Psychedelic Cognitive Behavioral Therapy: On Ketamine, Context and Competencies in "Assisted-Psychotherapy” (DeMarco, 2024)
There are many tools to help a psychotherapist help clients learn to speak the language of cognitive behavioral therapy, especially tools which may help facilitate a connection, including, but not limited to telehealth.
An evolving overview of cognitive behavioral therapy in modern psychedelic-assisted psychotherapy and ketamine psychedelic therapy See Preliminary Lit Review for more sources and summaries
"The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.”
(Kadriu, et al, 2020).
In the policy discussions on psychedelics medicines, psychedelic-assisted psychotherapy vs "psychedelic facilitators", and the various roles, scopes of practice, and competencies with all of their nuance, may not be addressed, or are summarily dismissed as not being evidence-based and too difficult to study.
Cognitive behavioral therapy is a set of concepts a psychotherapist may help you learn to apply in your ongoing mental health. Psychotherapists are licensed to work with these concepts with individuals and groups in person, at home, in hospitals, churches, disaster sites, in nature, or via telehealth.
Sometimes medicine is added to psychotherapy as directed by your healthcare provider, with some medicines falling under the umbrella term “psychedelic medicine”, which includes racemic ketamine, an off-patent generic drug, originally FDA-approved in 1970, and used as an anesthetic medicine in high-doses. Ketamine is on the WHO’s list of Essential Medicines, and has been concurrently studied at sub-anesthetic, yet fully psychedelic doses since 1970 for a number of mental health indications, including anxiety, depression, alcoholism, and PTSD. This 60+ years of research and practice is more robust than other psychedelic medicines, and has been studied for a number of indications longer than many FDA-approved psychiatric medicines approved for daily home use. This literature review aims through the research, to integrate some of the disparate parts of mental health care, which now includes psychedelic medicines, and a certain amount of disillusionment with the psychiatric pharmaceutical industries as these medicines are normalized once again as viable mental health care options.
Specific Preparation & Support for Different Medicines
There are various needs a client has when working with medicines that affect their mental health and well-being. All medicines, including traditional antidepressants like SSRI’s, come with precautions, risks, and expectations as to how to best support working with the medicine. A pharmaceutical company marketed the idea with a cartoon that depression is caused by “not enough serotonin”, although recent study suggests this is not the case. Vargas and colleagues write in 2023, in their study "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors":
“Serotonin, because of its polar chemical composition, cannot readily pass the neuronal cell membrane. Serotonin doesn’t induce plasticity. Therefore, boosting serotonin levels by selective serotonin reuptake inhibitors (SSRIs) was largely a futile effort for the meaningful treatment of depression. Only a small portion of patients respond.”
Another way to prepare for a medicine is to understand the risk of side effects that may be considered adverse. This study "Side effects of antidepressants during long-term use in a naturalistic setting” (Bet, et al, 2013) found:
Side effects of antidepressants are usually underreported in clinical trials and large scale naturalistic studies are restricted to six months of use. We examined the prevalence and nature of patient-perceived side effects and their determinants during long-term antidepressant use in a naturalistic setting. Subjects, aged 19 to 67 years, in the Netherlands Study of Depression and Anxiety were recruited from primary care and specialized mental health care covered 927 cases of single antidepressant use. In 64% of cases, on average, 2.9 side effects were reported... We show that antidepressant side effect, known from short-term studies, persist during long-term use and are associated with depression severity and antidepressant dose. A novel finding was that venlafaxine is associated with more profuse sweating and that weight gain appeared more specific in female users. Clinicians should be aware that, during long-term antidepressant use, side effects are common and persistent.
Racemic ketamine, a generic, FDA-approved medicine currently available around the world has been studied for over 60 years, is a type of medicine described as having psychedelic (dissociative, ego-dissolving, out-of-body) and/or other visionary effects, which require precautions and support, but different than for an SSRI. In much of the literature, the “psychedelic experience” is considered an adverse effect. The support and precautions relate to a minimum level of care, which range from very little care for very-low dose ketamine prescribed from medical providers with one point of view, to ketamine being administered via IV pump or drip directly to your bloodstream while blood pressure is monitored. When a medicine is given by injection, like benzodiazapine (Valium), for example, it may have an elevated level of risk, requiring ongoing monitoring compared to taking the medicine by mouth, which has allowed benzodiazepines to be prescribed for home use, as it as been for years, even though at higher doses these medicines are used for "to induce relaxation and cause amnesia prior to surgical operations.” These medicines are also prescribed for the treatment of anxiety, among other indications, like Xanax. From the FDA:
We reviewed postmarketing databases, adverse event cases reported to FDA,* and the published literature on abuse, misuse, addiction, dependence, and withdrawal associated with benzodiazepine use (see Data Summary). Our review found that benzodiazepines are widely prescribed in the U.S., often for long periods of time. They are also widely abused and misused, often together with alcohol, prescription opioids, and illicit drugs, which worsen the risks of serious problems. We also found that some patients have had serious withdrawal reactions after benzodiazepines were stopped suddenly or the dose was reduced too quickly. Some patients experienced withdrawal symptoms lasting many months.
