MIND BLOG

This interview is about the following publication: Yaden, D. B., Berghella, A. P., Regier, P. S., Garcia-Romeu, A., Johnson, M. W., & Hendricks, P. S. (2021). Classic psychedelics in the treatment of substance use disorder: Potential synergies with twelve-step programs. International Journal of Drug Policy, 98, 103380.

Treatment for people with substance use disorders is often based on classical psychotherapeutic principles, such as cognitive-behavioural therapy. However, two unorthodox approaches have existed since the 1950s that, at first glance, seem to incorporate opposing principles: 12-step abstinence-based programs and psychedelic therapy. In this interview, I exchange with David Yaden, PhD, who recently published a paper with his colleagues from John Hopkins University, in which they discuss potential synergies between these two treatment modalities.

L: For our readers who may be are unaware of this concept, could you shortly explain what 12-step programs are?

D: 12-step programs are peer-support groups that follow a guiding set of principles to help members maintain sobriety. Alcoholics Anonymous (AA) was the first 12-step program, and probably the one that most people are familiar with. Nowadays, there are 12-step groups intended to help with most addictive drugs as well as behaviors like gambling.

12-step groups sit a little uneasily with mainstream addiction treatments. While many clinicians encourage their patients to seek out 12-step groups as an adjunct to evidence-based therapies or treatments, 12-step programs are not themselves considered part of medical or clinical treatments. Moreover, many 12-step programs do not allow members to participate in some evidence-based drug treatments such as medication assisted treatments (e.g., methadone), which is considered a controversial practice among evidence-based clinicians and researchers who see this as preventing effective treatment. Lastly, a large Cochrane review showed that there is evidence suggesting that 12-step programs are effective for some people.¹ There are a complex set of dynamics at play here.

L: What do you think is the broad appeal of 12-step programs? Why has this program been able to spread successfully across the whole globe?

D: 12-step programs benefit from its members, who are often extremely engaged and can provide social connection and support to people who are often lacking it in their lives. The social support that many 12-step programs provide goes well beyond the amount of time that clinicians can provide due to the constraints of their schedules. For example, 12-step program members are teamed with another 12-step program member, who plays the role of a “sponsor.” New members can generally call their sponsor at any hour, day or night, if they are tempted to relapse or if they simply need someone to talk to.

Additionally, the 12-steps themselves are very easy to understand, and provide as their name implies, a step-by-step process to regain sobriety and remain sober.

Finally, 12-step programs are usually easily accessible and free, while healthcare resources can sometimes be inaccessible and/or difficult to afford in the US.

L: The 12-step programs explicitly mention spiritual experiences as catalysts of change. Could you elaborate on what is meant by that?  What is considered a spiritual experience in 12-step programs and how does this experience differ from or is similar to experiences induced by psychedelic substances?

D: The 12-step programs stem from Bill Wilson’s writings. Bill Wilson (b. 1895 – d. 1971) co-founded Alcoholics Anonymous (AA) after he achieved sobriety during a moment that he considered a “spiritual experience.” Here is Bill Wilson describing his experience:

“Slowly the ecstasy subsided. I lay on the bed, but now for a time I was in another world, a new world of consciousness. All about me and through me was a wonderful feeling of Presence. A great peace stole over me and I thought, “No matter how wrong things seem to be, they are all right…” (quoted by Ernest Kurtz²)

Notably, Bill Wilson was being treated with a substance called Scopolamine, which some consider a psychedelic (though it is not a classic psychedelic like psilocybin or LSD). He was undergoing treatment for alcoholism in a New York City hospital under the care of a physician who was attempting a new form of treatment. Most people are unaware that Bill Wilson’s first spiritual experience occurred under the influence of a psychedelic-like substance!

Spiritual experience plays a prominent role in 12 step programs. After all, it’s part of the 12 steps. The 12^th and final step reads: “Having had a spiritual experience as the result of these steps, we tried to carry this message to alcoholics, and to practice these principles in all our affairs.”³

L: With regards to your paper: What led you to think that synergies between psychedelic use and 12-steps programs could exist?

D: The spiritual experience that Bill Wilson described as prompting his sobriety is very similar to the subjective effects reported by many people taking psychedelics.  Bill himself made this point. Later in his life, Bill tried LSD (a classic psychedelic) under the care of a physician. He appeared to benefit from these psychedelic treatments, and Wilson provided a positive endorsement:

“It is a generally acknowledged fact in spiritual development that ego reduction makes the influx of God’s grace possible If, therefore, under LSD we can have a temporary reduction, so that we can better see what we are and where we are going – well, that might be of some help. The goal might become clearer. So I consider LSD to be of some value to some people, and practically no damage to anyone.” ⁴

Wilson’s endorsement of psychedelic treatments may surprise people – it certainly surprised us when we learned about it. According to one scholar, Joe Miller, who wrote US of AA, this fact may have even been actively suppressed by the board of AA.

L: So, what actual synergies do you see? Do you believe there is a benefit to combining the two approaches?

D: I want to be very clear on this point – in the paper, we are neither advocating nor denouncing the combination of psychedelics with 12-step programs.

However, we can’t help but notice the substantial similarities between psychedelic treatments, which many people report resulting in a spiritual-type experience, and the aims of 12-step programs, which aim to provide a kind of spiritual experience as a result of working the steps.

We thought it was interesting that 12-step programs tend to disallow members from participating in medication assisted treatments (MAT) because they are seen as “swapping one drug for another.” This can be unfortunate considering that MAT has been shown to be among the most effective ways of keeping people who have substance use disorders alive.

We were curious as to whether some 12-step programs might make an exception for treatments with psychedelics. Indeed, while they are drugs or kinds of medication, they provide experiences that are similar to (or identical to in some cases) the spiritual experiences that are at the heart of 12-step programs. Meanwhile, the founder of AA advocated combining 12-step programs with psychedelic treatments – and it could be that knowing about this endorsement from AA’s founder might be impactful or at least interesting to some members of 12-step programs.

