by  Dr. Malin Vedøy Uthaug

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic substance that can be found in plants (Pachter et al. 1959), the secretion of the Incilius Alvarius toad (Weil and Davis 1994), and made synthetically (Hoshino 1936). The substance is well-known for its short-acting properties (depending on the route of administration) with subjective effects summarized in the following soundbite: ‘we are all one.’ This “sense of oneness” is similar to the experiences of ego dissolution (Nour et al. 2016) and mystical experiences (MacLean et al. 2011) evoked by other psychedelics which has been correlated with betterment in mental health-related symptoms (Barsuglia et al. 2017; Griffiths et al. 2006; Uthaug et al. 2019; Uthaug et al. 2018).

Despite being an understudied substance, current research suggests that the use of 5-MeO-DMT can evoke similar (therapeutic) effects as that of longer-acting psychedelics like psilocybin (magic mushrooms) (Barsuglia et al. 2017). Its ability to evoke the aforementioned subjective effects paired with its short-acting properties makes 5-MeO-DMT an attractive substance for Psychedelic Assisted Psychotherapy (PAP) as it could bypass some of the logistical and financial hurdles that stand in the way of individuals getting treatment. This is why I decided to study 5-MeO-DMT’s effects and its implications for aiding in the treatment of various mental health-related disorders, including substance use disorder.

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My name is Malin Vedøy Uthaug, and I am currently working as a Postdoctoral Researcher at the Centre for Psychedelic Research at Imperial College in London. I recently joined Entheon Biomedical as a scientific advisor to aid in their quest to develop a treatment for substance use disorder using 5-MeO-DMT. For the past three years, as part of my Ph.D. work at Maastricht University in The Netherlands, I have conducted several studies on both ayahuasca and 5-MeO-DMT to explore their respective effect on mental health. Ayahuasca is a ‘psychedelic tea,’ a plant concoction containing N,N-Dimethyltryptamine (DMT) and monoamine oxidase inhibitors, used historically in a shamanic ceremonial context in the Amazon (Riba et al. 2003). 5-MeO-DMT is a similar substance to DMT known for its fast-acting properties, evoking a psychedelic experience within seconds that can last for 15-40 minutes (depending on the route of administration) (Uthaug et al. 2020; Weil and Davis 1994). I decided to write my Ph.D. on these substances primarily because ayahuasca is used in a ceremonial context, which I believe the scientific and medical communities can learn much from and that it will help us inform the design of PAP moving forward. Secondly, 5-MeO-DMT is a rather understudied substance that appears to have a similar therapeutic potential to longer-acting psychedelics such as ayahuasca and psilocybin (magic mushrooms). The fact that 5-MeO-DMT was and still is an unexplored territory compared to other entices my inner adventuress and fuels my motivation to pursue a career in psychedelic research.

My doctoral dissertation’s main objective was to explore whether the ingestion of ayahuasca and 5-MeO-DMT in a naturalistic setting was related to improvement in mental health-related variables. Those variables could include depression, anxiety, stress, mindfulness, satisfaction with life, creativity, empathy), and whether such an improvement depends on the magnitude of the psychedelic experience (i.e., the experience of ego dissolution). The five original studies I carried out are summarized in my thesis titled; “The Exploration of Naturalistically Used Ayahuasca and 5-MeO-DMT; An assessment of their respective Sub-acute and Long-term effects on Mental Health Related Variables”

The thesis consists of seven chapters where Chapter 1 assesses the need for a new treatment option or mood-related disorders such as depression, while Chapter 2-3 and Chapter 4-6, summarizes the studies on ayahuasca and 5-MeO-DMT, respectively. Finally, Chapter 7 discusses the key findings of the studies in a broader perspective, explains the implications of the findings, and provides recommendations as we move into PAP’s future.

For all of my studies, I made use of ‘naturalistic observational design.’ This design makes observations and assessments (i.e., questionnaires and computer tasks) in individuals who voluntarily consume psychedelics like ayahuasca and 5-MeO-DMT in a naturalistic setting. There are drawbacks of this design, such as the lack of control for possible influencing non-pharmacological variables (i.e., set and setting, group dynamics, expectation, suggestibility, the potential bias of both researcher and participant). Despite those drawbacks, the design allowed me to collect valuable information that could engender future research and prospective clinical trials.