In "Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing" (Swainson, et al, 2022), researchers report:
Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as well as the drug cost for IN esketamine itself, which makes generic ketamine alternatives an attractive option. Though evidence is limited, use of non-parenteral racemic ketamine formulations (oral, sublingual, and IN) may offer more realistic access in less rigidly supervised settings, both for acute and maintenance treatment in select cases. However, the psychiatric literature has repeatedly cautioned on the addictive potential of ketamine and raised caution for both less supervised and longer-term use of ketamine. To date, these concerns have not been discussed in view of available evidence, nor have they been discussed within a broader clinical context. This paper examines the available relevant literature and suggests that ketamine misuse risks appear not dissimilar to those of other well-established and commonly prescribed agents with abuse potential, such as stimulants or benzodiazepines. As such, ketamine prescribing should be considered in a similar risk/benefit context to balance patient access and need for treatment with concern for potential substance misuse. Our consortium of mood disorder specialists with significant ketamine prescribing experience considers prescribing of non-parenteral ketamine a reasonable clinical treatment option in select cases of treatment-resistant depression. This paper outlines where this may be appropriate and makes practical recommendations for clinicians in judicious prescribing of non-parenteral ketamine.
There are known risks. Treatment involves planning ahead to decrease any likelihood of harm, and to maximize the possibility that the medicine will help in your healing, and decrease suffering. Ketamine administered by mouth in the sub-dissociative range titrated to the individual client may be seen by ketamine specialist medical providers as an acceptable level of risk for their patients to take at home for a number of off label pain and mental health indications, as evidenced in ongoing scientific study and accepted practice in medical and mental health care.
The medical provider offers a medical and psychiatric diagnostic framework and prescribes a course of medicine treatment, and decides what level of safety is required. Ketamine by mouth has a history of being self-administered outside of a clinic, while ketamine via injection, iv, or by nose may have an escalated level of risk that your medical provider may feel is better managed in a medical setting. Insurance reimbursement is usually possible only with FDA-approved on-label indications. Spravato, the brand-name for half of the ketamine molecule, esketamine, is prohibitively expensive for many on its own, and has not been shown to be superior to generic racemic ketamine, which is already widely available in licensed compounding pharmacies around the world. Spravato is also prescribed as a chronic treatment, in addition to starting a new daily antidepressant, also a chronic treatment.
Research continues to show in ketamine specifically, and psychedelics generally, that the psychedelic experience can be an important factor in ongoing mental health. This experience involves a collaboration between a team of people.
- Medical / Psychiatric Provider / Prescribing Clinician: Tasked with assessing and diagnosing your condition and prescribing a course of treatment. This may include a medicine that affects your mental health in some way. That medicine, while in your body, may have acute effects, as in the case of ketamine. Medical providers work in offices and clinics, as well as via telehealth. These providers may elect to prescribe a medicine “off-label” if they have sufficient clinical rationale that it may help for a client population, such as those dealing with mental health symptoms such as anxiety or depression.
- Psychedelic Facilitator (Guide, Coach, Doula, bodyworker, etc): Supporting the acute experience of the medicine may be considered by some as a "psychedelic facilitator". This person may be additional to a psychotherapist, who you may or may not do ongoing integration with as part of your mental health care. They may be keenly beneficial in other ways of the body, mind, heart and spirit, and supporting a client safely through whatever medicine experience they may have. A psychedelic facilitator may be a shaman, yogi, curandera, massage therapist, physical therapist, or other type of body worker, chaplain, death doula, or whoever else the client may feel comfortable and safe with while on the acute effects of a medicine. The facilitator sits with the person in their home, in the office, at a retreat, hospice, in nature, in a ceremony, depending on the medicine and route of administration. A psychedelic facilitator is not a licensed mental health practitioner, and their role is not to diagnose, assess, or treat a mental health diagnosis. The facilitator may or may not have ongoing contact with the client outside of the acute medicine experience. Oregon has a psychedelic facilitator license. Colorado is also beginning to offer a non-clinician facilitator license. Other states are in talks to begin certifying facilitators who do not have a mental health practitioner license.
