Mechanisms of therapeutic change after psychedelic treatment in OCD

Abstract

Novel treatments are required for the 30–50% of individuals with obsessive-compulsive disorder (OCD) who remain resistant to first-line pharmacological and psychotherapeutic treatments. Recent pilot data suggest benefit from psilocybin-assisted psychotherapy (PAP) and from imagery rescripting (ImRs). We explore psychological mechanisms of change underpinning both interventions that appear to allow for reprocessing of negative emotions and core beliefs associated with past aversive events. A next critical step in PAP is the development of psychotherapeutic frameworks grounded in theory. We propose that basing PAP on an ImRs framework may provide synergistic benefits in symptom reduction, modification of core beliefs, and value-based living.

Current treatments for obsessive-compulsive disorder (OCD) have limited effectiveness. New alternatives are urgently needed. In pilot work we have begun to investigate two such approaches, psilocybin-assisted psychotherapy (PAP) and imagery rescripting (ImRs). We suggest that they may operate by similar mechanisms, creating opportunities for synergy.

The therapeutic potential of psilocybin across a range of psychiatric conditions has been the focus of intense and increasing attention in recent years (Sharma et al., 2023). Early data (Moreno et al., 2006) and survey-based reports of recreational use (Buot et al., 2023) suggest benefit in OCD. We are in the midst of two controlled trials of PAP for OCD (Ching et al., 2023); NCT03356483; NCT05370911), with promising early, anecdotal results (Kelmendi et al., 2023). There are, of course, potential risks associated with the use of any medication, including potential for dependence, toxicity, and overdose. We have seen cases of extreme anxiety and of increased suicidal ideation amongst the patients treated at our center. However, a recent review (Schlag et al., 2022) on the adverse effects of psychedelics concluded that there were minimal medical risks when psilocybin was used in a medical and/or regulated context. This review emphasized the importance of clinicians maintaining the highest ethical and safety standards, further serving to highlight the importance of developing and testing associated treatment protocols to accompany the use of psychedelics.

Most modern studies of PAP, including our own, have combined one or two doses of psilocybin with a substantial amount of psychological support (Ching et al., 2023); this combination has been described as the ‘psychedelic medicine’ paradigm (Kelley et al., 2023). It is widely believed that this intensive support is necessary for full therapeutic benefit, although opinions vary as to whether it is an essential ingredient for clinical improvement or merely a requirement for psychological safety.

This is a critical question. Understanding how to provide psychological support optimally during a period of acute vulnerability (Hartogsohn, 2016) is of paramount importance for treatment to be delivered safely and ethically. If specific psychotherapy is critical to clinical benefit, understanding the associated mechanisms of change will allow adaptation of treatment to particular circumstances; optimal psychotherapy may not be the same in every indication. Finally, the requirement of many hours of support by skilled personnel is an obstacle to their dissemination. If these treatments are approved by regulators and become more broadly accessible, identifying the minimum necessary level of support, at what integral junctures during treatment, is essential to promote access.

Several theories have sought to explain the role of psychological support in PAP, with distinct implications for treatment design. Psychedelic treatments may enhance the brain mechanisms underlying psychotherapeutic change, perhaps by opening a window of enhanced neural plasticity (Lepow et al., 2023). Psychedelic treatment may augment nonspecific but potent mechanisms of change associated with psychotherapy more generally (Gukasyan & Nayak, 2021) or may enhance more specific psychotherapeutic processes, such as the development of value-based living (Sloshower et al., 2020), extinction learning (Feduccia & Mithoefer, 2018), or cognitive flexibility (Torrado et al., 2023).

OCD presents an interesting case. It is well established that therapies based on extinction learning can be extremely beneficial in individuals with OCD (Reid et al., 2021), while insight-oriented psychotherapy is of limited benefit (King, 2017). One might expect, therefore, that individuals with OCD who benefit from psychedelic treatment do so through enhanced or accelerated extinction learning. However, the support that we provide in our ongoing trial of psilocybin for OCD is similar to that used in trials of depression and involves no structured extinction-based therapy (Ching et al., 2023). Participants’ narratives of how they experience improvement have tended to focus not on an attenuation of obsessions and compulsions, but rather on a recalibration of priorities and meaning (Kelmendi et al., 2022).

