This meta-review (2020) examines the therapeutic frameworks surrounding contemporary practices of psychedelic-assisted psychotherapy, with regard to the historic development of therapeutic models and contemporary insights into extra-pharmacological factors and underlying mechanisms. They highlight that these therapies entail greater environmental sensitivity from the patient’s perspective, which requires more meticulous attention for the preparation of the set and setting, a considerably resource-intensive endeavor.
Abstract
“Introduction: Combinations of psychotherapy with antidepressants are gold-standard psychiatric treatments. They operate through complex and interactional mechanisms, not unlike the reemergent paradigm of psychedelic-assisted psychotherapy, which promising research suggests may also be highly effective in even challenging populations.
Areas covered: We review the therapeutic mechanisms behind both conventional and psychedelic paradigms, including the evolution of this knowledge and the associated explanatory frameworks. We explore how psychedelics have provided insights about psychiatric illnesses and treatments over the past decades. We discuss limitations to early explanatory models while highlighting and comparing the psychological and biological mechanisms underlying many psychiatric treatments.
Methods: A narrative review was conducted based on a search in Medline/Pubmed up to January 1st, 2020, and iterative retrieval of references from recent reviews and clinical trials.
Expert opinion: The contextual model of the common factors of psychotherapy provides a powerful perspective on psychotherapy, antidepressants, and psychedelics, as well as 3,4-methylenedioxymethamphetamine (MDMA) and ketamine. It aligns well with key tenets of psychedelic-assisted psychotherapy. Conventional antidepressants and especially psychedelics may improve the efficacy of psychotherapy via neurochemical changes and increased environmental sensitivity. Combined treatments hold significant promise for advancing the knowledge and treatment of many forms of psychopathology.”
Authors: Kyle T. Greenway, Nicolas Garel, Lisa Jerome & Allison A. Feduccia
Summary
Psychotherapy and antidepressants are gold-standard psychiatric treatments, and may also be effective in challenging populations.
- Introduction
The global prevalence of psychiatric disorders is increasing, and there is a great need for new treatments, particularly for patients who have failed the existing treatments. Developing central nervous system drugs is associated with higher development costs, longer approval/development times, and greater rates of costly failures.
There have been some recent major advances in the realm of mood and anxiety disorders, with esketamine being the most important discovery in half a century.
The three molecules psilocybin, MDMA, and ketamine have been described as psychedelics, and when combined with specific forms of psychotherapy, they are called psychedelic-assisted psychotherapy (PAP). This article reviews the principles, history, and results of PAP.
- Methods
We performed two Medline/Pubmed searches and two Clinicaltrials.gov searches to identify studies on psilocybin, LSD, MDMA, and ketamine. We selected 239 studies for inclusion in this review.
- Conventional treatments
Combining psychopharmacological and psychotherapeutic interventions is now considered the gold standard in a wide variety of psychiatric conditions. Antidepressants are especially relevant because they are used to treat a wide range of conditions beyond depression.
3.1. Pharmacotherapies
The first drug to be described as an antidepressant was isoniazid, a tuberculosis treatment that was serendipitously observed to improve various symptoms associated with depression. The monoamine hypothesis led to the discovery of several new classes of antidepressants, including the tricyclics and SSRIs.
Antidepressants are preferred and effective treatments for many patients, but their short-term and long-term efficacy are subject to some debate. They are also associated with poor adherence, long medication trials, and potential side-effects like impaired sexual functioning.
Over the recent decades, antidepressant prescription rates have increased significantly, partly due to the increasing duration of antidepressant treatment courses and partly due to the increased risk of inappropriate re-initiation of antidepressant medication.
Conventional antidepressants remain important treatments in psychiatry, but the monoamine hypothesis has fared less well. Recent explanatory models emphasize the role of neuroplasticity, inflammation, and glutamatergic systems in depression.
3.2. Psychotherapy
Evidence-based psychotherapies like Cognitive Behavioral Therapy (CBT) are equivalently efficacious for depressive disorders as antidepressants, except for persistent depressive disorder. However, the availability of psychotherapy is often lacking, partly because of greater upfront costs and the false perception that it is not cost-effective.
Psychotherapy is an interpersonal intervention that relies on repeated encounters, a healing relationship, and a particular explanatory model, all within a structured therapeutic frame.
Modalities and techniques of psychotherapy are numerous and diverse. However, some common factors are shared amongst various approaches, and the systematic application of any therapeutic theory by a skilled therapist is beneficial regardless of that theory’s actual veracity.