In a nutshell, my dissertation work suggests that both ayahuasca and 5-MeO-DMT used in a naturalistic setting is associated with persisting betterment (up to 4 weeks) in mental health-related variables (Chapter 2-6) and that this is correlated with the experience of ego dissolution (Uthaug 2020). Furthermore, the research suggests that 5-MeO-DMT may have immunomodulatory potential through the downregulation of cytokine IL-6 (a biomarker for inflammation) (Chapter 5). This echoes the findings of previously reported anti-inflammatory actions of 5-MeO-DMT (Dakic et al. 2017; Szabo et al. 2014) but warrants further longitudinal assessments. Additionally, a retrospective survey-study on the effects of different administration routes of 5-MeO-DMT (Chapter 6) indicated that there was no significant difference in impact and experiences of 5-MeO-DMT when administered through vaporization or intramuscular injection (IM). However, the results revealed that IM evoked the phenomenon of reactivation (defined as flashbacks/re-experiencing [parts of] the experience) less frequently, induces a slower onset of acute effects and had a strong potential to bring about the release of physical tension (somatic release). The results add weight to the clinical considerations of 5-MeO-DMT through IM by Sherwood and colleagues (2019), who identified IM as the most favourable route of administration of 5-MeO-DMT for the following reasons; 1) it avoids the first-pass metabolism; 2) has high bioavailability; 3) it allows for precise control of dosage, and 4) evokes a gentle onset with a slightly longer duration of effects. 

Although the current scientific information about 5-MeO-DMT points to a similar (therapeutic) potential as other psychedelics (i.e. psilocybin), the findings from Chapter 3 (manuscript under review) in my dissertation work suggest that non-pharmacological factors such as set and setting may be steering some of the improvement in mental health-related variables. The “naturalistic placebo-control” study on the effects of ayahuasca ingested in a neo-shamanic setting signifies that while improvement in empathy was attributed to ayahuasca’s pharmacological actions, reductions in effect (depression, anxiety and stress) were moderated by non-pharmacological factors such as expectation and learning. Although we did not conduct a similar study on 5-MeO-DMT, it may very well be the case that such non-pharmacological factors played a role in the improvement in mental health-related variables following 5-MeO-DMT use too. Such factors may also include social desirability bias (Grimm 2010) and spiritual bypassing (Fox et al. 2017).

The latter is defined as the tendency to use spiritual ideas and practices to sidestep or avoid facing unresolved emotional issues, psychological wounds, and unfinished developmental tasks. Based on my observations in the field, and by watching over a hundred sessions in the underground, it seems that spiritual bypassing is a common occurrence in the underground where 5-MeO-DMT is used. My reasoning behind that is due to knowledge of the rapid onset and offset of 5-MeO-DMTs effects (through vaporization), and high doses used, which might push an individual to dissociate psychologically. Psychological dissociation is defined in Ralph Metzner’s book as ‘unconsciousness of one’s own bodily postures and gestures, vocalisations and verbalizations, as well as more or less disconnect of total awareness of ones surroundings‘ (2013). If a person dissociates during their experience with 5-MeO-DMT, they will not be ‘online’ to (somewhat) consciously work through material that may be causing them distress. Thus, there will be no resolution of unprocessed, unconscious material, and therefore it is very likely that the same pain will return. As Carl Jung once stated: what you resist persists.

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Additionally, from speaking with many participants and facilitators before and after sessions, I became aware of romanticized ideas and expectations that they held about 5-MeO-DMT. Many believed that medicine would somehow set them free from various mental health-related difficulties. In other words, the substance would do the healing work for them. The idea of a “quick fix” is not unusual in our society and is evident in other areas besides mental health. If I go on this vacation, I’ll be happier! If I get this job, I’ll be more satisfied.  However, these are nothing but fabricated subjective illusions. The only thing you need is to take full responsibility for yourself and so too for your healing. The solution isn’t externally, but internally. Psychedelics like 5-MeO-DMT may aid in that internal process, but it won’t do the work for you nor anyone else. 

I believe it is about time that beliefs about a ‘quick fix’ are reconsidered, not only by participants and facilitators of such ceremonies but also by individuals on a societal level. The reason for this is because healing is hard. If it were easy, we wouldn’t have a worldwide mental health epidemic and an urgent need for a novel treatment option for mental health-related disorders like addiction. 

