Psychedelic-Assisted Therapy for Substance Use Disorders and Potential Mechanisms of Action

This academic book chapter (2021) outlines the potential mechanisms of action of psychedelics in the treatment of substance use disorder (SUD).

Abstract

“Substance use disorders (SUD) represent a significant public health issue with a high need for novel and efficacious treatment options. In light of this high unmet need, recent results reporting beneficial outcomes of psychedelic-assisted therapy in SUD are particularly relevant. However, several questions remain with regard to this treatment approach. The clinical mechanisms of action of psychedelic substances in the treatment of SUD are not well understood. Closing this knowledge gap is critical to inform and optimize the psychotherapeutic embedding of the acute substance administration. In this chapter, we discuss potential mechanisms that have implications on psychotherapeutic approaches including induced neuroplasticity, alterations in brain network connectivity, reward and emotion processing, social connectedness, insight, and mystical experiences. Furthermore, we outline considerations and approaches that leverage these mechanisms in order to optimize the therapeutic embedding by maximizing synergy between substance effects and psychotherapy. Understanding the mechanisms of action, developing psychotherapeutic approaches accordingly, and evaluating their synergistic efficacy in scientific studies will be critical to advance the framework of psychedelic-assisted therapy for addiction, create evidence-based approaches, and achieve the best treatment outcome for patients with SUD.”

Authors: Nathalie M. Rieser, Marcus Herdener & Katrin H. Preller

Summary

Substance use disorders (SUD) are a significant public health issue with a high need for novel and efficacious treatment options. Understanding the clinical mechanisms of action of psychedelic substances in the treatment of SUD is critical to inform and optimize the psychotherapeutic embedding of the acute substance administration.

1 Introduction

Serotonergic psychedelic substances have been studied extensively for the treatment of various psychiatric disorders. Two modern clinical trials have reported beneficial long-term effects of psilocybin for nicotine and alcohol use disorder for up to 6 months, although these studies lack appropriate control conditions.

Psychedelics are usually administered with psychotherapeutic embedding, such as cognitive behavioral or motivational enhancement therapeutic approaches. However, the clinical mechanisms of action of psychedelics in SUD are not well understood, and testing these approaches empirically is essential to provide evidence-based psychedelic-assisted therapy.

In this chapter, we discuss potential mechanisms of action of psychedelics, including 5-HT2A receptor agonists, and highlight current knowledge gaps. We discuss the implications of these mechanistic hypotheses for the content and conduction of accompanying psychotherapy.

2.1 Induced Neuroplasticity

Maladaptive learning and memory processes are major characteristics of SUD, and chronic exposure to alcohol has been shown to reduce neuroplasticity. This may underlie learning deficits and reductions in cognitive flexibility observed in alcohol addicted patients.

Psychedelics induce neuroplasticity in the brain that may be leveraged in the therapeutic process. These changes are mediated through activation of the 5-HT 2A receptor, tyrosine receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR) signaling pathways.

It still needs to be investigated if the neuroplastic effects observed in animals translate to humans. If so, this may have important implications for the therapeutic embedding of a psychedelic experience.

2.2 Alterations in brain networks connectivity

Previous studies have shown that the functional architecture of the brain changes in patients suffering from substance use disorders, and that changes in the dACC-striatum circuit are a common mechanism underlying various SUDs.

Acutely administered psychedelics have been shown to alter thalamo-cortical connectivity patterns, which may lead to changes in thalamic gating of internal and external sensory and cognitive information, and a disruption of cortical information processing and changes in information integration in the psychedelic state.

Little is known yet about long-lasting effects of psychedelics on brain connectivity, but two studies report changes in resting-state functional connectivity and default mode network connectivity measured one week and one month after administration.

2.3 Alterations in emotion processing

Patients with SUD show difficulties in regulating negative emotions, believe it to be less socially acceptable to express negative feelings, and engage in rumination to deal with negative emotions. This may lead to maladaptive drinking pattern to reduce negative emotional states.

