OPEN Foundation

Other disciplines

How AI and language can help predict psychedelic treatment outcomes

Language is increasingly being used as a diagnostic tool in biomedical research and has recently begun to be leveraged in psychedelic research. It turns out analysing language through machine learning can help increase diagnostic accuracy and predict psychedelic treatment outcomes, which will play an important role in the future of psychedelic research.

Author: Maxim Siegel
Illustration: Anna Temczuk

Language as a diagnostic tool

Sigmund Freud and Carl Jung are arguably the most influential figures of the 20th century when it comes to psychological functioning and the human mind. Although their theories about the psyche eventually differed, they both considered language as a manifestation of the unconscious. Indeed, Freudian psychoanalysis proposed free association as a way of gaining access to unconscious processes, while Jungian psychology considered every act of speech as a psychic event, with each word carrying particular archetypal energies. Fast forward 100 years, innovations in biomedical science and technology have transformed language into a diagnostic tool for both affective and degenerative neuropathology, and language is increasingly being used as such in psychedelic research. 

Natural Language Processing, also known as NLP, is a field combining linguistics, computer science, and artificial intelligence. It applies computational techniques to the analysis and synthesis of natural language. One of the problems with natural language is that it often contains ambiguities in meaning, also known as semantic ambiguities, which are easily detectable by humans but not so much by computers. Luckily, models such as distributional semantics, count vectorisation and encoder-decoder modeling help decipher semantic ambiguities. Since its development, NLP has predominantly been used as an automation tool for google searches, spam email categorisation, voice recognition, and translations, but it is increasingly being used as a diagnostic tool in medicine. 

A few years ago, a team of researchers in Canada were able to identify linguistic features within narrative speech that were specific to Alzheimer’s Disease. Semantic impairment, acoustic abnormality, and syntactic impairment were all factors enabling the accurate identification of Alzheimer’s, based on patients’ short descriptions of a picture.

This led to the realisation that beyond its unconscious, psyche-revealing properties, natural language might also possess neuropathology-revealing properties. So what if language could be used as a biomarker for psychosis or affective disorders? More importantly, what if language could be used as a predictor of treatment outcome? It turns out these tools have already begun to be leveraged in psychedelic research.

Around four years ago, a team of researchers from Buenos Aires University’s Applied Artificial Intelligence Lab and Imperial College London’s Psychedelic Research Group decided to test a combination of NLP and machine learning. They tested this combination both as a diagnostic tool for patients suffering from treatment-resistant depression, and as a predictor of treatment outcome following a psilocybin challenge. 

Participants first underwent a psychological interview known as an Autobiographical Memory Test, an interview used to assess the degree of specificity of autobiographical memory. This interview was analysed using an NLP method known as Emotional Analysis, which quantifies the emotional content of spoken or written text. The NLP output was then fed as input into a machine learning algorithm, known as a classifier, trained at recognising depressed patients. 

On the basis of emotional analysis and specifically the use of positive words, which were less frequently used in depressed patients compared to healthy controls, the classifier was able to differentiate between depressed patients and healthy controls with a mean accuracy of 82.85%, close to 15% better than the mean accuracy of general practitioners unassisted by screening tests.  

Accurate Predictions

Perhaps more impressive than its ability to differentiate between depressed patients and healthy controls, was the classifier’s ability to differentiate between treatment responders and non-responders. Based on the same parameters it had previously used to diagnose depressed patients (NLP output and positive word frequency), the classifier was able to predict which patients would respond to a psilocybin challenge and which would not. 

Only the patients identified as “responders” were given the psilocybin challenge, whereas the “non-responders” were removed from the treatment arm. This manoeuvre had the effect of improving overall treatment response by 34% compared to the original experiment.  

Last year, a team at Johns Hopkins University used a similar approach to predict changes in substance use following a psychedelic challenge. They recruited individuals who reported quitting or reducing a number of addictive drugs following a psychedelic experience, and asked them for a verbal narrative of the experience.

They used an NLP method known as Latent Semantic Analysis, which analyses the relationship between semantic structures across different texts, to derive topic models that described the psychedelic narratives. These topic models were fed as input into three different machine learning algorithms to predict long-term drug reduction. The machine learning algorithms had an average predictive accuracy of 65%, and additional analyses revealed between-group differences in psychedelic experience narratives based on the derived topic models.

John Hopkins’ semantic analysis of psychedelic narratives and Buenos Aires University’s use of machine learning to identify patients suffering from depression, are two early but powerful examples of the ways in which language can be leveraged in psychedelic research through new technology.