The contextual model of psychotherapy posits three primary mechanisms of action: the real relationship, the creation of expectations through explanation of disorders and treatments, and the enactment of health promoting actions. The implementation of these mechanisms can vary dramatically amongst techniques and individual therapists.
The contextual model explains research findings of equivalent benefits between various psychotherapies in most psychiatric conditions, but fails to explain why certain approaches are superior in treating other conditions.
3.3. Shared pathways
Combining antidepressants with psychotherapy to treat depression may increase the tolerability of medication, reduce trial drop-out rates, and even reduce the use of immature defense mechanisms and dysfunctional thinking.
The contextual model may be applied to antidepressants, as the relationship between the prescriber and the patient provides the healing. Placebos routinely achieve 50% to 85% of antidepressant levels of efficacy, suggesting that acts like pill-taking can have major benefits.
Explanatory models can reduce the benefits of real medications, and this is demonstrated by studies that demonstrate that the effectiveness of antidepressants is partly mediated by the strength of therapeutic alliance.
One possibility is that modulating neurotransmitters with antidepressants increases sensitivity to the environment. This has been demonstrated in the STAR*D trial and may explain why higher doses of the antidepressant citalopram are associated with a greater positive impact from positive socioeconomic status markers.
This mechanism could explain why antidepressants with very distinct pharmacologic profiles tend to achieve remarkably similar levels of efficacy, and why antidepressants have a disappointing lack of benefits in patients with medical issues or addictions.
Psychotherapy can remodel dysfunctional neural circuits, and can have similar effects to antidepressants. This makes it similar to an epigenetic drug, and shows that effective treatment of psychopathology cannot be fully understood from purely biological or psychological perspectives.
4.1. How early research on psychedelics transformed psychiatry
Psychedelic-assisted psychotherapy is a new approach that integrates multiple paradigms. It was first synthesized in 1938 and distributed to investigators and clinicians worldwide.
LSD was viewed as mimicking psychosis by some, causing dream-like states that interested psychoanalysts, while others drew parallels between LSD and delirium tremens.
In every case, psychedelics challenged the dominant psychological conceptualizations of mental illness. For example, the psychotomimetic model conflicted with the view that psychotic disorders like schizophrenia arose from ‘refrigerator mothers’, and the monoamine hypothesis was consolidated by the appearance of imipramine in 1959.
Prior to the psychedelics, psychiatry had already seen other efforts at integrating biological and psychological treatments, including narcoanlaysis and various other agents. However, the shift toward biomedical models and the political backlash against recreational use led to this work being largely halted.
4.2. Psychedelic pharmacology and phenomenology
LSD is a highly absorbable semi-synthetic tryptamine that has strong affinity for a variety of receptors, including 5HT2A and 5HT1A. It causes profound alterations in cognition, sensory processing, and emotions.
Other psychedelics like psilocybin, DMT, and mescaline differ more pharmacokinetically than pharmacodynamically, but all agonize the 5HT2A receptor. They are considered to be exceptionally safe when administered with appropriate precautions, though safety concerns include the triggering of psychotic episodes and potentially lethal interactions with other medications/substances.
The profoundly altered state produced by 5HT2A agonism is multifaceted and heterogenous between individuals and studies, but consistently includes sensory distortions, feelings of ego dissolution or oceanic boundlessness, increased suggestibility, empathogenic effects on mood, and altered meaning-making.
4.2.1. Psychedelics and neural networks
Psychedelics may alter the communication between neural networks, resulting in a more present-moment state. The disintegration of the Default Mode Network (DMN) may be a key mechanism, as well as the disintegration of other networks, such as the cortico-striato-thalamo-cortical circuit of the salience network.
Psychedelic states may have several effects, including decreased constraints on cognition, increased communication between visual/auditory systems, and perceptual disturbances.
4.3. MDMA pharmacology and phenomenology
MDMA, a psychedelic substance, induces alterations in normal consciousness considered by some to be ‘psychedelic’. It reverses monoamine re-uptake transporters to effectively increase presynaptic concentrations of norepinephrine, dopamine, and especially serotonin, and subsequent release of hormones contributes to the subjective effects.
4.4. Ketamine pharmacology and phenomenology
Ketamine is a NMDA receptor antagonist that modulates glutamergic transmission. Its effects are similar to those of MDMA and LSD, including decreased movement, bodily sensation, and interactivity, as well as experiences of unity, spiritual experiences, insightfulness, visual phenomena, and altered meaning.
Ketamine was discovered in 1962 and has been used for anesthesia and pain management, and has been increasingly used for psychiatric conditions including anxiety disorders and PTSD. It is typically administered by repeated 40-minute IV 0.5 mg/kg infusions twice to thrice weekly, for months or years.