In parallel work, we have recently applied imagery rescripting (ImRs) to the treatment of OCD that is refractory to standard ERP (Maloney et al., 2019). ImRs, developed for trauma-related disorders, entails identification of negative interpretations of past aversive experiences and guided reprocessing of associated memories to resolve unmet emotional needs and modify core beliefs in a more desired direction (Arntz & Weertman, 1999). ImRs is thought to enhance one’s capacity to tolerate distress and facilitate opportunities to process and incorporate new information into the representation of memories during heightened states of affect while an aversive event is being recalled. Specifically, reprocessing of an emotionally charged memory through the ImRs technique is theorized to result in changing the dysfunctional meanings associated with the aversive event and modify related beliefs and emotions (Maloney et al., 2019; Arntz & Weertman, 1999). When the aversive memory is then triggered in future situations, it will no longer produce the same original dysfunctional cognitions and emotions and instead be associated with the more desired, adaptive core beliefs and emotions that were reprocessed through ImRs. While this approach was designed for the treatment of trauma, studies have shown benefit across a range of psychopathology (Kip et al., 2023).

ImRs has been reported to produce marked reductions in symptoms in individuals with OCD [Maloney et al., 2019; Veale et al., 2015; Tenore et al., 2020). A recent case report describes the process of therapy and a subject’s experience of symptom change in detail (Maloney et al., 2023). Several similarities emerge with the experience of an individual who benefited after treatment with psilocybin (Kelmendi et al., 2022). In both cases there was extended benefit, lasting over a year, after a relatively brief intervention. Subjects described a sustained improvement in the ability to sit with present feelings and tolerate negative affect with a reduced sense of self-judgment. Both described improved relationships, satisfaction, happiness, quality of life, and self-worth. Both described OCD-related thoughts as still present but less bothersome: “I can experience them and still be okay” (Kelmendi et al., 2022); “I’m just feeling less bothered and confused by the whole thing…[I] feel comfortable with the risk of making a mistake” (Maloney et al., 2023).

The success of ImRs in these early studies does not suggest that OCD should be reconceptualized as a trauma-related disorder. It is possible that OCD symptoms are triggered, sculpted, or even caused by traumatic events in some cases (Adams et al., 2018). Alternatively, ImRs may be a particularly effective way to target cognitive-affective belief structures that initiate or maintain OCD symptoms, such as perfectionism, excessive responsibility, uncertainty, and self-blame (OCCWG, 2003), even if the specific stressful event targeted is not directly related to OCD etiology or symptom content. Finally, improvement in OCD symptoms may be blocked by self-narratives that are tied up in highly meaningful autobiographical events; ImRs may untangle these narratives and facilitate the development of more constructive ones, permitting symptom improvement. For example, through ImRs treatment, the subject described in our case report (Maloney et al., 2023) achieved a more favorable resolution of an aversive memory associated with perfection and low self-worth that related to his father’s repetitive punitive approach to holding cutlery incorrectly: ‘I was probably doing this correctly….I’m OK and what I was doing was enough. My father was anxious, angry, and abusive; and my mother was too scared to help me. It was a terrible situation to be in and it’s understandable that I’ve felt anxious in my life. My parents couldn’t be good parents in that way and that was to do with them and not me. I was just trying to avoid punishment, but I didn’t need to keep trying to do everything perfectly as there was nothing that could have changed what happened. I hadn’t really done anything wrong. I’m not a bad person”.