L: Regarding the integration of psychedelics into 12-steps: What would the actual practice look like? How could psychedelics be integrated into a 12-step program?

D: We could imagine a few different possibilities – call the possible models initiatory, intermittent, or culmination. An initiatory model would suggest undergoing a psychedelic experience toward the beginning of the 12-step process in order to provide more motivation during what may be a difficult period of transition. An intermittent model might involve periodically engaging in psychedelic treatments over the course of the 12-step process, maybe once every few months or so, in order to maintain the momentum of treatment and sobriety. Lastly, a culmination model might involve having the psychedelic treatment along with the 12^th and final step as a kind of capstone to, and opportunity to reflect on, the entire process.

Again, these are just some possibilities, we don’t really know how this integration might look in the real world. It’s a topic that’s worth studying and would require interdisciplinary teams to do the research well. Let me reiterate that both here and in the paper, we are neither advocating or denouncing the combination of psychedelics with 12-step programs, but merely considering the subject.

L: What do you think the next steps would look like for this line of research? What are important aspects about this combination that need to be explored?

D: We’re launching some research projects to study groups that are apparently already engaged in integrating psychedelics into the 12-step process. Yet again, I want to reiterate that we’re not supporting or condoning integrating psychedelics into 12-step groups (it is currently illegal in the US and therefore legally risky). But we do want to learn more about this practice – the potential safety issues that come up, whether it’s effective, and how the integration fits with 12-step philosophy as well as with current mainstream evidence-based treatments. There are a number of interesting and important psychological, medical, legal, and anthropological questions to address in this framework.

L: Finally, what would the best possible care for patients with substance use disorders look like? What do you envision the ideal future of treatment to look like?

D: I am a psychological and psychopharmacological researcher, so I study psychological and pharmacological interventions. I think there is a great deal of progress that can be made on both of these fronts. It’s important to note that there are treatments currently available for people who suffer from substance use disorders, and I encourage this population to take advantage of these existing evidence-based treatments.

Learn more about substance use disorders on MIND’s Elements of Science.

At our lab at Johns Hopkins, the Center for Psychedelic and Consciousness Research, we are conducting studies and collecting promising data on the potential efficacy of psychedelics for the treatment of substance use disorders. We need more and better research to follow-up on preliminary findings (something that researchers like Matt Johnson, Albert Garcia-Romeu, and Peter Hendricks are currently working on), but it does seem that psychedelics have the potential to help treat some patients with substance use disorders. On the other hand, community-based peer support groups like 12-step programs also appear to be effective, as the recent Cochrane review showed.

Ultimately, though, several larger social forces and policy-related issues need to be addressed to allow people with substances use disorders to obtain access to the services and resources they need.

To summarize, “the best possible care for substance use disorders” would likely involve the integration of access to economic resources and social services. The same goes for psychological and pharmacological treatments. There are no easy or simple solutions here.

The aim of our paper was to highlight a somewhat complicated situation – integrating psychedelics into 12-step programs – and to try to understand their dynamics a little better. I think we probably succeeded more in raising questions than we did at providing concrete answers.

1. Kelly JF, Humphreys K, Ferri M. Alcoholics Anonymous and other 12‐step programs for alcohol use disorder. Cochrane Database Syst Rev [Internet]. 2020 [cited 2021 Sep 30];(3). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012880.pub2/full
2. Kurtz E. A.A.: The Story by Ernest Kurtz. Harpercollins; 1988.
3. Alcoholics Anonymous. Alcoholics Anonymous Big Book. 4th ed. Hazelden; 2001.
4. Hartigan F. Bill W.: A Biography of Alcoholics Anonymous Cofounder Bill Wilson. Thomas Dunne Books; 2000. 256 p.

The growing field of social interoception—which examines how social emotions arise from subjective appraisal of bodily states—calls for a rebranding of mental health issues as “social health issues” and builds the case for new forms of embodied social treatment, including psychedelic-assisted therapy. I spoke with researchers at UC San Diego, the University of Utah’s Social Development Lab, and the University of Zurich to find out more.

It was by studying a part of the brain called the insula that neuroscientist John Allmann first realized self-awareness and social awareness are part of the same functioning¹. Tucked deep within the Sylvian fissure, a connectivity hub disguised as an island unto itself, the insula is one of the main brain structures responsible for translating body states into social emotions. It starts doing this for us the moment we are born, recasting intimate touch into feelings of pleasure or a harsh tone from a parent into feelings of shame. If we do not receive appropriate care as children, the way the insula encodes the relationship between our bodies and social emotions can cement in a maladaptive way, leading to a propensity for mental health issues later in life². Mounting evidence shows that it may be possible to change this relationship, since the insula also plays a role in therapeutic practices like mindfulness meditation, body trusting, and psychedelic-assisted therapy. Taken together, these findings suggest that the link between body, self, and social emotions plays a bigger part in mental health than we might think, highlighting a need for more forms of therapy which directly target social emotions through the body.

The Bodily Self

The insula’s main function—helping us recognize what we are experiencing based on what we sense—is called interoception. It allows us to interpret an “empty stomach” as physical hunger or “butterflies” as excitement or fear. As mentioned above, social emotions arise from this process. Despite the connection between interoception and social emotions, little scientific attention has been given to the social origins of interoception.