The combination of NLP and machine learning as methods to analyse language have reliably shown their value as both diagnostic and predictive tools, and can be used to optimise clinical trials. They allow for a more personalised treatment, whereby non-responders are spared the emotional rollercoaster of an acute psychedelic experience. 

Freudian psychoanalysis, Jungian psychology and NLP share the conception that hidden semantic structures within language are associated with underlying processes, whether psychological, social, or physiological. A century ago, language was the glass through which Freud saw the unconscious mind. Today, language analysed by machine learning may very well be one of the prisms through which we can come to understand the psychedelic experience.

References:

1. N.B. This is different from “Neuro-linguistic programming” (NLP), which is a form of psychotherapy developed in California in the 1970s, mainly used as a method of personal development by promoting skills including communication.

2. Fraser, K. C., Meltzer, J. A., & Rudzicz, F. (2016). Linguistic Features Identify Alzheimer’s Disease in Narrative Speech. Journal of Alzheimer’s disease : JAD, 49(2), 407–422. https://doi.org/10.3233/JAD-150520

3. Carrillo, F., Sigman, M., Fernández Slezak, D., Ashton, P., Fitzgerald, L., Stroud, J., Nutt, D. J., & Carhart-Harris, R. L. (2018). Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression. Journal of affective disorders, 230, 84–86. https://doi.org/10.1016/j.jad.2018.01.006

4. Carey, M., Jones, K., Meadows, G., Sanson-Fisher, R., D’Este, C., Inder, K., Yoong, S. L., & Russell, G. (2014). Accuracy of general practitioner unassisted detection of depression. The Australian and New Zealand journal of psychiatry, 48(6), 571–578.

5. The original experiment consisted of a combination of psychotherapy and pharmacological treatment with psilocybin that resulted in 41% treatment response. By differentiating between treatment responders and non-responders this experiment resulted in 75% treatment response.

6. Cox, D. J., Garcia-Romeu, A., & Johnson, M. W. (2021). Predicting changes in substance use following psychedelic experiences: natural language processing of psychedelic session narratives. The American journal of drug and alcohol abuse, 47(4), 444–454. https://doi.org/10.1080/00952990.2021.1910830

A Really Good Day : How Microdosing Made a Mega Difference in My Mood, My Marriage and My Life

A Really Good Day : How Microdosing Made a Mega Difference in My Mood, My Marriage and My Life. Ayelet Waldman. Little, Brown Book Group. ISBN: 978-1472152893

A first-hand account of microdosing and its positive effects. Waldman charts her experience over the course of a month and looks into the newest research and policies governing LSD. This book will be interesting for anyone curious about how microdosing LSD can affect daily living.

Buy this book through bookdepository.com and support the OPEN Foundation

Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness

Abstract

Background: With support from the Radcliffe Institute for Advanced Study at Harvard University, we convened researchers representing palliative care, psychosocial oncology, spiritual care, oncology, and psychedelic-assisted therapies. We aimed to define priorities and envision an agenda for future research on psychedelic-assisted therapies in patients with serious illness. Over two days in January 2020, participants engaged in an iterative series of reflective exercises that elicited their attitude and perspectives on scientific opportunities for this research. Objectives: The aim of the study is to identify themes that shape priorities and an agenda for research on psychedelic-assisted therapy for those affected by serious illness. Methods: We collected data through preconference interviews, audio recordings, flip charts, and sticky notes. We applied thematic qualitative analysis to elucidate key themes. Results: We identified seven key opportunities to advance the field of psychedelic-assisted therapies in serious illness care. Four opportunities were related to the science and design of psychedelic-assisted therapies: clarifying indications; developing and refining therapeutic protocols; investigating the impact of set and setting on therapeutic outcomes; and understanding the mechanisms of action. The other three pertained to institutional and societal drivers to support optimal and responsible research: education and certification for therapists; regulations and funding; and diversity and inclusion. Additionally, participants suggested epistemological limitations of the medical model to understand the potential value and therapeutic use of psychedelics. Conclusions: Medicine and society are witnessing a resurgence of interest in the effects and applications of psychedelic-assisted therapies in a wide range of settings. This article suggests key opportunities for research in psychedelic-assisted therapies for those affected by serious illness.