Psilocybin and LSD attenuate the recognition of negative facial expressions in healthy participants and reduce the neural response to negative stimuli in the amygdala. However, depressed patients show increased emotional responsiveness the morning after psilocybin administration.

Psychedelics may have a modulatory effect on emotion processing, particularly the perception of negative stimuli. This may decrease substance use by decreasing negative affect, enhancing the ability to regulate negative affect, and strengthening adaptive problem solving.

2.4 Alterations in reward and stress processing

Reinforcing effects of psychoactive substances depend on dopamine release in the ventral tegmental area and the Nucleus Accumbens, and are also caused by environmental factors such as sensitization, stress, priming dose, or drug-related cues. Chronic drug use induces neuroadaptations that cause a long-lasting decrease in sensitivity to natural reinforcers.

Serotonin is a neurotransmitter involved in the regulation of stress, anxiety, cognitive functions, social behavior, and reinforcement of properties of drugs. Serotonin neurotransmission is reduced in patients with AUD after alcohol-withdrawal, which reinforces craving and relapse.

2.5 Increased Social Connectedness

Patients with SUD show dysfunctional social cognition and interaction, which may lead to decreased social contact and support. This may increase the probability of relapse and hinder treatment efficacy.

Studies with healthy controls show that classic psychedelics acutely decrease feelings of social exclusion and increase emotional empathy, prosocial behavior, and the desire to be with other people. This may suggest that psychedelics may improve social ties within daily-life, as well as the patient-therapist relationship.

2.6 Subjective Experiences and Personal Meaning of the Experiences

Patients with SUD often show difficulties in self-awareness, interoception, and insight. This may be due to a dysfunctional neural circuit involving the insula, anterior cingulate cortices, probably orbitofrontal cortex, and ventromedial prefrontal cortex.

Some studies propose that mystical experiences are essential to attribute personal meaning to the psychedelic-induced experience and a positive treatment outcome, and that they are associated with smoking cessation and decreased temptation to use the substance.

Insightfulness, partially overlapping with the concept of mystical experiences, is often an essential characteristic of the psychedelic experience and may therefore represent an important mediator of treatment success in SUD.

Psychedelics may increase insight, increase realization of negative consequences of problematic behavior patterns and substance use, alter the prospect of life, influence one’s conviction that change is possible, reduce ambivalence, and facilitate personality change. However, divergent results were reported for personality change after psychedelic admission.

Patients with SUD reported post-acute alterations of self-perception and more control over their own choices and behavior after a psychedelic experience within a clinical setting. However, two studies in mice reported neuroplasticity was induced by psilocybin with ketanserin pretreatment, which also reduced alcohol-seeking.

3 Therapeutic Implications

It is widely accepted that psychedelics should be administered in combination with psychotherapeutic treatment for SUD, but it remains unknown which psychotherapeutic strategies are best suited to be combined with psychedelic interventions.

Evidence-based psychotherapeutic interventions for SUD include mainly contingency management (CM), cognitive-behavioral therapy (CBT), and motivational interviewing (MI), or variants and combinations thereof. Psychedelics may contribute to enhanced and more sustained effects of CM interventions. MI focuses on resolving ambivalence related to behavioral decisions between substance use and other activities, and enhances motivational engagement in non-substance related ‘rewarding’ activities. Psychedelics might enhance the therapeutic potential of MI interventions by fostering brain connectivity changes.

We are currently conducting a study investigating the clinical and mechanistic effects of psilocybin in AUD. The accompanying psychotherapeutic interventions are based on the BRENDA-approach, which is rooted in the principles of MI. In our study, we extended the BRENDA-approach to include therapeutic elements specific for psychedelic-assisted therapy. Patients were instructed to focus on themselves, to immerse themselves in whatever may come up, and to avoid judging the situation or the content.

Future studies should focus on leveraging synergies between psychedelic-specific mechanisms of action and psychotherapeutic elements to achieve the best psychedelic-assisted therapy possible.

