Software-Assisted Psychedelic-Assisted Psychotherapy: Part 1

“May you live in interesting times”

—Chinese Proverb/Curse


A Chimera is a mythical creature with a lion’s head, a goat’s body, and a serpent’s tail first described by Homer in the Illiad.

According to Wikipedia:

“The term "chimera" has come to describe any mythical or fictional creature with parts taken from various animals, to describe anything composed of very disparate parts, or perceived as wildly imaginative, implausible, or dazzling.”

The three-headed, wildly imaginative, implausible, and dazzling chimera we are concerned with today is not a beast of the mythical past but of the technological future: Software-assisted Psychedelic-assisted Psychotherapy.

Kimære – Wikipedia

ATAI launches IntroSpect Digital Therapeutics

On Monday, ATAI announced it’s latest portfolio company, Introspect Digital Therapeutics;

“…ATAI Life Sciences… announced the launch of its digital therapeutic platform IntroSpect Digital Therapeutics, Inc. David Keene, who brings almost two decades of experience in tech- and healthcare-related fields, will serve as CEO and will be leading ATAI's efforts to bring digital therapeutics (DTx) and precision psychiatry to bear on the mental health epidemic…

We’ve been expecting this announcement as we discussed last week in Highlights and Analysis of ATAI’s Fireside Chat digital therapeutics are a central piece of ATAI’s strategy as infrastructure which will allow psychedelic medicine to scale.

I expect the Introspect platform will interface with many of the other ATAI portfolio companies, but they have indicated that they are first focused on Treatment-Resistant Depression and Substance Use Disorder which makes sense since ATAI’s solutions to these issues are COMPASS & DemeRx, their Psilocybin and Ibogaine programs respectively are programs in which the scalability issue is most pressing.

From the information available, there are three pillars to the Introspect DTx platform:

  • Magnifies the effect

“IntroSpect will create digital tools and devices that will “magnify” the effects of drugs in development at ATAI’s companies, David Keene, CEO of IntroSpect, told Fierce MedTech.”

(This prospect of software magnification is the most compelling and will be the subject of part 2 on Friday)

  • Allows for Remote Monitoring

“Another use case is remote monitoring, which could make psychedelic treatments available for patients who live far away from treatment centers. The technology could come in handy at Compass Pathways, for example, which is working on a psilocybin therapy for people with treatment-resistant depression.”

  • Digital Aftercare

“What separates apart a recreational psychedelic experience versus a clinical one is the clinical setting and aftercare therapy,” Keene said. “This type of aftercare can help patients take advantage of the neuroplasticity—the brain’s ability to change itself—that comes with a psychedelic experience and use it to make life changes”

We’ll return to ATAI, Introspect, and Software-Assisted Psychedelic-Assisted Psychotherapy, but we need to explore the topic of Digital Therapeutics briefly as there is surprising overlap between DTx and Psychedelics and the two will be intimately linked.

Digital Therapeutics 2.0

This announcement from ATAI comes days after a watershed moment for the field of Digital Therapeutics.

The FDA approved the first video game for the treatment of ADHD developed by Boston based Akili.

“The U.S. Food and Drug Administration (FDA) has granted clearance for EndeavorRx as a prescription treatment for children with attention-deficit/hyperactivity disorder (ADHD). Delivered through a captivating video game experience, EndeavorRx is indicated to improve attention function as measured by computer-based testing in children ages 8-12 years old with primarily inattentive or combined-type ADHD, who have a demonstrated attention issue”

This is significant because DTx, as a field, has been limited in its ability to create a therapeutic effect directly.

The term has referred to the use of digital and Internet-based health technologies to make behavioral and lifestyle changes that indirectly affect clinical endpoints through behavior modification, this is what we mean by DTx 1.0.

Apps ping you with reminders, incentives, messages of support, etc. to encourage healthy eating, exercise, to take medication or other behaviors. They have been based on engaging with users through accountability, incentive, and reward programs. Telehealth and group support services are included in this framework, as well.

Perhaps the poster child of DTx 1.0 is Omada Health. Founded in 2011 with the mission to combine “behavioral science, human-centered design, and technology” to drive behavior change for diabetes prevention. CEO Sean Duffy is, in fact, given credit for coining the term Digital Therapeutics back in 2014.

However, Nikhil Krishnan, healthcare analyst and author of the Out of Pocket newsletter, made the case that Akili’s EndeavorRX marks the leap from Digital Therapeutics 1.0 to 2.0 on yesterday’s A16Z podcast.

“One really cool thing about this is Akili is a therapeutic through and through. It is not trying to incentivize a behavior change to induce the therapeutic effect. The goal of the video game is to actually induce the therapeutic effect directly which brings a lot of the promises of true scaleability.”

Software-as-a-Drug

When we think of the term ‘drug,’ we tend to refer to small molecules that are designed to “fit” into specific receptors on specific cells or proteins to alter the physiological processes in some way. For example, a class of HIV medication known as Non-nucleoside reverse transcriptase inhibitors (NNRTIs) binds and blocks the HIV enzyme called reverse transcriptase, which prevents HIV from replicating.

This requires extreme precision.

