases with higher treatment resistance levels
• Accelerated TMS showed higher remission rates compared to conventional TMS
• Ketamine produces rapid remission rates with single infusion and increases with additional treatments
• Other emerging treatments like ketamine Cy and other psychedelic drugs are being researched

Delayed remission speculation

• Some patients experienced delayed remission with accelerated TMS
• Ketamine is rapid-acting, while SSRIs may have delayed onset of benefits
• Speculation suggests older adults may have reduced brain plasticity affecting accelerated TMS results
• Study involves scanning participants to understand the mechanisms behind delayed remission

How Nolan became The Ibogaine Bachelorette

• Researcher partnered with veterans' non-profit for ibogaine trial
• Approval process involved IRB for ethical and safety considerations
• Researcher's open-minded approach to exploring different treatments, including ibogaine
• Ibogaine has a one in 300 risk of fatal arrhythmia, causing stigma and bias in the research community

The origin of Nolan’s interest in ibogaine

• Nolan came across ibogaine while stuck in the San Salvador airport and read a book by Daniel Pinch.
• He found the book Breaking Open the Head very informative and intriguing.

Amazing results of the quickest-recruiting study Nolan has ever run

• Nolan conducted a study with Veterans having traumatic brain injury and depression, which yielded unexpectedly positive outcomes.
• The study got published in Nature Medicine, a prestigious journal, and has received attention for its results.

Dealing with alexithymia and self-reporting inaccuracies in research

• There is a challenge in psychedelic trials with patients accurately reporting their treatment experience and symptoms.
• Nolan discusses the difficulty of accurately measuring mood in patients with alexithymia and the need for careful clinical assessment.

Ibogaine research gets federal funding (approved since this conversation took place)!

• Nolan mentions that federal funding for ibogaine trials has been approved in the National Defense Authorization Act, recognizing the potential of psychedelic therapy for the military community.
• He highlights the importance of research validation and the hope for increased focus and funding in this area.

Isolating the ibogaine effect

• The study presented in Nature Medicine focused solely on the effects of ibogaine and isolated its impact from other potential influences like 5m DMT, which is often used in conjunction with ibogaine in some settings.

The value of life review on ibogaine

• Ibogaine produces a stereotyped trip with a replay of emotionally salient memories
• The replay occurs as a Life review or slideshow, shaping the mind and providing insights into one's own reasons and the reasons of others
• It enables a cathartic re-evaluation and understanding of traumatic memories, often related to childhood trauma
• Ibogaine enables a profound or cathartic effect, potentially improving traumatic brain injury and facilitating a reconsolidation of problematic memories

How ibogaine differs from other psychedelic treatments

• Ibogaine's effects differ from classic psychedelics like psilocybin or ayahuasca, mainly affecting a broad range of receptor systems and upregulating brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF)
• It affects 5-HT2A receptors to a lesser extent and is termed as a "neurogen" or atypical psychedelic due to its dreamlike state and broad receptor system effects
• Limited studies have shown its potential in treating alcohol addiction, possibly attributed to the upregulation of GDNF in the dopamine system

The challenge behind synthesizing naturally occurring compounds

• Ibogaine's unique and complex effects make it difficult to replicate synthetically, as it interacts with multiple neurotransmitter systems and produces a symphony-like effect
• Its promiscuous nature and simultaneous effects on important ratios make it sophisticated, challenging to reproduce through synthetic means
• Understanding and studying ibogaine will require advanced neuroscience tools to capture its effects in real-time

Coping with ibogaine’s cardiac risks(01:24:55)

• Improving the safety profile of ibogaine is a critical question
• Potential risks need to be compared to existing risks of the specific individual
• Modifications to the ibogaine molecule to reduce cardiac risks
• Introducing IV magnesium as treatment for potential heart rhythm issues
• Use of monitored cardiac bed and involvement of cardiologists in administration

Understanding habitual action through ibogaine, Ozempic, caffeine, and alcohol. (01:32:56)

• There is no evidence of a direct overlap in mechanism between drugs designed for type 2 diabetics and drugs for psych addictions
• Drugs like semaglutide and OIC are having an effect on various types of cravings, leading to societal ripple effects
• In a trial involving ibogaine, participants quit their caffeine intake, which put a pause between stimulus and response, creating a moment of unbiased choice
• Ibogaine seems to introduce a level of choice and a period of time between habitual actions, potentially affecting habits differently than drugs like OIC

