Researchers in biological psychiatry are currently progressing within a ‘third wave’ of discussions, as described by Henrik Walter , to develop new approaches for investigating and classifying psychiatric disorders. According to Walter, the first wave of biological psychiatry was characterized by the linking of mental disorders to physiological processes, while the second wave was driven by the discoveries that genetics and medication could influence mental disorders. Now, in the face of under-powered research and overestimation of neurobiological explanations, third wave discussions highlight the importance of big data-driven multilevel approaches using predictive modelling and allocate emphasis on the ‘mental’ of mental disorders in the search for aetiology and treatment. Yarkoni and Westfall  suggest taking into account a range of epistemological levels, including environmental and behavioral, while modeling psychiatric disorders; and subsequently evaluating the capacity of these models to predict disorder-specific symptoms. Walter suggests that psychiatric disorders may be described as disorders of consciousness and/or intentionality, and that a philosophy of mind perspective can help to better understand these psychological constructs and how they might relate to neurological mechanisms. In this essay, I suggest that research with psychedelic substances can, to a certain extent, facilitate these goals.
EARLY IMPACT OF PSYCHEDELIC SUBSTANCES
In 1956, Humphry Osmond  first classified serotonergic hallucinogens as ‘psychedelic’, meaning ‘mind-manifesting’. He chose this name to highlight their capacity to reveal latent or unconscious aspects of the mind.
Researchers had already begun to investigate psychedelic substances in the late 1930s . This was at the beginning of the ‘second wave’ of biological psychiatry, when the potential neurochemical underpinnings of psychiatric disorders were first hypothesized. Psychedelic research of the time sparked models and theories still acknowledged in biological psychiatry today. Researchers investigating the psychoactive properties of mescaline, a serotonergic hallucinogen, were among the first to develop a neurochemical model of a psychosis [5,6]. Instead of taking the usual backward-engineering approach to investigating a disorder, they were the first to attempt manipulating neurobiology to induce symptoms which together satisfied the criteria of a classified mental disorder. This later led to the still prominent NMDA model of schizophrenia [7-9]. Insights regarding the neurochemical mechanisms of serotonin were largely influenced by the discovery and research on a chemical with a structure very similar to serotonin: lysergic acid diethylamide, much better known today as LSD. The effects of both of these chemicals in the brain were studied during the same period of time and it was quickly recognized that LSD interacts with the processes of serotonin . Since LSD and other serotonergic hallucinogens had already been used to model psychosis, LSD became a tool to study the role of serotonin on behavior. This research launched great academic interest in brain chemistry and catalyzed the idea that neurochemical events could influence behavior and thereby play a role in psychopathology [11,12]. At the same time, psychiatrists were realizing that psychedelic substances also showed potential for treating various mental disorders . Unfortunately, the inferences we can make using these early studies are limited because they employed outdated methodologies and often did not implement placebo-control groups.
HOW CAN PSYCHEDELICS FACILITATE GOALS OF BIOLOGICAL PSYCHIATRY TODAY?
Much in the same way as early psychedelic research helped illuminate the relations between certain mental phenomena and the underlying neurochemical processes, so can future psychedelic research help elucidate the links between cognition and biology. A major focus of current biological psychiatry is to view psychiatric disorders as interacting and dynamic processes which are not just of various neuro-biological levels, but also mental and environmental . Psychedelics may help develop this perspective since their effects can be studied from a very broad range of epistemological levels, including pharmacological, psychological, clinical, philosophical, anthropological, and societal levels. Through stimulating serotonin receptors, psychedelics initiate deep alterations in common mental functions including basic cognitive processes and mental constructs (e.g. working memory and the sense of self) . Thus, research using psychedelic substances is intrinsically multi-level and can help elucidate the biological mechanisms underlying various properties of the mind. Moreover, clinical treatments with these substances prescribe a multi-level approach, combining the manipulation of neurobiology with psychotherapeutic strategies and specific treatment settings. Furthermore, the study of psychedelics may help bridge western biological psychiatry with indigenous healing traditions, as well as shedding light on the role of spirituality and the sense of “awe” in well-being and treatment.