Irrespective of the specific mechanism, ImRs explicitly encourages reliving of past memories to modify meaning and associated core beliefs. Interestingly, this also happens during psilocybin treatment, albeit with less explicit guidance than is specified in the Imagery Rescripting-OCD protocol and manual (in preparation). For example, one subject (Kelmendi et al., 2022) recounted reliving key past events, themes, and accompanying feelings (positive and negative) that highly attuned facilitators helped him to explore and navigate with intuitive prompts. This was in marked contrast to his previous pattern of seeking to avoid or suppress uncomfortable affect. We have treated over 40 OCD patients with psilocybin and over 40 patients with ImRs and have observed similar qualitative patterns of change in other responders, with a recall of emotionally powerful memories, generally with positive valence (in preparation, Ching et al., 2024). Further examples (in preparation) of patients who were able to achieve similar resolutions of past events during psilocybin treatment to that observed during ImRs treatment include a patient who was able to recall a memory of his father teaching him to drive while drunk: “I had a vision of that experience… I had a sense that he was trying to do that over again, and he was trying to do it right. He wasn’t drunk. And then I just had this overwhelming sense of love from him, and that he was sorry for, you know, everything that had happened.” Another patient reported resolution of beliefs pertaining to responsibility associated with a past memory of providing an anonymous tip to his school that a fellow student was in possession of illegal drugs who was then expelled and later committed suicide: “Am I responsible for him committing suicide?’ And the answer is, ‘No, I never mentioned him…’ Nobody was ratted on. We were trying to keep people safe.”

Hypothesis.

These parallels lead us to a pair of hypotheses, one mechanistic and the second therapeutic. Mechanistically, we suggest that the psychological mechanisms of change underlying ImRs in individuals with OCD overlap with those produced by psilocybin, in cases where these treatments are of benefit (Kelmendi et al., 2022; Maloney et al., 2019; 2023). More specifically, we propose that both interventions allow for reprocessing of negative emotions and cognitions associated with past stressful or traumatic events. As illustrated by the two case reports (Kelmendi et al., 2022; Maloney et al., 2023), and consistently observed in other responders we have treated, untangling these negative associations can have marked benefit for symptoms, modifying core beliefs and enhancing function and value-based living. (While our focus here is on OCD, based on the striking parallels between ImRs and psilocybin effects that we have observed in this population, we note that these principles could apply equally to certain other psychiatric conditions. Indeed, this may be an explanation for the transdiagnostic efficacy of psilocybin that recent literature seems to suggest).

This leads to our second, therapeutic hypothesis. We propose that a psychotherapy based on imagery rescripting may be well suited to support the psilocybin experience of individuals with OCD. If these two interventions do indeed operate by similar mechanisms they may synergize, optimizing benefits – that is, an ImRs-guided psychotherapeutic intervention may provide larger or more durable change than the supportive model that is being used in most studies, including ours. This could take several forms. Future research could benefit from contrasting the use of ImRs prior to or after the psilocybin experience. Delivering ImRs prior to psilocybin dosing might guide experience during the session towards key memories and themes, making the session more efficiently therapeutic. Alternatively, psilocybin may prime subsequent ImRs, making a session shortly after psilocybin still more effective; such a post-dosing session might be focused on whatever autobiographical events arise naturally during the psilocybin experience. These possibilities are not mutually exclusive; ImRs-based therapy could be used both to prime and to process the psilocybin experience. A randomized control trial to contrast these three options (‘prior to’; ‘post’; and ‘prior and post’ the psilocybin experience) of ImRs delivery would be optimal to examine changes in quantitative measures and qualitative experiences.

Conclusion.

These ideas are of course speculative, and based on what are, to date, only sparse, anecdotal observations (Kelmendi et al., 2022; Maloney et al., 2023). Neither psilocybin dosing nor ImRs has been shown to be effective in a rigorous controlled trial – though early results engender optimism (Moreno et al., 2006; Kelmendi et al., 2022; Maloney et al., 2019; Veale et al., 2015; Tenore et al., 2020; Maloney et al., 2023). Testing these ideas will be difficult – if both psilocybin dosing and ImRs prove to be effective, demonstrating synergistic benefit will be challenging. Nevertheless, theory-driven development of new strategies for support of psilocybin treatment with specific psychotherapies is a critical next phase in the development and optimization of psychedelic therapeutics.

Highlights:

• Understanding how to safely and effectively deliver psychedelic assisted psychotherapy (PAP) based on specific psychotherapeutic frameworks grounded in theory is a critical next step in the development and optimization of treatment.

• Psychological mechanisms of change underpinning two novel alternative treatments for OCD: psilocybin and imagery-rescripting (ImRs) are explored.

• An ImRs-guided psychotherapeutic framework may be well suited to synergistically support the psilocybin treatment experience of individuals with OCD.

• Future research suggestions are provided whereby ImRs psychological intervention could be included to prime and process the psilocybin treatment experience for OCD and a range of other psychological conditions.