Clinic of the Future Part IV: A Brief Primer on Emergent Neurotechnologies

And some final thoughts on the FDA Decision

Throughout writing these dispatches over the last few years, my mental model of the psychedelic space has been underwritten by the assumption that then MAPS, now Lykos Therapeutics, had FDA approval in the bag.

As a close observer/participant, it is humbling to have not hedged my intuitions differently. So, I want to quickly share my learning and the update to my model so that perhaps you can, too.

1. Question Claims and Seek a Greater Understanding of Risk

   1. I should have pressed Rick during our conversation for the podcast about the potential points of failure of promising progress markers like Breakthrough Therapy Designation and Special Protocol Assessment. 

   2. I wish I had recognized that a Non-Directed, Transpersonal-inspired therapeutic modality with no scientific track record would be an issue for an ostensibly evidenced-based process.

2. Don’t Underestimate the Power of Narratives

   1. Based on rumors of allegations—rather than actual allegations—both the ICER Committee and FDA Advisory Committee had no choice but to assume that sexual misconduct extended beyond the well-documented, reported, and acknowledged case of sexual abuse by study therapist Richard Yensen.

3. The Overton Window¹ is Opaque

   1. Studying the ‘psychedelic renaissance’ is a great example of the relationship between scientific progress/innovation and the friction of social inertia (regulation, cultural perception, adoption, etc.). The view from inside the bubble is not the view from outside the bubble—I thought psychedelics had made more cultural and political progress than they have².

As a matter of cultural adoption, scientific inquiry, and clinical application, psychedelics are still extremely promising; however, ‘The Last Mile’ will be longer than expected.

I’m curious if this resonates with readers. Let me know what you think in the comments or by replying to this email.

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Before the FDA decision, I had been brainstorming ideas for a series I am calling The Clinic of the Future, which orients promising, emergent treatments and frameworks according to four domains:

• Relational: the intentional and supportive relationship with clinicians, therapists, family, peers, community, and network.

• Experiential: interventions and practices that create acute subjective and sensate experiences that catalyze systemwide updates (altered states, exposure therapy, thermal therapy, schema surgery, etc.).

• Energetic: the growing number of neuromodulation tools that stimulate neural tissue (brain, vagus nerve, peripheral nerves, etc.) with a precise dosage of energy (i.e., transcranial-focused ultrasound).

• Metabolic: the innate connection between metabolic processes and subjective well-being (i.e., ketogenic therapy for psychiatric conditions).

My thesis is that the pinnacle of care will be a multimodal, collaborative, and holistic combination of two or more categories.

In Part II & III, we covered the Relational and Experiential domains. 

Today, we’ll look at the Energetic.

Emergent Neurotechnology

Some of you will be disgusted by how I use the term ‘energetic’ and I don’t blame you.  

Not Qi, Prana, life force, or inner healing intelligence…but Neurostimulation. 

In another dispatch, I’ll explain why I think Qi, Prana, etc., are better situated in the ‘Experiential’ or ‘Relational’ categories and why ‘entropy’ is probably a better word than ‘energy’ for what these ancient concepts are pointing to and how we can integrate them into modern practice. To be sure, I am not castigating these terms as nonsense as many do (quite the opposite).

But for now, let’s focus on neurostimulation.

From Wikipedia:

Neurostimulation refers to the purposeful modulation of nervous system activity using invasive or non-invasive means to deliver electrical, magnetic, or other forms of energy to specific neural targets.

The field of neurotechnology is undergoing an inflection point as new techniques move from the lab to clinical trials and clinics.

Techniques like Transcranial Magnetic Stimulation, Deep Brain Stimulation, Spinal Cord Stimulators, and Peripheral Nerve Stimulators have been around for a while but the new developments are particularly promising.

While most of the attention, fascination, and trepidation has been with invasive approaches—most notably Brain-Computer Interface (BCI) from Neuralink, Elon Musk’s company—here, I want to focus on another emergent technology that feels more clinically realistic and promising—a non-invasive approach called Transcranial Focused Ultrasound (tFUS).

Transcranial Focused Ultrasound

tFUS is a non-invasive form of neurostimulation that uses ultrasound waves to target tissue deep within the brain.

As the name suggests, the procedure involves passing ultrasound waves through the skull to reach specific brain regions to modulate neural activity.

Unlike traditional ultrasound, which has been used as an imaging tool for decades, tFUS focuses ultrasound waves to a precise point, allowing for targeted stimulation.

The result of this stimulation is the controlled modulation of neural activity in a specific region of the brain, an intervention that is proving beneficial for several stubborn conditions like Parkinson’s, Alzheimer’s as well as several psychiatric conditions.

Here is a picture of what the procedure looks like from the Institute for Advanced Consciousness Research website:

TMS vs. tFUS

The proposed critical advantages of tFUS compared to other brain stimulation modalities like transcranial magnetic stimulation (TMS) include:

• Spatial resolution

• Depth of penetration 

• The ability for a technician to ‘steer’ the treatment.