In highly specific conditions, like HIV, this method works wonderfully, suppressing viral loads below the threshold of detection. However, in complex, multisystem, multifaceted conditions, like the kind that psychedelic medicine is principally concerned with, this approach often falls short. (See SSRI side effects, Opioid epidemic, SUD relapse, etc.)

The promise of Digital Therapeutics 2.0 is a fundamentally different mechanism of action in which an algorithm, delivered by video game, or Virtual Reality or some other mode, directly influences neural pathways involved with the conditions and symptoms.

Again from the a16z podcast, this time, Vijay Pande of Andreeson Horowitz:

“I love that idea of marrying a digital approach with something as engaging as a video game to get at the underlying physiologic mechanism of cause which often times we don’t necessarily see with digital therapeutics… that are really focused on “what are the underlying neural pathways that drive a lot of the symptoms of ADHD and finding a way through a game of stimulate the right sensory and motor components to ultimately have a therapeutic impact.”

Centaurs and Chimeras

A Centaur is a mythical Greek creature, half-man, half-horse.

In chess, a centaur is a team made up of a human player and a computer.

“Centaur chess, or advanced chess was popularized by Garri Kasparov, the world chess champion defeated by Deep Blue, the IBM chess computer. Centaurs tend to be stronger than pure human or pure computer players, sometimes a team of an average human and a computer achieving higher ratings than top grandmasters. Centaur chess is just one example of human-artificial intelligence cooperation.”

The realization that an average human chess player and an average computer chess program can cooperate to beat Grandmasters and more sophisticated chess programs is an example of Moravec’s Paradox.

This is the recognition that humans and computers have opposite strengths and weaknesses. In the domain of psychedelic-assisted therapy, where human therapists are limited (high costs, limited availability, repeatability, etc.), Digital Therapeutics can fill the gaps with zero marginal costs, on-demand availability, repeatable processes.

The COVID crisis has seen the rapid adoption of telehealth and other DTx 1.0 modalities and this adoption will likely continue as patients and providers adjust.

However, when we introduce the psychedelic experience to the equation, the centaur model morphs into the chimera model.

We covered technology-enabled Psychedelic Clinics when evaluating an Eleusis patent application a few weeks ago:

“I admit that I am a Luddite and my imagination is lacking when it comes to the practical applications of technology and data science in this domain.

My bias is to favor natural products with an empathic (human) guide but I also recognize this doesn’t scale and patchouli isn’t everyone’s cup of tea.

The “control center” makes me think of a scenario in which a computer is monitoring real-time ECG, fMRI, HRV, and other data and making inflight changes to the set and setting, such as music, temperature, visual field, perhaps titrating blood levels of the active agent in order to drive certain responses.

Yes, this is cool, useful, and awesome human ingenuity. But I also get Black Mirror vibes—techno-optimists rarely stop to ask “in what ways can this go horribly wrong?”

(we’ll get into the Black Mirror scenarios in part 2 data, consent, second-order effects, etc.)

The Akili approval offered a glimpse of the future that I could not see as clearly when I wrote the above, (but I am still a card-carrying Luddite.)

The basis of an intervention like a video game for ADHD is predicated on potentiating neuroplastic changes in relevant neural circuits.

What do psychedelics do? (Besides revealing the face of God and showing us “that all matter is merely energy condensed to a slow vibration. That we are all one consciousness experiencing itself subjectively. There is no such thing as death, life is only a dream, and we’re the imagination of ourselves.” (Bill Hicks))

They promote structural and functional neural plasticity, of course.

But, at least as far as I can understand it, it is perhaps more accurate to say that they loosen the rigidity of synaptic connections. Then through a combination of the experience and appropriate integration and conceptual reframing positive and desired changes can be realized.

In other words, a neuroplastic window is opened by psychedelics where carefully designed strategies of interpersonal relating, conceptual-behavioral habit change, and yes, even software can imprint upon the neural circuitry to magnify the effect.

It is the leap from DTx 1.0 to DTx 2.0 as exhibited by Akili’s recent milestone that offers this possibility of magnifying the effects of treatment through technology and not merely send reminders, messages of support, and incentives to modify behavior—in Digital Therapeutics 2.0 the software is the drug.

While this is fascinating and endlessly interesting, there is a tendency for the techno-optimists to jump ahead and underestimate (or fail to openly discuss) the Last Mile Problem and the pitfalls of such technology.

In part 2, we’ll get into that as well as how the changing definition of a ‘drug’ can help close the Innovation and Delivery gap.

Interesting times, no doubt.


Effect Size Revisited

Last week a paper titled “A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapyset me on the road to perdition in which I invoked information which I had misinterpreted to be a sign that the unusually large effect size of psychedelic interventions allowed MAPS to cut a sample size in half.

I made the first correction here, but need to mention that the MAPP1 protocol was not given permission to cut enrollment based on effect size but rather as an extenuating circumstance caused by COVID. Again, I regret the error and will be revisiting the concept and more specific ways the unusually large effect size of psychedelic therapy effects clinical trials and drug development.


Alright, thank you again for reading, sharing, and commenting.

Pro subscribers, we’ll see you on Friday for Part 2 and a round up of the week’s news.

Zach