At the University of Utah’s Social Development Lab, Kristina Oldroyd’s pioneering work suggests that early social experiences significantly impact areas of the brain responsible for interoception by influencing the development of the bodily self. Oldroyd’s research team has found that insensitive caregiving—which includes responding inconsistently to a child’s needs or rejecting distress altogether—can impair a child’s ability to form accurate representations of bodily sensations³. For example, when a child who is learning to walk falls down and feels physical pain, a sensitive response from a parent might be, “That must have hurt,” whereas an insensitive response would be, “You’re fine, that didn’t hurt, get back up.” For the child to become comfortable detecting, acknowledging, and expressing bodily cues, the parent must notice what the child is experiencing, draw joint attention to it, and label it³:

“To the extent that caregivers recognize, honor, and respect their children’s bodily experiences, the child will develop more accurate interoception,” Olroyd explains. “To the extent that a child’s bodily experiences are denied, devalued, ignored, or punished by parents, the child will find ways to avoid feeling them, and develop a distorted sense of interoception.”³

Oldroyd maintains that the way we learn to regulate physical pain is no different from the way we learn to regulate emotional pain—in both cases, we are socialized through our bodily experience. Neuroscientific studies support her theory, showing that children who are classified as having anxious or avoidant attachment styles have markedly lower insular volume than securely attached children⁴. If the bodily self remains unchanged throughout those children’s adult lives, when relationships become more complex and social-emotional regulation increasingly important, Oldroyd believes it is poor interoception itself which may lead to disorders like anxiety, depression, and addiction. It may also lead some of us farther away from social connection when, ironically, that may be what we need the most.

Interoception and Social Health

“One idea I’m working with,” says Andy Arnold, a psychologist and interoception expert at the University of California San Diego and Visiting Professor at Knox College, “is that interoception might be a critical mechanism for evaluating needed resources in our lives. If interoceptive understanding is turned down, then one might not be able to accurately sense the lack of needed resources [like] social connection and act accordingly.” For example, addiction could be a misevaluation of resources where you “overevaluate the drug but underevaluate other stimuli in your life,” Arnold told me, adding that the insula probably plays a critical role in this process.

It also works the other way around: substance abuse disrupts interoception and damages the insula. Brain images of people with alcohol use disorder show significantly reduced grey matter in the insula, marked by a profound loss of von Economo neurons (or “empathy cells”)⁵, a relatively recent evolutionary specialization in humans thought to be crucial for interoceptive sensitivity and prosocial behavior⁶. Paradoxically, in certain cases, damage to the insula actually reverses addictive behaviors. In a 2015 study on addiction, researchers at the University of Southern California observed: “On the one hand, alcohol dependence damages the insula. On the other hand, damage done to the insula reduces cravings for alcohol.”⁷

But this is not a contradiction if you view addiction as social health issue. The insula might normally motivate us to seek social reward, but if we cannot understand our social-emotional needs based on what we are feeling, we might turn to substances to resolve this uncertainty. Heavy substance use may be like putting the wrong type of fuel in the tank: when the brain and body crave social connection, giving it something else harms the engine over time although it appears to run fine. In this case, perhaps the habitual relationship with the drug outlasts the original motivation to use it. On the other hand, damaging the insula outright may destroy its record of the substance as a substitute for social reward, and therefore immediately reduce one’s craving for it.

The insula shows us just how misguided we may be in labeling disorders like addiction, anxiety, depression, and substance abuse as “mental health” issues. If interoception initially develops in the context of interpersonal relationships, then so do many of our afflictions—and so, too, should our treatments.

Connecting Through the Body

In November 2019, Arnold and his colleague, neuroscientist Karen Dobkins, published the first academic discussion of what they call “social interoception,” arguing that interoceptive ability facilitates social connection⁸. To understand how interoception might work in a social situation, imagine an encounter that raises one’s heart rate—a response meant to enhance alertness and prepare one for “fight or flight.” Dobkins and Arnold believe it may not be one’s physiological response per se that causes social stress, but rather one’s subjective interpretation of it. They reference a series of studies by researchers in Munich who used social stress tests designed around impromptu public speaking⁹ and social exclusion¹⁰ in a game setting to measure interoception. The researchers found that people with higher interoceptive accuracy reported fewer negative emotions after the challenging social situation, despite their heart rate and skin conductance being similar to participants with lower interoceptive accuracy. In other words, two people can have the same internal body state but experience completely different levels of social discomfort.

“This leads to the interesting idea that perhaps greater interoceptive accuracy allows one to identify the physiological response as resulting from an objective, external ‘social situation’ rather than an attribute of oneself,” Dobkins and Arnold say. “This could reflect better emotional regulation in social situations.” Oldroyd echoes these ideas in her own work: “It is the bias to interpret bodily signals in a negative manner, rather than the noticing of bodily signals, that contributes to both the cognitive and behavioral symptoms of anxiety.”

There is an important subtext to these statements: Maybe we are not born with our various social neuroses. Maybe we are born with a bias towards positive social signals, towards bonding with others. Poor interoception, often developed in the context of an adverse childhood, may be what shifts the bias towards negative signals. The way to shift it back, Dobkins says, would be to start listening to and trusting your body before your mind jumps to conclusions. In their own work on loneliness, Dobkins and Arnold found that one measure of interoception in particular—body trusting—predicted variations of subjective loneliness amongst university students at UCLA¹¹, suggesting that connecting with your body allows you to connect with others, whether that means making more friends or different friends. The more you trust your own body, the better you become not only at reading yourself but at reading and connecting with other people.

“You know the feeling when you and another are ‘on the same page’?” Dobkins says. “Well, that’s not what I am talking about. That’s the mind reporting back and saying that, ‘the other person and I believe or want the same thing.’ Connection is body-based. It’s a knowing in the body. Which means you need to know your body.”

The growing field of social interoception may help us better understand and treat not only loneliness but anxiety, addiction, eating disorders, depression, and other conditions traditionally associated with thought patterns rather than body signals. In fact, social interoception may be a key piece in the puzzle of explaining how psychedelic-assisted therapy functions.

Psychedelic Drugs and Interoception

As part of the Salience Network, one of the main functions of the insula is to orchestrate activity between other networks, including the Default Mode Network and the Central Executive Network. In 2017, Robin Carhart-Harris and his research team at Imperial College London found hypo-connectivity of the insula to be “a neurobiological signature of the MDMA experience,” correlating it with reduced anxiety, altered bodily sensations, and changes in interoception¹². “Further understanding of how MDMA affects the insula,” Carhart-Harris writes, “might be crucial to elucidating the neurobiological underpinnings of re-emerging interest in MDMA as a therapeutic adjunct to psychotherapy in the treatment of anxiety disorders including PTSD.” Other teams have found similar results, linking insula hypo-connectivity to the LSD experience¹³.