- Psychedelic-assisted psychotherapy
Soon after its discovery, LSD attracted the attention of psychoanalysts who were deeply interested in internal mental processes and concepts like ego. PAP evolved from psychoanalytic origins and embraced spirituality and music as important components of the therapeutic approach.
5.1. Modern protocols
Stanislav Grof’s classic 1980 book LSD Psychotherapy is one of the most referenced clinical approaches, and is used in nearly all modern PAP studies including those employing psilocybin, ketamine, and MDMA.
This protocol consists of three phases: preparation, treatment, and integration. It differs significantly from conventional pharmacological and psychotherapeutic approaches, which aim to create change via years or months of corrective experiences.
Patients are assessed for their appropriateness for the treatment, including readiness for potentially intense and challenging experiences. The preparation phase includes discussing biographic, medical, personal, and spiritual histories, and forming a therapeutic relationship.
Patients are typically prepared with flight instructions that include directions to mentally surrender to the experience, trust, let go, be open, and to work through challenging experiences to perhaps achieve therapeutic emotional breakthroughs.
The second phase of treatment involves drug administration, which typically lasts 8-12 hours. Two therapists or monitors are present to increase safety and permit brief breaks during long sessions.
The therapist/monitor is often referred to as a guide, as a reflection of the desired stance of non-directiveness, and the emphasis on patient autonomy and internal strengths may have partly arisen as a necessary measure to avoid excessive influence of psychotherapists given the increased suggestibility associated with psychedelics.
5.2. Set and setting
Sociological research suggests that the set and setting of psychedelic use is important for both safety and efficacy. This is achieved by establishing a strong therapeutic alliance and an intention for healing, and by providing a less sterile and more aesthetically pleasing treatment environment.
5.3. Music
Music therapy is an effective treatment of mood disorders, and PAP uses music as a core component to enhance patient experiences. The presence of music can conflict with the desired nondirective therapeutic stance, but resistance can be mitigated by encouraging negative reactions to specific music with openness and acceptance.
5.4. Integration
Following treatment, several non-drug sessions of ‘integration’ take place, often lasting for several hours. These sessions often incorporate elements from various schools of psychotherapy, and encourage patients to engage in various health-promoting activities.
6.1. Psychedelics
Psilocybin is remarkably similar to LSD, and is used with similar methods. It has a shorter half-life and is associated with less public stigma than LSD, and has shown promising results in the treatment of OCD, smoking cessation, treatment-resistant depression, and to initiate meditation/spiritual practices.
Modern research on recreational users and healthy controls has found benefits of psychedelics, possibly even without concurrent psychotherapy. There have been reports of injuries and deaths resulting from recreational use of psychedelics, which typically occurred in the setting of ingesting multiple substances and/ or dangerously uncontrolled environments.
LSD and psilocybin are considered to be amongst the least dangerous drugs in recreational users, and their use may be associated with less abuse of other substances.
6.2. MDMA
Since 2000, MDMA-assisted psychotherapy has been under investigation as a treatment for chronic treatment-resistant PTSD. Results indicate substantial improvements in PTSD symptoms and adequate tolerability to the treatment protocol, and long-term (12 or more months) reductions in PTSD symptoms have been observed following treatment.
MDMA is considered to have a moderate abuse liability amongst recreational users, and the potential for problematic use is low when administered under supervision.
6.3. Ketamine
Ketamine has been used in the treatment of depression, anxiety, PTSD, as well as alcohol, heroin, and cocaine addiction. Its anti-addiction effects may be partly explained by the psychedelic-like experiences it engenders within a psychotherapeutic frame.
- Expert opinion
Psychiatry has evolved over the preceding decades from primarily biological or psychological models of disease to more nuanced, integrative frameworks. Combinations of psychotherapy with antidepressants, psychedelics, MDMA, and ketamine are even more complex, involving bidirectional and potentially synergistic interactions.
PAP has many challenges, including carefully selecting and preparing patients, avoiding medication interactions, and overcoming stigma. It is not clear if the high standards of clinical trials will translate to the clinic.
Whether psychedelic treatments become mainstream remains to be seen, but they have much in common with current psychiatric treatments and could be enriched through considering some of their key tenets.
Significant further research is needed to move PAP into mainstream clinics and hospitals. These studies should be demographically diverse and include treatment-resistant subpopulations, and long-term studies should be conducted to demonstrate that the benefits obtained from PAP can indeed be maintained.