TMS has a relatively low spatial resolution, making it difficult to selectively target small, discrete brain areas. Conversely, tFUS can achieve millimeter-level precision in targeting specific brain regions, allowing for more focused and localized stimulation. The high spatial precision of tFUS enables more targeted neuromodulation, potentially leading to more effective therapeutic outcomes.

Where TMS is limited in its ability to reach deeper structures due to the rapid attenuation of the magnetic field, tFUS can reach deeper brain regions, thereby opening up the possibility of targeting more therapeutic targets, including those involved in conditions like addiction, depression, and neurodegeneration.

With TMS, targeting a different brain region typically requires changing the equipment, which is a time-consuming and labor-intensive inconvenience. The emerging tFUS devices can steer the ultrasound beam to target different brain regions in real-time without physical hardware changes.

Psychedelic Parallels

Also interesting are several parallels between this class of neurotechnology and psychedelic therapies.

Scientific Roots in the 1950s 

Both tFUS and psychedelic therapies have a long history of research and exploration, even though they are now emerging as novel therapeutic approaches.

The fundamental principles behind tFUS, such as using ultrasound for neural modulation, were first discovered in the 1950s, but the field languished for decades before being rediscovered and advanced in the 2000s. Similarly, the therapeutic potential of psychedelics has been known for a long time, with research dating back to the 1950s. Still, their study was suppressed and stigmatized until the recent resurgence of interest.

New Treatment Paradigms

Both tFUS and psychedelic therapies represent a significant shift away from the dominant pharmaceutical model of treating neurological and psychiatric conditions.

Instead of relying on chronic drug administration, these approaches aim to induce lasting changes in brain function and behavior through targeted interventions. This shift challenges the traditional medical paradigm and offers a new paradigm for how we treat these complex conditions.

Harnessing Neuroplasticity

A key aspect of both tFUS and psychedelic therapies is their ability to harness the brain's natural capacity for neuroplasticity, the ability of the brain to adapt and change in response to experience.

By modulating neural activity and connectivity, these interventions can potentially facilitate the formation of new neural pathways and the reorganization of brain networks, leading to long-term therapeutic effects. This plasticity-enhancing mechanism departs from the static, symptom-management approach of many conventional treatments.

Clinical Infrastructure Requirements

Effectively implementing both tFUS and psychedelic therapies requires the development of specialized clinical infrastructure and therapeutic support systems.

These interventions are not simple “take a pill and go” treatments but rather involve complex procedures, patient monitoring, and integration of the therapeutic experience. Clinicians, therapists, and other healthcare providers will need to be trained and equipped to deliver these novel treatments safely and effectively.

Challenges and Future Directions

Despite its promising potential, tFUS is still mainly in the research and development phase. It will face several critical challenges before being widely adopted in clinical settings.

Regulatory Hurdles

One of the primary obstacles is obtaining FDA clearance. The regulatory landscape for tFUS devices is uncertain as a new treatment approach. It is likely to be classified as a new class of medical devices, requiring more regulatory scrutiny than another TMS device and more extensive clinical trials to establish safety, efficacy, and long-term outcomes.

Technical Challenges

Substantial technical challenges must also be overcome. One major hurdle is precisely targeting through the skull, for instance.

While tFUS offers superior spatial resolution and depth of penetration compared to other neurostimulation modalities, achieving consistent and accurate targeting across diverse patient populations—considering variations in skull thickness and shape—remains a significant technical challenge. Moreover, researchers are still working to understand the optimal pulse parameters and the full range of effects that tFUS can induce in the brain.

Another crucial consideration is the durability of therapeutic effects. While preliminary studies show promising results, the long-term efficacy of tFUS in treating chronic neurological and psychiatric conditions remains to be fully established.

Integrating tFUS with Other Therapies

Looking forward, one of the most exciting possibilities is the integration of tFUS with other therapeutic modalities.

Combining tFUS with psychedelic therapies, for example, could potentially amplify the neuromodulatory effects of both treatments, leading to more profound and enduring changes in brain function.

Similarly, pairing tFUS with psychotherapy might enhance the ability to rewire maladaptive neural circuits, providing a more holistic approach to treating complex conditions like depression, addiction, or PTSD.

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While tFUS is a promising and versatile technology with the potential to revolutionize non-invasive brain stimulation, it is still in the early stages of development. Significant research, technological refinement, and clinical trials are required to fully realize its potential. If these challenges can be met, tFUS could become a cornerstone of future therapeutic strategies and clinics.

1. The Overton window is a political concept that describes the range of ideas and policies considered acceptable by the mainstream population at a given time.

2. My neighbor just turned 76. In the Fall, he dries his cannabis plants on the deck for a few weeks ahead of harvesting. He’s a boomer stoner. When I told him what I do for work, he said, “That shit (psychedelics) makes you crazy,” having no experience of his own to ground this opinion. This surprised me. Had he not read How to Change Your Mind???