Research on the neural correlates of different types of mindfulness meditation points to the insula and the body as well. Commenting on a study on Loving Kindness, Focused Attention, Open Monitoring, and Mantra Recitation, Carhart-Harris notes that although these four meditation styles are clearly dissociated by their neural correlates, there are “a few recurrent patterns of activity modulation, in particular in the insula, an important multisensory area heavily involved in interoceptive awareness”¹⁴. He suggests that involvement of the insula in all four styles of meditation points towards “the central role of the attentional control of bodily awareness, and awareness of breathing in particular, during various contemplative practices.” As we’ve seen, body awareness is closely linked to social emotion, which may help explain the benefits of both mindfulness meditation and psychedelic therapy.

Psychedelics and Connectedness

At the University of Zurich, Katrin Preller studies the social health benefits of psychedelics. Her work in this area confirms Allmann’s notion that how we see ourselves is inextricably intertwined with social perception. For example, psilocybin and LSD have been found to reduce social pain specifically through alterations in self-processing¹⁵, which include experiences of unity and connectedness.

“One of the main aspects of the psychedelic experience is the sense of connectedness – with the universe, nature, but importantly also with the social environment,” Preller told me. “Furthermore, we see an increase in emotional empathy which may be an important factor contributing to the feeling of connectedness. In clinical trials, we are currently testing the hypothesis that this experience contributes to the efficacy of psychedelic-assisted therapy.”

In a successful series of Johns Hopkins studies targeting psilocybin and nicotine addiction, participants “identified social factors, i.e., smoking as a way of connecting with other people, that contributed to their addiction.” ¹⁶ They reported psilocybin-induced feelings of love and connection with their environment and other people, independent of smoking as a social factor, as important for quitting smoking¹⁷. “Psilocybin may have re-instated social reward processing, helping patients to overcome their addiction,” Preller speculates. “My hope is that therapy will focus more on social cognition and the social environment of patients. For example, social trainings may aim at re-instating social reward processing in addicted patients, helping them to re-connect with their social environment.”

Research on the insula and social interoception suggest that the body is the main channel through which these changes must occur. Feelings of love and connection are exactly that—feelings. It seems we must feel the social reward, hold it in our bodies, to stop needing its replacement. In doing so, maybe we restore some kind of default setting. For all we know, “connectedness” may not be an additive feeling at all. On the contrary, it may be the stripped-down, primordial sensation that the self is socially constructed. And while it may be a new feeling to the psyche, Oldroyd’s work suggests it is not a new feeling to the body. Perhaps this is why psychedelic experiences can feel so profound to some: deep in their bodies, they’ve always known.

From Global Connectivity to Local Plasticity

In April 2019, researchers at Johns Hopkins University published an animal study showing that MDMA reopens a “critical period” when the mouse brain is sensitive to learning the reward value of social behaviors¹⁸. Although it is a neurobiological study, attributing the reopening  to heightened, oxytocin-induced brain plasticity, the behavioral mechanism sounds very much like Oldroyd’s childhood theory of interoception: Critical periods were first described in snow geese in the 1930s when goslings were found to bond with an object if their mother disappeared 24 hours after they hatched, but not 48 hours after they hatched. You can imagine which goslings would be best able to socialize their bodily cues going into adulthood, assuming geese are self-aware enough to do so. In the Hopkins study, adult mice who were given MDMA showed prosocial behavior in a way normally seen only in juveniles, forming positive associations between companionship and a certain type of bedding in their enclosure. Neuroscientist Gül Dölen and her team found that this happened only if the drug was given to mice when they were with other mice, not if it was given to mice while they are alone. “This suggests that reopening the critical period using MDMA may depend on whether the animals are in a social setting,” Dölen says.

Embodied Therapy in Social Settings

Although Dölen suggests this kind of treatment may work in humans by strengthening the psychotherapist-patient bond, I would argue it is also a case for a different type of therapy altogether—something along the lines of social embodied therapy, or group bodywork led by psychotherapists. Social reward learning occurs through the body, in a social setting, in large part because we are socialized through our bodies early in our lives. If the therapeutic aim is adaptive social connection, then why not place a greater emphasis on connection as therapy?

Indeed, it seems questionable that any of us should heal as isolated subjects, when we are born to bond, and when the rest of our lives are built around connection. No matter how great your relationship is with your therapist, the dynamic is often that of an object being scrutinized under a microscope. Modern therapy still whiffs of stigmatization and quarantine—our problems so private that they must be kept a secret. Even Somatic Experiencing therapy, which at least reveals these problems to us through the body, largely treats each person in isolation. We do not necessarily have to share our problems to heal. In fact, some PTSD patients become asymptomatic after psychedelic assisted therapy sessions where no words are exchanged¹⁹. But it may be the case that we can only re-open the doorways of social learning—and heal from social illnesses—through the body, through each other, and through the part of the brain that so ironically appears to stand alone.

References

1. Chen, I (2009). Brain Cells for Socializing. Smithsonian Magazine.

2. Khalsa S et al (2018). Interoception and mental health: a roadmap. Biological Psychiatry. 10:004. doi: https://doi.org/10.1016/j.bpsc.2017.12.004

3. Oldroyd K, Pasupathi M and Wainryb C (2019). Social Antecedents to the Development of Interoception: Attachment Related Processes Are Associated With Interoception. Psychol. 10:712. doi: 10.3389/fpsyg.2019.00712

4. Lim L, Radua J, Rubia K (2014). Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis. J. Psychiatry 171 854–863. 10.1176/appi.ajp.2014.13101427

5. Senatorov V-V, Damadzic R, Mann C-L, Schwandt M-L, George D-T, Hommer D-W, Heilig M, Momenan R (2015). Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons. Brain, 10:305. doi: https://doi.org/10.1093/brain/awu305

6. Yang L, Yang Y, Yuan J, Sun Y, Dai J, Su B (2019). Transcriptomic Landscape of von Economo Neurons in Human Anterior Cingulate Cortex Revealed by Microdissected-Cell RNA Sequencing. Cerebral Cortex. 29, 2, 838–851. doi: https://doi.org/10.1093/cercor/bhy286.