3.1 Implications of Induced Neuroplasticity

Psychedelics may open a neuroplastic window of opportunity during which learning (including extinction learning) are facilitated. It is conceivable that psychedelic-induced neuroplasticity may greatly facilitate the processes of learning new behaviors that can replace drug use habits.

In synergy with psychedelic-induced plasticity, therapeutic approaches based on extinction learning may also prove to be more effective in SUD. Additionally, neurofeedback approaches may be helpful in supporting patients in developing novel strategies to avoid relapse or deal with negative emotions.

The acute experience of psychedelics may shape treatment outcomes. It may be important to avoid deeply frightening experiences during the acute effects, and to frame towards positive and non-drug-related experiences during preparation sessions.

3.2 Implications of Alterations in Brain Network Connectivity

Under the influence of LSD and psilocybin, brain connectivity changes reveal a pattern of increased connectivity between sensory and decreased connectivity between associative brain regions. This suggests that psychedelics may help patients gain a new perspective on themselves.

It is currently unclear if the changes in brain connectivity induced by psychedelics persist beyond the acute drug effects, but a targeted intervention that encourages a change of perspective may promote beneficial clinical outcomes.

The functional architecture of an individual’s brain as measured with resting-state fMRI may represent a predictive biomarker for acute psychedelic effects and treatment success.

3.3. Implications of Alterations in Emotion, Stress, and Reward processing

During the acute and post-acute phase of psychedelic drug action, the neural response to negative stimuli is decreased, which may allow patients to face negative memories and emotions instead of suppressing or avoiding them. This may complement and enhance the effects of psychotherapeutic interventions like CBT or mindfulness-based relapse prevention.

Psychedelics may normalize serotonin neurotransmission and decrease craving by increasing mood and reducing stress and attentional bias. Integration sessions may focus on the normalization of natural rewards processing, but the process of negative emotion processing must be carefully embedded in therapy.

3.4 Implications of Social Connectedness

Increased emotional empathy induced by psilocybin may benefit the treatment of SUD by increasing social activity and decreasing social isolation. This may improve the patient-therapist relationship and make social interactions in general more meaningful and valuable. The use of family members or people close to the patients in the therapeutic process is already being done in MDMA-assisted treatment of PTSD-patients.

3.5 Implications of Subjective Experiences and Personal Meaning

Psychedelics induce self-awareness, create insight, and increase interoception. Self-awareness and insight may lead to a better understanding of the disorder, increased self-awareness, and motivation, and a new perspective on the rationale for the addiction-related behaviors. Although self-efficacy is a good predictor of treatment outcome in SUD, there is no clear consensus on how to therapeutically enhance the perception of self-efficacy in SUD patients. Psychedelics may provide an important contribution in this context.

A main mechanism of action of psychedelics is gaining insight. It is essential to outline dysfunctional behavior patterns and define goals for the future during the preparation phase and encourage changing of behavior and thinking patterns during integration sessions.

3.6 Implications for dose-finding and dosing regimen

In-vivo experiments with mice showed that low doses of psilocybin lead to faster extinction learning and increased hippocampal neurogenesis, but there are currently no studies investigating the effect of psychedelics on learning in humans.

While results point to the beneficial effect of low doses, some studies suggest that higher doses may be needed for clinical efficacy in patients with AUD. However, anecdotal reports also suggest a beneficial effect of very low, sub-threshold doses of psychedelics, so called microdoses. The most promising dosing regimen for patients with AUD and smoking cessation is currently being investigated. A single dose may be enough, but repeated doses may be necessary for long-term treatment outcome.

4 Conclusion

In this chapter, we have outlined various potential mechanisms of action of psychedelics that may have significant synergies with psychotherapeutic approaches. It will be important to establish evidence-based psychotherapeutic interventions and optimize therapeutic approaches to achieve maximally beneficial treatment effects for patients. In this chapter, we have outlined knowledge gaps, but also suggested possible psychotherapeutic interventions that seem well suited for a psychedelic assisted therapy of SUD. These interventions include fostering creative thinking styles, including family members or friends in the therapeutic process, and enabling changes of perspectives and behaviors within a MI framework.

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