Ibogaine for TBI. (01:39:17)

• Ibogaine might have a role in traumatic brain injury (TBI), as it seemed to lead to a dramatic improvement in TBI disability in a mixed population
• The mechanism of action for this improvement is not well understood but may involve interacting with multiple neurotransmitter systems simultaneously
• It is suggested that a pure TBI population, such as football players, could be studied to further explore the potential role of ibogaine

Ibogaine for alleviating opioid withdrawal symptoms. (01:43:48)

• Ibogaine can attenuate or blunt the physical withdrawal symptoms of opioid withdrawal, such as diarrhea, headache, and sweating
• This effect is unique to ibogaine and not found in other psychedelics or drugs like ketamine
• Ibogaine's broad efficacy across various psychiatric diagnoses makes it important for the scientific community to thoroughly understand its mechanisms

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Ibogaine in Kentucky

• A group in Kentucky is considering using lawsuit money for opiate overprescription to fund novel therapeutics, not just conventional treatments.
• Conventional treatments for opiate use disorder include replacement therapy, opiate blocking drugs, and brain surgery for treatment-resistant patients.
• The group is exploring deep brain stimulation (DBS) as a potential treatment for opiate use disorder, which involves surgically implanting a device into the reward system to reduce pleasure from opiates.
• There are concerns about the risks associated with DBS and using ibogaine, an extract from a root in an African country, as potential treatments.
• The debate in Kentucky revolves around whether the money should be used for these novel therapies and whether they should be studied further.

Weighing ethics with potential outcomes in research

• Ethical and funding approval for studies on extended fasts in humans depends on whether the benefits significantly outweigh the risks.
• An example is provided where the risk of harm outweighs the benefit, making the trial ethically unjustified.
• Research on extended fasts in humans has been limited, despite studies being conducted in animals, with potential justifications around metabolic psychiatry and exploring the effects of fasting on certain psychiatric conditions.

Can ibogaine be sourced (or synthesized) sustainably?

• Rachel Nuwer wrote a National Geographic article on the implications of global demand for ibogaine and iboga, pointing out the ethical issues of extraction from iboga trees.
• Ibogaine can be sourced through extraction from a tree in Ghana and other places in Africa containing a voan gene, or through a simple chemical synthesis pathway.
• Full chemical synthesis of ibogaine is challenging due to its complex chemistry with two chiral centers.
• There is interest in finding a sustainable method that does not rely on tree extraction.

Does 5-MeO-DMT complement ibogaine enough to justify its collection?

• 5-MeO-DMT is present in various plants and nuts, commonly known within the context of Bufo alvarius (desert toad).
• The practical use of 5-MeO-DMT following ibogaine administration is known as the "gray day," which can involve depressive symptoms and anxiety.
• 5-MeO-DMT seems to take the edge off the "gray day," potentially bridging people out of a difficult period following ibogaine administration.
• The use of 5-MeO-DMT alongside ibogaine raises questions about its long-term effect, potential benefits, and FDA regulatory complexity.
• The complexity of assessing the therapeutic benefits of 5-MeO-DMT paired with ibogaine poses challenges, and the clinical use of 5-MeO-DMT alongside ibogaine is currently based on anecdotal evidence.

What might Psychiatry 4.0 look like? (02:11:04)

• Speculation on future of psychiatry, potential use of focused ultrasound for deep brain stimulation
• Discussion on current broad tools for brain stimulation and neurotransmitter focus
• Example of patient undergoing deep brain stimulation experiencing changes in musical taste
• Predictions about potential future ability to manipulate specific content in the brain
• Application of neurostimulation to change trait hypnotizability
• Exploration of using nanotechnology to deliver ketamine and other psychedelics to specific brain regions

Could we develop therapies to change hand dominance? (02:19:35)

• Discusses challenges and possibilities of changing hand dominance
• Examples of constraint therapy and brain reorganization in stroke patients
• Speculation on potential for changing critical periods and brain plasticity for neuro rehabilitation
• Interest in disrupting and exploring spaces where fewer people are working, such as using psychedelic drugs for treating neuro deficits

Boosting Performance

• Reports of increased visual acuity and color contrast with certain psychedelics
• Athletes have reported performance-enhancing benefits from some psychedelics
• Possibility of using neuromodulation for hard-to-detect performance enhancement in sports
• Patients in the study reported remission of symptoms after using brain stimulation and rapid-acting tools for depression
• Patients experienced being present in the moment and increased mindfulness after treatment