7. Droutman V, Read S-J, Bechara A (2015). Revisiting the role of the insula in addiction. Trends in Cognitive Neuroscience. 10:005. doi: https://doi.org/10.1016/j.tics.2015.05.005

8. Arnold AJ, Winkielman P and Dobkins K (2019). Interoception and Social Connection. Psychol. 10:2589. doi: 10.3389/fpsyg.2019.02589

9. Werner N. S., Duschek S., Mattern M., Schandry R. (2009). Interoceptive sensitivity modulates anxiety during public speaking. Psychophysiol. 23 85–94. 10.1027/0269-8803.23.2.85

10. Werner N. S., Kerschreiter R., Kindermann N. K., Duschek S. (2013). Interoceptive awareness as a moderator of affective responses to social exclusion. Psychophysiol. 27 39–50. 10.1027/0269-8803/a000086

11. Arnold AJ, Dobkins K (2019). Trust Some Body: Loneliness is Associated with Altered Interoceptive Sensibility [Abstract and Poster]. Emotion Preconference for Society for Personality & Social Psychology, Portland, Oregon.

12. Walpola, I, Nest T, Roseman L, et al (2017). Altered Insula Connectivity under MDMA. 42, 2152–2162. doi: 10.1038/npp.2017.35

13. Preller et al (2019). Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. doi: 10.7554/eLife.35082

14. Millière R, Carhart-Harris RL, Roseman L, Trautwein F-M and Berkovich-Ohana A (2018). Psychedelics, Meditation, and Self-Consciousness. Psychol. 9:1475. doi: 10.3389/fpsyg.2018.01475

15. Preller KH, Schilbach L, Pokorny T, Flemming J, Seifritz E and Vollenweider FX (2018). Role of the 5-HT_2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study. Journal of Neuroscience. 38 (14) 3603-3611. doi: 1523/JNEUROSCI.1939-17.2018

16. Noorani T, Garcia-Romeu A, Swift TC, Griffiths RR, Johnson MW (2018). Psychedelic therapy for smoking cessation: qualitative analysis of participant accounts. J Psychopharmacol. 32:756–69. doi: 10.1177/0269881118780612

17. Preller KH and Vollenweider FX (2019) Modulation of Social Cognition via Hallucinogens and “Entactogens”. Psychiatry 10:881. doi: 10.3389/fpsyt.2019.00881https://doi.org/10.1038/s41586-019-1075-9

18. Nardou R, Lewis EM, Rothhaas R. et al. (2019). Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569, 116–120.

19. The Tim Ferriss Show Transcripts: Marcela Ot’alora—How to Become a Psychedelic Therapist (#396): https://tim.blog/2019/11/25/marcela-otalora-transcript/

WORKING DEFINITION

Coaching is an umbrella term for a broad range of approaches to creating sustainable change. Most approaches to coaching are defined as a bespoke, collaborative, focused and future-oriented conversation in which coach and coachee work in partnership towards progress on an agreed outcome; usually some form of development in learning, awareness, meaning, purpose, performance, quality of life or other forms of personal and/or professional growth.

The coach facilitates this process through the application and integration of a variety of approaches, styles, skills and techniques that are appropriate to the context in which the coaching takes place and within the bounds of their professional training. A coach may move freely between different facilitation styles, such as exploring, supporting, challenging and suggesting, and they will utilize these as and when appropriate and always with the aim of helping the coachee to move towards the agreed outcome. While suggestions or advice from the coach may be helpful and welcomed by the coachee, the main aim of coaching is to support and enable coachees to make their own decisions, take responsibility for their actions (or lack thereof), or process and integrate any insights, learning or experiences.  

In the context of psychedelics, a coachee may seek the support of a coach to prepare for or integrate a psychedelic experience. Leading up to a psychedelic journey, coaches support their coachees to set intentions, create awareness around harm reduction and safeguarding, and prepare them for the medicine journey and subsequent integration. After a psychedelic experience, the coaching work may focus on helping the coachee process their experience, acknowledge and solidify any new learning, create new habits based on insights gained during the psychedelic experience and generally carry the learning over into the coachee’s life and/or career in concrete and sustainable ways. Coaches may choose to be present during the coachee’s psychedelic experience, but they will not attempt to coach during this time. 

Given the potency of psychedelic compounds and an increased tendency for coachees to be affected profoundly by high-dose experiences, coaches offering their services around psychedelic journeys must have a heightened ethical responsibility and will pay special attention to aspects of their service that are aimed at keeping their coachees safe from harm. Hence, coachees who seek coaching around a psychedelic experience will be resourceful, able to cope relatively well with any personal or professional challenges, and they will be free from mental health diagnoses as well as not suspecting that there may be any. Coaching may be a valuable tool for clients with a clinical diagnosis as long as the coaching isn’t focused on treating the diagnosed condition and as long as it doesn’t interfere with the coachee’s ability to engage in the coaching process. 

While successful integration coaching may have therapeutic qualities and/or outcomes and the coach’s work may be informed by therapeutic approaches, coaches will contract clearly and ethically as to ensure they only provide services that they are willing and able to provide, and they will refer to an appropriate mental health or other professional when they approach or overstep their professional boundaries. We acknowledge that there can be significant overlap between therapy, counselling, mentoring, consulting, teaching and guiding, so in order to draw these boundaries in a meaningful way, every coach needs to be guided by their intuition in combination with the ethical framework they ascribe to and the working agreement they have made with the coachee. 

Psychedelic coaches must work within their competencies and have gone through a level of training that is appropriate to the coachee’s context and situation. This should include an understanding of, and additional training in, relevant psychological and/or therapeutic frameworks when supporting clients with high-dose experiences, especially considering the speed at which transformation can take place induced by these states.  