INVESTIGATING THE ‘MENTAL’ IN MENTAL DISORDERS: THE SENSE OF SELF
Discussions in philosophy of mind have strong implications for our concept of ‘self’: what the function of ‘me’ is and how this experience comes about. The concept of self is also relevant in discussions regarding mechanisms and symptoms of various psychiatric disorders . The sense of self in depressive  and anxiety  disorders is subject to evaluations of inadequacy, in narcissistic personality disorder  the self is grandiositized, in dissociative identity disorder  it is fragmented, in schizophrenia  some aspects of self-concept are disrupted.
For decades, researchers and psychedelic-drug users have reported that psychedelics can strongly disrupt the sense of self, and that this “disintegration” of the self is part of the core of the psychedelic experience. These reports initiated the development of questionnaires to assess self-disintegration [20,21], studies on the neural correlates of self , and facilitated the development of philosophical theories of the self (ie. narrative and embodied self , self as an emergent property of binding processes ). Researchers have further hypothesized that this self-disintegration, also called drug-induced ego-dissolution can lower psychological defenses and that in therapy this disintegration can provide the patient with sufficient space to reconstruct a more adaptive self-concept . Indeed findings thus far reveal that the drug-induced ego-dissolution, when experienced with positive emotions (labelled ‘oceanic boundless’), was associated with improved clinical outcomes in patients with depression  and well-being in patients with life-threatening cancer . Thus, by providing a biochemical model of self-disintegration, psychedelics can aid further investigations of the construction and mechanisms of the self-concept. These investigations could contribute to biological psychiatry by elucidating a mental property that is often disturbed in psychiatric patients and by prompting theories on treating such disturbances . Of course it is important to recognize that the self-disintegration as modeled by psychedelics may not generalize to self-disintegration through other means. Nonetheless, we can consider psychedelics as tools to biochemically manipulate certain mental functions. Moreover, we can allow research with psychedelics to inspire us in the direction of modelling mental functions and behaviors through new means, such as novel substances, or less invasive techniques.
FROM MULTILEVEL MODELS TO MULTILEVEL TREATMENT: PSYCHEDELIC-ASSISTED THERAPY
Currently, the most common approach to multilevel treatment entails considering several techniques that have independently shown promising effects and attempting to combine them in order to maximize treatment outcomes . For example, medications might be prescribed in order to sufficiently stabilize a patient to engage in psychotherapy. The administration of psychedelics in therapy is often termed ‘psychedelic-assisted therapy’ or ‘psychedelic psychotherapy’ and inherently develops this multilevel approach further by investigating the synergistic effects of biochemical alterations with psycho-therapeutic strategies . This synergistic effect is hypothesized to lower psychological defenses, facilitate adaptive emotional insights, increase the malleability of the patient’s belief system, and allow stronger access to autobiographical memories [31,32]. The clinical trials thus far suggest that only a few sessions are needed to obtain clinically significant positive outcomes, and that these improvements can remain significant after 6 months [33-36] and up to 4.5 years . This also indicates that psychedelic-assisted therapy could be more cost- and time-efficient than most current treatments [37,38]. Researchers are now attempting to clarify the specific biochemical process by which psychedelics aid therapy and which psycho-therapeutic strategies provide the most synergistic effects.
Discussions regarding the role of environmental factors in psychiatric treatment are currently limited to whether a patient requires inpatient care or can be treated at home. Thus, environmental factors contributing to treatment are largely under-studied and likely underestimated. Research on the placebo effect  provides a first glimpse that the visual characteristics and rituals of psychiatric medications and procedures can have significant effects on clinical outcomes. The psychedelic experience is greatly influenced by environmental factors, and thus psychedelic-assisted treatment requires optimizing the treatment setting. Environmental factors that can influence the treatment include music , nature, and familial items [33,43]. Researchers uncovering which variables to consider in psychedelic-assisted therapy are also studying indigenous contexts where these substances are combined with specific rituals for healing in the safety of nature and a supportive community [44-45]. Such an approach could inspire us to reconsider environmental influences during treatment and reminds us that we might gain important insights from studying healing rituals of non-Western cultures. In this way, psychedelics present an opportunity to investigate the interaction between biological, psychological and environmental mechanisms in psychiatric treatment, and psychedelic-assisted therapy can be viewed as one of the first initiatives towards developing multi-level treatments.