Beaussant, Y., Tulsky, J., Guérin, B., Schwarz-Plaschg, C., Sanders, J. J., & Radcliffe Institute for Advanced Study Working Group on Psychedelic Research in Serious Illness (2021). Mapping an Agenda for Psychedelic-Assisted Therapy Research in Patients with Serious Illness. Journal of palliative medicine, 24(11), 1657–1666. https://doi.org/10.1089/jpm.2020.0764

Link to full text

Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice

Abstract

Psychedelic and mindfulness interventions have been shown to improve mental ill-health and wellbeing, with a range of clinical processes and effects in common. However, each appear to contain specific challenges in the context of mental health treatment. In this Perspective, we focus on a set of distinct affordances, “useful differences”, within psychedelic and mindfulness interventions that might address common challenges within the other intervention. Accordingly, we propose a set of applied synergies, indicating specific ways in which these two promising interventions might be combined for greater benefit. Metaphorically, on the journey toward mental health and wellbeing, we propose that psychedelic treatments may serve the role of Compass (initiating, motivating, and steering the course of mindfulness practice), with mindfulness interventions serving the role of Vehicle (integrating, deepening, generalizing, and maintaining the novel perspectives and motivation instigated by psychedelic experience). We outline a set of testable hypotheses and future research associated with the synergistic action of psychedelic and mindfulness interventions toward improved clinical outcomes.

Payne, J. E., Chambers, R., & Liknaitzky, P. (2021). Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice. ACS pharmacology & translational science, 4(2), 416–423. https://doi.org/10.1021/acsptsci.1c00034

Link to full text

Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice

Abstract

Psychedelic Harm Reduction and Integration (PHRI) is a transtheoretical and transdiagnostic clinical approach to working with patients who are using or considering using psychedelics in any context. The ongoing discussion of psychedelics in academic research and mainstream media, coupled with recent law enforcement deprioritization of psychedelics and compassionate use approvals for psychedelic-assisted therapy, make this model exceedingly timely. Given the prevalence of psychedelic use, the therapeutic potential of psychedelics, and the unique cultural and historical context in which psychedelics are placed, it is important that mental health providers have an understanding of the unique motivations, experiences, and needs of people who use them. PHRI incorporates elements of harm reduction psychotherapy and psychedelic-assisted psychotherapy, and can be applied in both brief and ongoing psychotherapy interactions. PHRI represents a shift away from assessment limited to untoward outcomes of psychedelic use and abstinence-based addiction treatment paradigms and toward a stance of compassionate, destigmatizing acceptance of patients’ choices. Considerations for assessment, preparation, and working with difficult experiences are presented.

Gorman, I., Nielson, E. M., Molinar, A., Cassidy, K., & Sabbagh, J. (2021). Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice. Frontiers in psychology, 12, 645246. https://doi.org/10.3389/fpsyg.2021.645246

Link to full text

Associations between lifetime classic psychedelic use and markers of physical health

Abstract

Background: In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence physical health.

Aims: The purpose of the present study was to investigate the associations between lifetime classic psychedelic use and markers of physical health.

Methods: Using data from the National Survey on Drug Use and Health (2015-2018) with 171,766 (unweighted) adults aged 18 or above in the United States, the current study examined the associations between lifetime classic psychedelic use and three markers of physical health (self-reported overall health, body mass index, and heart condition and/or cancer in the past 12 months) while controlling for a range of covariates.

Results: Respondents who reported having tried a classic psychedelic at least once in their lifetime had significantly higher odds of greater self-reported overall health and significantly lower odds of being overweight or obese versus having a normal weight. The association between lifetime classic psychedelic use and having a heart condition and/or cancer in the past 12 months approached conventional levels of significance, with lower odds of having a heart condition and/or cancer in the past 12 months for respondents who had tried a classic psychedelic at least once.

Conclusion: The results of the present study suggest that classic psychedelics may be beneficial to physical health. Future research should investigate the causal effects of classic psychedelics on physical health and evaluate possible mechanisms.

Simonsson, O., Sexton, J. D., & Hendricks, P. S. (2021). Associations between lifetime classic psychedelic use and markers of physical health. Journal of psychopharmacology (Oxford, England), 35(4), 447–452. https://doi.org/10.1177/0269881121996863

Link to full text

The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges

Abstract

Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

Dos Santos, R. G., Bouso, J. C., Rocha, J. M., Rossi, G. N., & Hallak, J. E. (2021). The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges. Risk management and healthcare policy, 14, 901–910. https://doi.org/10.2147/RMHP.S300656