Coaches in the psychedelic space will be in regular supervision. If the coach is in doubt whether coaching is an appropriate intervention with regards to the coachee’s context, the coaching may take place in parallel with therapy for safeguarding, or a therapist may be kept “on call” in the event that additional support is needed at any point in the integration journey. Psychedelic integration coaches assume an important function as potential gateways into mental health support services. Hence, coaches working in this field will have a relevant and vetted referral network. 

An additional important function of the psychedelic integration coach regards the implementation of change. Psychedelic experiences can elicit powerful insights and high levels of motivation to jump into action. Such action may or may not be conducive to the coachee’s contracted goals or wellbeing if implemented too quickly, and the coach therefore acts as an important buffer on the journey of translating insight into action. 

Some coaches may work or consider working with clients who are under the influence of a psychedelic substance. Under the influence of high, medium or even low doses people should be regarded as vulnerable, and coaches must not attempt to coach them during this state. That said, microdosing (sub-perceptual doses of psychedelics) arguably is unlikely to cause any risk to coaching clients, though the knowledge base is still scarce. Therefore, caution is required when working with coachees who are microdosing psychedelics during the contracted coaching period.

Code of Ethics

The Coaching & Psychedelics Section has developed a Code of Ethics for coaches working in the psychedelic field. Read the full text here.

Publication Discussed in this ASC Study Monitor interview:
Milne, N., Thomsen, P., Mølgaard Knudsen, N., Rubaszka, P., Kristensen, M., and Borodina, I. (2020) Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives. Metabolic Engineering, 60:25-36

J: Welcome, Nick. Thank you so much for coming!  In your lab at The Novo Nordisk Foundation Center for Biosustainability, you have mainly worked on projects related to sustainability. What made you interested in psilocybin?

N: The research center where I worked is the Center for Biosustainability – A core focus of the center is to develop bio-based processes to replace non-renewable synthetic chemistry. I have always been interested in mental health, and particularly how we treat mental health, or rather how badly we treat mental health today. I was also always interested in the potential of psilocybin.

J: Psilocybin is not a mainstream medication yet; it is actually still quite far from it. At the same time, your research topic sounded like a great idea; was it really so easy to pursue?

N: At the time, it was undoubtedly a bit of a risk, and the first time I pitched the idea, I got laughed at! Eventually, what swayed people was showing them the clinical data. About two years ago, there was a lot of excellent clinical data starting to come out that showed the potential of these molecules, and I think that was what really swayed the people at the center to kind of say: ‘Okay, let’s give this a go.’ Thankfully, it has spun out into a company, and now, a year later, the psychedelics industry is becoming a promising one.

Interested in learning more the psychedelics industry and the current legal context? Check out our INSIGHT 2021 conference in September, which includes presentations by Charles Raison, M.D., on an open science approach to drug development, and a workshop on legal and ethical considerations in psychedelic research by Dr. Fabian Wenner.

J: And just a little bit over one year later, you have already published your results! That went pretty quickly.

N: It was indeed fast! Even by our standards, it did go very quickly, and the time it took to go from idea to proof of concept was only about four months. It took a while to put everything into publication form, but the research went surprisingly well. Thankfully there was a bunch of other researchers who helped a lot with this project which made the whole thing go faster.

Photo by Mogana Das Murtey and Patchamuthu Ramasamy, CC BY-SA 3.0, via Wikimedia Commons

J: That sounds great! Could you then summarize what you found in your study and how difficult it was to obtain these results?

N: Our research’s primary goal was to identify how Psilocybe mushrooms produce psilocybin and then figure out how to replicate that process in Saccharomyces cerevisiae, also known as brewer’s yeast. The biosynthetic pathway to produce psilocybin was discovered a couple of years ago, but notably, not all of the genes were found. Since biosynthesis is a process requiring a concerted action of genes involved in synthesis, transport, and regulation it is necessary to classify them all. The main genes identified were the ones that catalyzed the critical reactions, but there was a couple that were left out and still needed to be found. We had to dig a little bit into the genome of Psilocybe cubensis to find the missing genes. We then introduced them into yeast by transferring the genetic material.

We were able to demonstrate the production of psilocybin, which was a good start, but a lot of the work was focused on figuring out how to produce more psilocybin. Basically, the way that we did that was to work on the native yeast metabolism. Essentially how this works is that the genes that we transferred from Psilocybe cubensis work together with the genes that could transform tryptophan into psilocybin. Tryptophan is an essential amino acid, but it is also an amino acid that yeast produces endogenously, and actually, most species do. The most challenging part of the work was increasing tryptophan production – so playing around with the native yeast metabolism to increase the rate of tryptophan production, which subsequently led to more psilocybin production.

The last thing we did was to play around with the genetic code of the Psilocybe genes a little bit so that we could divert production towards some of the other intermediates and derivatives of the pathway. For example, we showed that we could make a small tweak and produce aeruginascin instead of psilocybin, and we showed that by introducing entirely foreign genes, we could make molecules that did not yet exist in nature.

J: Other studies, however, successfully demonstrated the production of psilocybin in E. coli.¹ Could you explain why did you chose brewer’s yeast and what was the advantage of it?

N: I think, first, it is good to explain why it is a good idea to produce psilocybin in living cells in the first place. Today, apart from our method, there are two main ways of getting psilocybin – either you have to grow the mushroom, or you have to synthesize it chemically. When it comes to the mushroom, if you have seen what a mushroom looks like, it is not that easy to grow, and the psilocybin accumulates in tiny quantities in the mushroom.

J: Psilocybin is also found not evenly distributed across the different parts of the mushroom, so I imagine that extracting psilocybin from large quantities of Psilocybe cubensis must be tricky.