Although more research is needed, there is scientific literature supporting 5-MeO-DMT as an adjunct in therapy for various mental disorders. The idea would be to use it as a catalyst for a therapeutic process (i.e., Psychedelic Assisted Psychotherapy). A person would be supported by a therapist to lean into painful and repressed thoughts. Ideally, the patient undergoes therapeutic sessions before and after to prepare for and integrate the therapy with 5-MeO-DMT. The latter is particularly important, for as the title of the book by Jack Kornfield reads; after the ecstasy, the laundry.

What makes the effects of 5-MeO-DMT any different from the effects of other psychedelics? What does 5-MeO-DMT do that psilocybin or ayahuasca can’t? We do not know yet, but what we do know is this: Previous reports from participants who received ayahuasca-assisted therapy stated that it helped them release the pain or trauma that was being masked by their substance use (Argento et al. 2019). Ayahuasca, it has been suggested, exerts its anti-addictive effect through biochemical, physiological, psychological, and transcendent pathways (Liester and Prickett 2012). Firstly, ayahuasca targets several brain regions associated with addiction, and secondly, reduces dopamine levels in mesolimbic pathways related to the development and maintenance of chronic substance use.

Furthermore, it has shown to help resolve trauma, and finally, induces transcendent experiences pathways (Liester and Prickett 2012).

Additionally, the setting (ritualistic) in which ayahuasca is used and the sense of community it facilitates has also been suggested as an essential factor in addiction cessation (Talin and Sanabria 2017). The latter, a group setting, has shown to be particularly important in the treatment of addiction (Flores 2001). 5-MeO-DMT might hold a similar potential as ayahuasca for the treatment of substance use disorder for similar reasons. Despite not being used in a similar group setting, research has shown that 5-MeO-DMT target several brain areas associated with addiction (Barsuglia et al. 2018; Dakic et al. 2017), and elicit profound mystical experiences akin to that of high-dose psilocybin experiences (Barsuglia et al. 2017). Furthermore, previous research suggests that 5-MeO-DMT has low addiction potential and excellent safety profile (Davis et al. 2018), anti-inflammatory properties through the sigma-1 receptor (Szabo et al. 2014; Uthaug et al. 2019a), the therapeutic potential for various mental health disorders (Davis et al. 2018).

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This still doesn’t tap into what makes 5-MeO-DMT so different, but I hope that the following might explain why: 

In my opinion, while being mindful of my own bias, it seems to me that 5-MeO-DMT has this unique ability to amplify a person’s interoception (sense of the internal state of the body) to a different, and yet to be understood extent which I think can have important implications for treatment of addiction as well as Post-traumatic Stress Disorder (PTSD). From my perspective, it seems that 5-MeO-DMT can pierce through the dissociative veil that is ‘protecting’ people with addiction or PTSD from unprocessed material like trauma and thus get them in contact with their body. Under the influence of 5-MeO-DMT, while in a supportive therapeutic context, a person could have a chance to get in touch with the reality of the autonomic nervous system and the dysregulation that may be in it. This provides an opportunity to work through material that has been repressed and caused “issues in the tissues” (trauma).

With regards to addiction and based on statements and writings by Dr. Gabor Maté, someone who is misusing a substance (or more) is doing so to dim away or run away from pain. In his view, the place to target in treatment is not the addiction but the illness that is causing it. According to Dr. Maté that pain needs to be felt through to go away for ‘addiction starts and ends with pain.’ 

Like Dr. Gabor Maté, I also believe that pain needs to be acknowledged and felt. If not, it will continue to return like ‘pop-up notifications’ on a smart-phone as a reminder that something needs attention. I also believe that 5-MeO-DMT may help individuals feel through these things if done in the right setting with proper support from a therapist. The therapeutic relationship is also a key component of treatment success.

That said, it is premature to make conclusions about the place for 5-MeO-DMT in mental health treatments at the current time. There are still many unanswered questions to address, which will require rigorous research designs, testing and analysis. To that end, I am delighted to have joined Entheon Biomedical as an advisor. As we continue to search for, investigate and find the answers to many of these lingering questions, with the ultimate aim of developing therapies that will support those recovering from substance use disorder.  