- Licensed Mental health providers are trained to assess and treat mental health conditions. With advanced training in applying a medicine or set of medicines to the individual's ongoing mental health and well-being, mental health clinicians like marriage and family therapists (LMFT's), clinical counselors (LPC, LMHC), clinical social workers (LCSW), nurse practitioners (NP) or their doctoral counterparts, such as clinical psychologists (PsyD) are supporting what the medicine is doing acutely in the body (mind/brain) as well as supporting the client in an ongoing, professionally-sanctioned relationship within scopes of practice and competencies unique to the therapist. This practice, generally called mental health counseling or psychotherapy, exists within the current accepted medical structure in the US and most other countries. This has historically been done in therapist offices, in a client's home, in a church or temple, wildnerness camp, schools, hospitals, etc. Licensed mental health practitioners may have experience working with SSRI's, animal-assisted therapy, psychedelic experiences, sex therapy, or any number of other sub-specialities. Licensed clinicians have practical experience working in these areas as practicums during graduate training, as well as 3000 or more supervised clinical hours (akin to a medical residency) before being licensed, as well as passing knowledge and ethics exams, being fingerprinted, etc. After being licensed, ongoing continuing education is required both to maintain the license, but also to ethically maintain a level of competency in the mental health therapist’s areas of practice. Colorado is beginning to offer clinical psychedelic facilitator certifications for mental health specialists. In the rest of the world, presumably any licensed mental health provider may provide psychotherapy that is assisted by medicines such as ketamine, SSRI’s, entactogens, neuroplastogens, and/or plant medicines, and do so competently when trained.
Sex is not part of this relationship, with any member of a psychedelic treatment team.
Ketamine-assisted psychotherapy with a highly-trained mental health specialist involves learning and applying a set of concepts, such as cognitive-behavioral therapy, to support the new neural connections and new ways of thinking that accompany successful treatment with this medicine, which has been described similarly to medicines like MDMA, DMT, LSD, 5-MEO-DMT, ibogaine, psilocybin, psilocin, arketamine, esketamine, r-MDMA, and others. Many of these medicines are making their way through the FDA approval process, sponsored by various pharmaceutical corporations.
Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature (Drozdz, et al, 2022)
"The use of Ketamine Assisted Psychotherapy (KAP) can potentially fulfil the unmet clinical need for an effective treatment for multiple complex and often comorbid pain, psychological, and substance use disorders. Ketamine’s demonstrated ability to produce antidepressant and anxiolytic effects likely interacts with the processes involved in psychotherapy, ideally as a conduit for rapid-change, increasing treatment engagement and adherence, building the therapeutic alliance, and lowering defensiveness by providing reprieves from distressing symptomology while inducing transpersonal experiences at higher doses. Continued engagement in psychotherapy after ketamine administration may prolong the often-transient effects of ketamine and allow for the integration of psychological insights into everyday functioning. While at present there is no standard approach to the application of KAP, it is important to prepare and support the patient during ketamine administration and to offer follow-up psychotherapy sessions to maintain positive effects and delay or eliminate relapse. As KAP research continues to evolve, a focus on increasing the duration of positive effects may lead to effective interventions and maintenance programs, improving KAP such that it becomes an effective, long-lasting treatment for complex, resistant, and chronic conditions for people living with pain, mental health, and substance use disorders."
And a nice section on dosing escalation / exploration / titration:
"The theorized effectiveness of ketamine in psychotherapy is based on: (a) increased acss to traumatic memory via enhanced synaptic connectivity; (b) decreased central sensitization via downregulation of the prefrontal cortex, and (c) enhanced extinction of previously paired pain-related memories.21 Therefore, KAP can utilize a dosage escalation strategy to achieve different levels of trance, increasing to full out-of-body experiences.23")
In a psychotherapy model, the therapist and client conceptualize their plan for the client’s ongoing mental health and quality of life, curating the therapeutic process, and providing a container and therapeutic alliance in which to explore what comes up for the client.
Psychedelic therapy historically involves talking to the psychotherapist before, possibly during, and after each time you work with the medicine, especially initially. Integration psychotherapy sessions are generally within a few days of a medicine session. Clients may go on to make sense of their journey in ongoing counseling as needed, with body work, yoga, or other pursuits.