N: Exactly! If we are thinking about commercial applications, we would need massive amounts of mushroom biomass. It would be challenging to extract, and the complexity of this process makes it very difficult for pharmaceutical applications. If we want to use psilocybin in humans, it needs to be very pure, and the production needs to be very consistent. On top of that, most pharmaceutical drugs are derived from non-renewable resources, including psilocybin. Synthetic psilocybin is derived from benzene, which is a fossil fuel.  It is also very environmentally hazardous and the chemical synthesis methods generate toxic waste, so there is undoubtedly an urgent need to develop a more sustainable way, which leads us to production in microorganisms.

And why yeast instead of E. coli? That’s an excellent question; in my mind, there are two reasons – the first is that yeast is  the world’s oldest example of domestication. A thousand years ago, humans started domesticating yeast to produce beer, and fast forward to today; we have this organism bred essentially to thrive in an industrial environment – it does exceptionally well in beer fermentation and ethanol production. That is because it has evolved over all these years to tolerate the very extreme conditions of industrial-scale fermentation.

Still, importantly for psilocybin, the other main reason is that yeast is a very close relative of Psilocybe mushrooms from an evolutionary point of view. They are both from the same kingdom – they are both fungi, so this makes a crucial difference if you want to express foreign genes in an organism; it helps if they are already closely related, and for Psilocybe this is very important. Hydroxylation, which is the key enzymatic step, does not work in bacteria such as E. coli. E. coli is actually missing an organelle – an essential piece of machinery that would allow this enzyme to work. Hence, reconstruction of the entire pathway is virtually impossible in bacteria. Other reports have successfully produced psilocybin in E. coli, but essentially, they had to circumvent this problem by feeding their strain a synthetic compound. From a cost point of view and from an environmental point of view, it is not really feasible. Our study has used sugar as a starting substrate, so it is very sustainable, and we can achieve a much lower cost of production, and our process is almost CO₂ neutral.

Photo by Thomas Thompson on Unsplash

J: The sustainability of the process is definitely a significant advantage over other methods. You have also fine-tuned the yeast metabolic pathway, but it is probably not optimized yet for large scale production. What exactly would you have to improve to make it optimal for production on an industrial scale?

N:  The main challenge is to increase the amount of sugar that gets converted into psilocybin. Beyond that, to reach commercial-scale production satisfactory enough to be used for human clinical trials, we need to scale the process from one liter to thousands of liters. The fermentation development is critical, and of course, the other issue that we need to look into is how to efficiently purify psilocybin from the fermentation broth.

J: How far is the work, do you think, from achieving a production protocol available to be used industrially? 

N: This work is what we are doing at Octarine right now. It is already feasible to produce small amounts of psilocybin, but to produce the quantities needed for human clinical trials and eventually commercial applications, there is still a little way to go.  Still, the biggest hurdle is the regulatory approval, so we can have a production process ready considerably faster than the regulatory bodies will give the authorization to use it.

J: You have used the method of introducing foreign pieces of DNA into the yeast genome. This has been done already with gene-editing techniques like CRISPR all over the world, and it is not a new thing to do, but there is always a risk involved in the process of playing around with genomes of living organisms, which may produce some unwanted effects. Have you observed any of these?

N: Indeed, it can be a big issue. Not only expressing foreign genes in heterologous hosts [an organism naturally lacking the gene of interest] but also just producing molecules which the organism has not encountered before. In our case, thankfully, we did not see any of these issues. That is another good reason for using yeast – it tolerates foreign gene expression very well and it typically does well when faced with a foreign metabolite. The natural host often produces these molecules for a very good reason, so there has to be a reason why mushrooms produce psilocybin. Often the produced compound acts as a deterrent, which means it is a toxin to microorganisms. This is the case with, for example, cannabinoids, which we also work with. Cannabis produces cannabinoids primarily as an antimicrobial, so if you are trying to produce it in a microorganism, you are going to come across toxicity effects. Thankfully we have not seen any issues so far in the psychedelics we are working with.

J: Right. You have also achieved a stable transformation of the cells, which means that the foreign genetic material is integrated forever.

N: Exactly! This is another excellent reason for using yeast. It is very easy to integrate straight into the genome and integrate stably, so essentially the genes are in there without any selection pressure or anything to force them to stay there.

J: Usually antibiotic resistance genes are transferred together with genes of interest, so that when an antibiotic is introduced into the growth medium the cells are continuously forced to express the foreign genes. You have managed to integrate your genes of interest without any antibiotic selection?

N: Yes, and that is important for large scale production, you do not want to have antibiotics or any sort of selection pressure, both from a cost point of view – antibiotics are expensive – but also from a human safety point of view – you do not want antibiotics in your mixture, and you also do not want any activation of the antibiotic resistance genes.

Photo by Thisisengineering on Unsplash

J: Next to all those impressive achievements, you have managed to do another thing – to synthesize a novel molecule that has not existed in nature before, N-acetyl-4-hydroxytryptamine. Could you tell us about this compound and if you are going to investigate it in more detail in the future?

N: We are not only interested in producing psilocybin; we are also interested in the range of other molecules that Psilocybe mushrooms produce. We were inspired by the fascinating findings in the research on cannabinoids, which shows that some of the minor cannabinoids have new or improved functions. For example, CBD seems to be very effective at treating epilepsy, but one of the minor cannabinoids, CBDv, potentially could be even better. The amount of evidence is growing, and it suggests that the same could be true for Psilocybe mushrooms, so we are, of course, very interested in all of the derivatives and all the intermediates that the Psilocybe mushroom produces.

Going beyond that, one of the things that we are very interested in, especially at Octarine, is how we can use biological machinery to create molecules that do not exist in nature. At least in theory, enzymes should be vastly superior to synthetic chemistry. They should be able to catalyze reactions that synthetic chemistry cannot do, do it much more efficiently, and under much more favorable conditions. The trick here is figuring out how you can ‘convince’ an enzyme to catalyze a reaction it does not normally do. That is a part of the core technology that we are developing at Octarine, but in this paper, we just wanted to demonstrate the potential of natural enzymes to be coaxed into catalyzing reactions, which they do not normally do.  That was an example with this molecule N-acetyl-4-hydroxytryptamine, which is essentially half psilocybin and half melatonin. In general, we are very interested in investigating the properties not only of novel molecules that are produced in our platform but also the properties of some of the minor tryptamines that Psilocybe mushrooms and other psychedelic organisms produce.