SPIRITUAL WELL-BEING AS A NEW LEVEL TO THE MULTILEVEL APPROACH OF THIRD WAVE PSYCHIATRY?
Health as defined by the World Health Organization in their constitution  concerns three dimensions: physical, mental, and social. Already in 2003, researchers from Thailand  suggested expanding this biomedical model to include a 4th dimension: spiritual well-being. Since then, the World Health Organization has taken steps to assess and incorporate spiritual well-being by developing a quality of life scale  that assesses spirituality, religiousness, and personal beliefs. Researchers in biological psychiatry have also investigated the effects of spiritual or religious attitudes on well-being, proposing that clinicians should assess and cater to the spiritual needs of their patients [49-52]. The findings thus far reveal that religious or spiritual attitudes may serve as a coping or protective mechanism for mental health and may facilitate remission from psychiatric disorders [53,54].
Although a dimension of spirituality may be a beneficial addition to multilevel approaches in biological psychiatry, researchers have struggled both to define the concept and to investigate its underlying mechanisms. In contemporary psychedelic research, the term ‘mystical experience’ is often used to describe the spiritual or religious dimension of an intense psychedelic experience [55-57]; notably, the extent of reported psychedelic-induced mystical experience significantly correlates with positive clinical outcomes in patients with nicotine addiction , anxiety and depression [34,36]. Some researchers have suggested that the sense of awe intrinsic in such experience might underlie the beneficial effects of psychedelics . These findings suggest that spiritual experiences, in relation to mental health, deserve closer scrutiny; and that psychedelics could serve as a potent tool to help us define and study spirituality and its effects.
LIMITATIONS OF CURRENT PSYCHEDELIC RESEARCH
The findings reported above suggest that biological psychiatry can benefit from implementing psychedelic research programs; but it is also important to note that the biological mechanisms by which psychedelics initiate these benefits are currently not fully clear. Modern psychedelic neuroscience is still in its infancy, and because of the difficulties intrinsic in administering powerful psychoactive substances while performing neuroimaging, the few published studies lack sufficient power to draw strong conclusions. All 13 neuroimaging studies were conducted on only 9-15 subjects, of which 0-5 subjects were female [60-70]. Moreover, these studies either investigated the effects over the full brain or on a large number of regions of interests (ROIs; e.g. 401 ROIs ). Although the effect sizes appear quite large, neuroimaging studies with a broad focus and small sample sizes are susceptible to false positives with large effects . Moreover, most of the above cited fMRI studies collected scans for only 6-7 minutes, which may not be sufficient to capture a potentially dynamic psychedelic effect and could explain some of the variability between studies. Lastly, although several studies used placebo-control groups, experimental blinding in psychedelic research is difficult to achieve since psychedelics have very strong and specific effects. Participants can thus often tell what condition they are in, meaning that condition-related expectations may have influenced the results.
Due to these limitations, it is hard to draw strong and specific conclusions from the neuroimaging studies published thus far. The current consensus regarding the general biological mechanism is that the psychedelic effects are driven by their stimulation of the serotonin 2a receptors , which leads to disintegration of functionally connected regions (the default mode network, in particular), reduced activation in connector hubs, and increased functional connectivity between regions that are normally not connected. In this way, psychedelics are thought to increase the entropy of brain activity, enabling a general state of unconstrained cognition [63,72]. How this increased entropy exactly relates to the self, to spirituality, and to therapeutic outcomes remains to be investigated with adequately powered designs.
Research with psychedelics could facilitate the field of biological psychiatry in three ways: by providing an opportunity to neurochemically investigate certain mental phenomena such as the self, by using a multilevel approach in both research and treatment with important emphasis on environmental factors, and by inspiring us to learn from non-Western cultures and ‘non-scientific’ concepts such as spirituality. It is important to note that research with psychedelics is still in the beginning stages and the quality of, especially neuroimaging, research must be improved. Fortunately, these issues can be tackled by motivating researchers in biological psychiatry to contribute to the study of these substances.
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