 

References

Barsuglia J, Davis A, Palmer R (2017a) Characterization of mystical experiences occasioned by 5-MeO-DMT-containing toad bufotoxin and comparison with prior psilocybin studies. Psychedelic Sci 23

Barsuglia JP, Davis AK, Palmer R, Lancelotta R, Windham-Herman M, Peterson K, Polanco M, Grant R, griffiths R (2017b) Characterization of Mystical Experiences Occasioned by 5-MeO-DMT-Containing Toad Bufotoxin and Comparison with Prior Psilocybin Studies 3rd International Psychedelic Science Conference

Barsuglia JP, Polanco M, Palmer R, Malcolm BJ, Kelmendi B, Calvey T (2018) A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder. Progress in brain research 242: 121-158

Dakic V, Nascimento JM, Sartore RC, de Moraes Maciel R, de Araujo DB, Ribeiro S, Martins-de-Souza D, Rehen SK (2017) Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific reports 7: 12863

Davis AK, Barsuglia JP, Lancelotta R, Grant RM, Renn E (2018) The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: benefits, consequences, patterns of use, subjective effects, and reasons for consumption. Journal of Psychopharmacology 32: 779-792

Flores PJ (2001) Addiction as an attachment disorder: Implications for group therapy. International Journal of Group Psychotherapy 51: 63-81

Fox J, Cashwell CS, Picciotto G (2017) The opiate of the masses: Measuring spiritual bypass and its relationship to spirituality, religion, mindfulness, psychological distress, and personality. Spirituality in Clinical Practice 4: 274

Griffiths RR, Richards WA, McCann U, Jesse R (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology 187: 268-283

Grimm P (2010) Social desirability bias. Wiley international encyclopedia of marketing

Hoshino TaS, K. (1936) Über die synthese des bufotenin-methyl-äthers (5-methoxy-n-dimethyl-tryptamin) und bufotenins (synthesen in der indol-gruppe. xv). Bull Chem Soc Jpn 11: 221-224

Liester MB, Prickett JI (2012) Hypotheses regarding the mechanisms of ayahuasca in the treatment of addictions. Journal of psychoactive drugs 44: 200-208

MacLean KA, Johnson MW, Griffiths RR (2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of Psychopharmacology 25: 1453-1461

Metzner R (2013) The Toad and the Jaguar: a Field Report of Underground Research on a Visionary Medicine: Bufo alvarius and 5-Methoxy-dimethyltryptamine. Regent Press, Regent Press

Nour MM, Evans L, Nutt D, Carhart-Harris RL (2016) Ego-Dissolution and Psychedelics: Validation of the Ego-Dissolution Inventory (EDI). Frontiers in Human Neuroscience 10: 269

Pachter IJ, Zacharias DE, Ribeiro O (1959) Indole alkaloids of Acer saccharinum (the Silver Maple), Dictyoloma incanescens, Piptadenia colubrina, and Mimosa hostilis. The Journal of Organic Chemistry 24: 1285-1287

Sherwood A, Kaylo K, Kargbo R, Davis A, Lancelotta R, Uthaug M, Barrow B (2019) CLINICAL CONSIDERATION OF 5-MeO-DMT International Forum on Consciousness, Madison, Wisconsin

Szabo A, Kovacs A, Frecska E, Rajnavolgyi E (2014) Psychedelic N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PloS one 9

Talin P, Sanabria E (2017) Ayahuasca’s entwined efficacy: An ethnographic study of ritual healing from ‘addiction’. International Journal of drug policy 44: 23-30

Uthaug M, Lancelotta R, Szabo A, Riba J, Ramaekers J (2019a) Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgement. Psychopharmacology: 1-13

Uthaug M, Lancelotta R, van Oorsouw K, Kuypers K, Mason N, Rak J, Šuláková A, Jurok R, Maryška M, Kuchař M (2019b) A single inhalation of vapor from dried toad secretion containing 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. Psychopharmacology: 1-14

Uthaug M, van Oorsouw K, Kuypers K, van Boxtel M, Broers N, Mason N, Toennes S, Riba J, Ramaekers J (2018) Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution. Psychopharmacology 235: 2979-2989

Uthaug MV (2020) The Exploration of Naturalistically used Ayahuasca and 5-MeO-DMT; An assessment of their respective Sub-acute and Long-Term effects on Mental Health Related Variables. Maastricht University

Weil AT, Davis W (1994) Bufo alvarius: a potent hallucinogen of animal origin. J Ethnopharmacol 41: 1-8