Increasing Access through Telehealth
"At-Home Ketamine" is being prescribed by medical providers who view the medicine as the catalyst for your healing, as a result of a physical body imbalance. Sometimes these providers work for companies charging a high price for monthly refills on this generic medication that is widely available in licensed compounding pharmacies around the world. Some of these providers view mental illness as a chronic disease where something is wrong in your body for which they believe ongoing medication is required. Other providers are prescribing doses of ketamine that may have an experiential component without the licensed mental health support trained and experienced in dealing with the emotions and behaviors of individuals and groups. The experience, indeed considered an adverse effect in many studies, is considered by psychedelic practitioners to be part of the process.
With ketamine by mouth, a medicine session via telehealth looks similar to a medicine session in an office or clinic. Psychotherapists working remotely use modern tools to connect with clients beyond the confines of a medical office, tending to privacy and safety needs as appropriate. Ketamine by mouth has been prescribed to self-administer for decades, and has been studied in repeat use in humans for as long as 18 years. Some humans are susceptible to bladder issues, heart issues, psychiatric issues, or find ketamine to be something easily misused.
Consider Hull, et al, in 2022 in their study "At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial", concluding:
At-home KAT response and remission rates indicated rapid and significant antidepressant and anxiolytic effects. Rates were consistent with laboratory- and clinic-administered ketamine treatment. Patient screening and remote monitoring maintained low levels of adverse events.
(Also of note in this study was the specific study of the side effects, again described here as "dissociation" where they write: "Influence of side effects and degree of dissociation for this treatment were determined for subpopulations".)
This research was expanded in a logitudinal study by Mathai, et al, 2024 "At-home, telehealth-supported ketamine treatment for depression: Findings from longitudinal, machine learning and symptom network analysis of real-world data”.
A sample of 11,441 patients was analyzed, demonstrating a modal antidepressant response from both non-severe (n = 6384, 55.8 %) and severe (n = 2070, 18.1 %) baseline depression levels. Adverse events were detected in 3.0-4.8 % of participants and predominantly neurologic or psychiatric in nature. A second course of treatment helped extend improvements in patients who responded favorably to initial treatment. Improvement was most strongly predicted by lower depression scores and age at baseline. Symptoms of Depressed mood and Anhedonia sustained depression despite ongoing treatment.
...
At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement in patients with depression. Strategies for combining psychedelic-oriented therapies with rigorous telehealth models, as explored here, may uniquely address barriers to mental health treatment.
When working with ketamine by mouth (oral or sublingual), the effects are much less sudden than IV-administered ketamine, and studies continue to show that there can be an experience (dissociation, or emergence phenomenon, psychotomimetic, are recurring descriptors, and considered as Adverse Effects), but that most people find any unwanted experience or effects were minimal and short-lived, and find the resulting benefits to be noticeable and substantial. The acute effect, depending on the dose and route of administration ranges from 1-3 hours, and which may feel like a deep meditation. Having a sober adult around to take care of you if anything comes up, or who can call for help if you needed medical attention is a way to decrease the risk of misusing the medicine in a way that may lead to harm. For many suffering with pain, stress, burnout, addiction, anxiety and depression, even suicidality, the positive effects may be noticeable within 1-2 hours.
Here is Tsang, et al, in 2023 "Safety and tolerability of intramuscular and sublingual ketamine for psychiatric treatment in the Roots To Thrive ketamine-assisted therapy program: a retrospective chart review”:
These findings suggest good safety and tolerability for RTT-KaT among individuals seeking treatment for mental health issues. The majority of participants did not experience adverse reactions and the adverse events that were recorded involved transient symptoms that were resolved with rest and/or medications. The group therapy model described provides a comprehensive approach and presents a promising model for operating a KaT program in a community setting.
In person, or via telehealth, the mental health provider monitors the client while under the acute effects of the medicine. In the case of telehealth, the psychotherapist may ask a client to provide an Emergency Contact to be a sober sitter during the medicine session, checking in periodically on their safety. In case of emergency, both the sober sitter and/or the therapist would contact 911 and the medical provider, as would happen in a psychotherapist's office, retreat setting, psychiatry clinic, or telehealth visit. In tandem with the sober sitter, the therapist sees the dose the client is taking, how they administered it, and monitoring what comes up for the client to integrate in psychotherapy sessions. Progress in psychotherapy may be reported to the medical provider before clients receive further refills on the medicine. In some cases, the psychotherapist may ask the client to take a beginning and ending blood pressure as further data for the prescribing clinician, but as a cognitive behavioral intervention in relaxation, as is the music and eyeshades method used in studies and in practice. A cognitive behavioral therapist views these as behavioral interventions to promote relaxation and openness to having an experience with the medicine that feels healing, and not like a “Serious Adverse Event” (SAE).