Link to full text

The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology

Abstract

This review illustrates the relevance of shamanism and its evolution under effects of psilocybin as a framework for identifying evolved aspects of psychedelic set and setting. Effects of 5HT2 psychedelics on serotonin, stress adaptation, visual systems and personality illustrate adaptive mechanisms through which psychedelics could have enhanced hominin evolution as an environmental factor influencing selection for features of our evolved psychology. Evolutionary psychology perspectives on ritual, shamanism and psychedelics provides bases for inferences regarding psychedelics’ likely roles in hominin evolution as exogenous neurotransmitter sources through their effects in selection for innate dispositions for psychedelic set and setting. Psychedelics stimulate ancient brain structures and innate modular thought modules, especially self-awareness, other awareness, “mind reading,” spatial and visual intelligences. The integration of these innate modules are also core features of shamanism. Cross-cultural research illustrates shamanism is an empirical phenomenon of foraging societies, with its ancient basis in collective hominid displays, ritual alterations of consciousness, and endogenous healing responses. Shamanic practices employed psychedelics and manipulated extrapharmacological effects through stimulation of serotonin and dopamine systems and augmenting processes of the reptilian and paleomammalian brains. Differences between chimpanzee maximal displays and shamanic rituals reveal a zone of proximal development in hominin evolution. The evolution of the mimetic capacity for enactment, dance, music, and imitation provided central capacities underlying shamanic performances. Other chimp-human differences in ritualized behaviors are directly related to psychedelic effects and their integration of innate modular thought processes. Psychedelics and other ritual alterations of consciousness stimulate these and other innate responses such as soul flight and death-and-rebirth experiences. These findings provided bases for making inferences regarding foundations of our evolved set, setting and psychology. Shamanic setting is eminently communal with singing, drumming, dancing and dramatic displays. Innate modular thought structures are prominent features of the set of shamanism, exemplified in animism, animal identities, perceptions of spirits, and psychological incorporation of spirit others. A shamanic-informed psychedelic therapy includes: a preparatory set with practices such as sexual abstinence, fasting and dream incubation; a set derived from innate modular cognitive capacities and their integration expressed in a relational animistic worldview; a focus on internal imagery manifesting a presentational intelligence; and spirit relations involving incorporation of animals as personal powers. Psychedelic research and treatment can adopt this shamanic biogenetic paradigm to optimize set, setting and ritual frameworks to enhance psychedelic effects.

Winkelman M. J. (2021). The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology. Frontiers in pharmacology, 12, 619890. https://doi.org/10.3389/fphar.2021.619890

Link to full text

Trends in the Top-Cited Articles on Classic Psychedelics

Abstract

This study was designed to identify trends in the top-cited classic psychedelic publications. The top 50 publications on classic psychedelics with the greatest total of number of citations and annual citation rate were identified and pooled. Unique articles (n = 76) were dichotomized by median year of publication (2010.5); the differential distribution of study characteristics between the “Recent Cohort” (n = 38) and “Older Cohort” (n = 38) were documented. The Recent Cohort had a greater annual citation rate (median 76.0, IQR 38.5 to 101.5) compared to the Older Cohort (median10.0, IQR 5.2 to 19.3, p < .001). The Recent Cohort included a greater number of clinical studies (n = 26 [68.4%] vs. n = 9 [23.7%]) while the Older Cohort included more basic science and preclinical studies (n = 21 [55.3%] vs. n = 2 [5.3%], p < .001). Psilocybin was the predominant psychedelic studied in the Recent Cohort (n = 25 [65.8%] vs. n = 9 [23.7%]) while lysergic acid diethylamide (LSD) was predominantly studied in the Older Cohort (n = 25 [65.8%] vs. n = 18 [47.4%], p = .013). The Recent Cohort included more studies examining affective disorders (n = 15 [39.5%] vs. n = 3 [7.9%]) and substance use disorders (n = 6 [15.8%] vs. n = 0 [0.0%]), while the Older Cohort included a greater number of pharmacological outcomes (n = 29 [76.3%] vs. n = 6 [15.8%], p < .001). This study identified and documented trends in the top-cited classic psychedelic publications. The field is continuing to form a foundational understanding of the pharmacological effects of psychedelics and is now advancing with the identification of therapeutic uses within clinical populations.

Lawrence, D. W., Sharma, B., Griffiths, R. R., & Carhart-Harris, R. (2021). Trends in the Top-Cited Articles on Classic Psychedelics. Journal of psychoactive drugs, 53(4), 283–298. https://doi.org/10.1080/02791072.2021.1874573

Link to full text

Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway

Abstract

Aims: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis.

Materials and methods: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo.

Key findings: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo.

Significance: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Zhu, Y. G., Lv, Y. X., Guo, C. Y., Xiao, Z. M., Jiang, Q. G., Kuang, H., Zhang, W. H., & Hu, P. (2021). Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway. Life sciences, 270, 119112. https://doi.org/10.1016/j.lfs.2021.119112

Link to full text