J: Melatonin is a sleep hormone found in the human brain and psilocybin acts on serotonin receptors. Do you think this new type of tryptamine could also have some psychoactive effects in humans?

N: I would say it is too early to speculate. This work is more about a production proof of concept, but what I can say is that, in general, the idea is that we are creating new molecules in the hope of creating a better version of psilocybin or a molecule that has a different therapeutic effect. This is essentially the work that is going on right now – we try to figure out what these molecules do and whether they could be interesting from a therapeutic point of view.

J: It seems like there is a whole new generation of compounds waiting to be discovered, which is very exciting! Now, imagine somebody gives you an unlimited grant for Octarine, for any research project. What would it be?

N: This is a very good question and what comes to my mind is that in nature, there are thousands and thousands of interesting molecules that have interesting therapeutic effects, and we have been exploiting these natural sources since, well, forever.

J: That is true in the indigenous context, but in Western medicine they have been relatively neglected.

N: Exactly, and I think part of the reason is that there is a big gap that exists between understanding what these molecules do and figuring out how we can produce them. There are plenty of examples of molecules that we know exist in nature, and we even know that they have remarkable therapeutic properties, but we do not have the tools yet to produce them in quantities suitable for pharmaceutical application.  For a very long time we had no idea how the natural organism produced them. It was only in the last few years that we actually figured out how cannabis makes cannabinoids and how Psilocybe mushrooms make psilocybin. However, for the thousands of other molecules, we have little idea how they are produced, and we have no idea which enzymes and which genes are responsible. I think this is a bottleneck in developing natural molecules for therapeutic applications.

Photo by Markus Spiske on Unsplash

J: What exactly would be the first big step to improve this situation?

N: In my opinion, the main problem is speed – we have methods in place for elucidating biosynthetic pathways, but they are incredibly laborious and time-consuming. There have been considerable advances in obtaining increasingly large data sets on cellular processes. Perhaps using things like machine learning or artificial intelligence to take some of the guesswork out of the interpretation of this data could be a significant improvement. We make some good guesses about what we think is going on, but then we spend a very long time testing it, and far too often… we are wrong.

J: So, computer modeling could definitely speed up the process.

N: I think so. Taking the human aspect out of it and improving our methods of figuring things out would definitely improve our best guesses on which genes are involved. It would be a giant leap in the field, I think.

J: I will keep my fingers crossed for the developments in Octarine. My last question relates to what you said before about the first time you pitched your idea to others and it was met with… not the most fertile ground. Do you have any hints for researchers and students about how to push for this kind of research?

N: I think that, at least in the research community, the stigma around these molecules is rapidly decreasing.  In my opinion, it is because we can look at the clinical data and it is fairly black and white that these molecules hold a lot of promise, so it is not the research community that needs to worry about stigma; it is the public perception which I think is a more significant issue. In general, a part of how I got into the field was looking at the clinical data and being convinced that there is something interesting there. I always think that a good place to start is to dive deep into the data and see for yourself the potential of these molecules.

One of the great things about this field, as well as with cannabinoids, is that it brings together people from entirely different backgrounds. I could never imagine that I would be working with all different kinds of researchers, but that just shows how promising these industries are and that it requires collaboration from so many different backgrounds. In my case, the background is yeast and microbiology. I have spent my career making biofuels and trying to decrease fossil fuel emissions, so it is fascinating how different experiences can be relevant. The field is developing thanks to people applying the skills they have picked up in one area and figuring out how it can be applied to the psychedelics industry. I think that would be my advice – look at the skills you have and try to see how they can be applied to this new industry because I really believe that there is so much opportunity for development in the ecosystem.

J: Thank you so much for this advice! One piece of good news that I could share with you is that the Central Institute of Mental Health (ZI) Mannheim have just recently announced the start of a psilocybin-depression study lead by Prof. Dr. Gerhard Gründer. The MIND Foundation participates in this research and our clinical partner OVID supports with therapists at the second study center in Berlin – and both are thus providing additional financial resources for the study. It is the first study of this kind with the prospect of being funded by German governmental funds.

N: I think that in the world, the momentum is very rapidly building, and I read about this the other day. It is a huge moment, since public funding is being used for psychedelic research. One thing that was really encouraging for us is that one of our investors is the Danish government.

J: That is amazing!

N: The Danish government has a venture fund and they are one of our biggest investors. For us, that is a hugely positive sign for industry in terms of overcoming the stigma – the fact that public institutions and even governments are getting behind this kind of research. Even the FDA has a lot of positive things to say about psychedelics and they are very pragmatic about this, so indeed, times are changing and I have no doubt that five years from now, this will not be an issue anymore and it will become clear that psychedelics can be used for therapeutic benefit.

J: As soon as the pharmaceutical industry recognizes the benefits?

N: Essentially, that is what we have seen with cannabinoids.

J: That is true; the therapeutic use of cannabinoids became mainstream so quickly.

N: It is essentially mainstream by now, right? The majority of people agree that cannabis is therapeutic and it is a pharmaceutical drug now, so seeing how that has changed in such a short amount of time makes me really think that psychedelics will closely follow.

J: It makes me optimistic as well, so fingers crossed for that and thank you so much for the talk!

N: Thanks, I appreciated the time.

For more on this and many other issues in psychedelic research, be sure to check out our INSIGHT 2021 conference program and pre-conference workshops.

References

1. Adams, A. M., Kaplan, N. A., Wei, Z., Brinton, J. D., Monnier, C. S., Enacopol, A. L., Ramelot, T. A., & Jones, J. A. (2019). In vivo production of psilocybin in E. coli. Metabolic engineering, 56:111–119.

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