In "Music as an Intervention to Improve the Hemodynamic Response of Ketamine in Depression— A Randomized Clinical Trial”, researchers Greenway, et al, (2024) write:
Beyond psychiatric contexts, the stimulatory hemodynamic effects of ketamine have received extensive study, both as desirable (eg, in surgical contexts) and as potentially harmful (eg, in procedural sedation),5 but never in relation to music, to our knowledge. The magnitude of the hemodynamic effects observed in this study suggests that ketamine research should consider potential influences of contextual factors, including auditory stimuli. Ketamine’s unique psychoactive effects may amplify the effects of music and other environmental influences, as has been long observed in the anesthesiology literature.
Ketamine-assisted psychotherapy, facilitated remotely, with ongoing support and a sober sitter with you during the acute effects of the medicine, taken by mouth (or suppository) is a possibility for some clients. For others, they may need a higher level of medical intervention during the acute medicine stage, and go on to work with the psychotherapist in person or via telehealth in the days before and following the medicine administration. For others with additional comorbidities, in-patient options may be more suitable.
There are many tools a psychotherapist may use to help clients learn to speak the language of cognitive behavioral therapy, especially tools which may help facilitate a connection, including, but not limited to telehealth. While some medicines may be deemed by your medical provider as safe for use outside of a clinic setting, psychotherapists may offer services throughout the state in which they're located via telehealth, in addition to whatever local, in-home, or in-office support they may provide, as indicated in the scopes of their mental health practitioner license. Licensed marriage and family therapists often provide in-home services, for example.
In the article "Using Telehealth to Implement Cognitive-Behavioral Therapy” (Dent, et al, 2018), researchers write:
Therapists are required to be experienced in cognitive-behavioral therapy, adept at telehealth care delivery, and knowledgeable about the care of high-risk populations with general medical conditions and behavioral health issues or who are navigating life transitions. Behavior coaches are master’s-level clinicians, with a degree in psychology, nursing, or a related field, and have at least two years of clinical behavioral health experience.
...
"Behavioral health conditions are prevalent among patients with medical comorbidities and often go unrecognized or untreated because of barriers, including inadequate identification of patients in need and insufficient access to high-quality behavioral health care. We have described a nationally scaled telehealth model designed to overcome barriers to identification and enrollment into therapy. Participants were highly satisfied and experienced clinically meaningful improvements in behavioral health outcomes, further underscoring the potential impact that a telehealth solution could have in optimizing treatment outcomes."
These are some of the nuances that are often missed in the larger discussions among policy makers as they decide for the rest of us how to roll out a powerful medicine without getting hooked on it, yet consuming of it to fuel capitalism. There is not much money to be made, comparatively, in small private practices offering quality integrated care, charging for their time and overhead to work with the least amount of generically available medicine the most effectively. Ketamine-assisted psychotherapy, whether in a therapist's office or at home, has been shown to help people suffering with a number of indications considered "off-label". FDA-approved as an anesthetic in 1970, racemic ketamine has been administered, at least once, to billions of people (Billions!) around the world, across age and disease spectrum, in clinics, homes, and on battlefields. Over 5000 studies on ketamine and depression add to the decades of study on cognitive behavioral therapy (over 61,000 results on pubmed) and over 100 years of study of psychedelic medicine experiences as being adjunctive to psychotherapy. It takes several million dollars to take a medicine through the FDA-approval process, limiting the FDA approval of off label medicines such as ketamine, psilocybin, LSD, MDMA, DMT, and other generically available, off-patent molecules that have been studied in conjunction with psychotherapy for over a century.
In 2024’s "Ketamine-assisted psychotherapy, psychedelic methodologies, and the impregnable value of the subjective—a new and evolving approach" Wolfson & Vaid, write:
The ketamine session provides therapeutic impact along many different axes. An experience of safety and defensive softening permits deeper contact with feeling states and aspects of the self that previously needed to be disconnected from for emotional survival. Reconnecting with these disavowed states and self-aspects in a field of safety and relational care allows for trauma metabolism and release that heals early wounds and integration through reconnection contributing to integrity and resilience. New insights and knowledge are frequently accessed both during and after sessions. Navigation of the ketamine experience cultivates the platform of an awareness state—a new or revived witnessing of one’s self—such as new views and attitudes, reframing, connection, affection and love, improvement in reality testing and sensitivity to the body and its sensations and states. The ‘letting go’ increases our capacity to notice and observe the symphony of qualia, the great show of being alive and sensate, interdependent, and connected, fostering mindfulness and loving kindness toward self, others and rooted in nature.
Some Historical Context to the “Assisted-Psychotherapy"
In The Encounter That Introduced Peyote to Western Science, researchers describe John Mooney’s 1893 experience on peyote written up in the 1896 Therapeutic Gazette and cited in this bibliography from 1928, which cites research throughout the early 1900’s. Merck first synthesized MDMA in 1912, and Parke, Davis synthesized ketamine in 1962, comparatively.
Mooney took the peyote back to Washington DC, where he gave around half of the buttons to the chemistry division of the Department of Agriculture, and another batch to the medical department of Columbian (now George Washington) University. By this time, a few Western doctors and cactus traders had heard tales of peyote’s wonderful properties and purchased samples from the peyoteros who supplied it around the Texas-Mexico border, and the Detroit pharmacists Parke, Davis were developing a mild tincture as a cardiac stimulant. But its visionary and spiritual powers were still unexplored by Western science. Columbian’s professor of materia medica, Daniel Webster Prentiss, used the buttons Mooney supplied to conduct the first scientific trials.
In 1897, after reading Mitchell’s article, the German chemist Arthur Heffter made a series of self-experiments with peyote extracts and isolated the compound that was responsible for the visual hallucinations: an alkaloid that he named “meskalin.”
Modern psychotherapy developed in the late 1800’s with cognitive behavioral therapy studied since the 1950’s, and whether delivered at home, via telehealth, or in person, continues to be shown to be measurably effective for a number of indications, and must be considered alongside psychedelic medicine in research and practice. Additionally, the results of CBT are measurable by observable differences in the brain as evidenced on fMRI.
In the Dunlop, et al, 2017 paper "Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder”, researchers write:
“Remission from major depression via treatment with CBT or medication is associated with changes in rsFC (resting state functional connectivity) that are mostly specific to the treatment modality, providing biological support for the clinical practice of switching between or combining these treatment approaches. Medication is associated with broadly inhibitory effects. In CBT remitters, the increase in rsFC strength between networks involved in cognitive control and attention provides biological support for the theorized mechanism of CBT. Reducing affective network connectivity with motor systems is a shared process important for remission with both CBT and medication.”
In the meta-analysis spanning over 20 years of psychotherapy research "A systematic review and meta-analysis of transdiagnostic cognitive behavioural therapies for emotional disorders" (Schauffele, et al, 2024) researchers state:
Transdiagnostic cognitive behavioural psychotherapy (TD-CBT) may facilitate the treatment of emotional disorders. Here we investigate short- and long-term efficacy of TD-CBT for emotional disorders in individual, group and internet-based settings in randomized controlled trials (PROSPERO CRD42019141512). Two independent reviewers screened results from PubMed, MEDLINE, PsycINFO, Google Scholar, medRxiv and OSF Preprints published between January 2000 and June 2023, selected studies for inclusion, extracted data and evaluated risk of bias (Cochrane risk-of-bias tool 2.0). Absolute efficacy from pre- to posttreatment and relative efficacy between TD-CBT and control treatments were investigated with random-effects models. Of 56 identified studies, 53 (6,705 participants) were included in the meta-analysis. TD-CBT had larger effects on depression (g = 0.74, 95% CI = 0.57–0.92, P < 0.001) and anxiety (g = 0.77, 95% CI = 0.56–0.97, P < 0.001) than did controls. Across treatment formats, TD-CBT was superior to waitlist and treatment-as-usual. TD-CBT showed comparable effects to disorder-specific CBT and was superior to other active treatments for depression but not for anxiety. Different treatment formats showed comparable effects. TD-CBT was superior to controls at 3, 6 and 12 months but not at 24 months follow-up. Studies were heterogeneous in design and methodological quality. This review and meta-analysis strengthens the evidence for TD-CBT as an efficacious treatment for emotional disorders in different settings.
In comparing 53 different studies on psychotherapy, these researchers conclude that what they found “strengthens the evidence of transdiagnostic cognitive behavioral therapy psychotherapy is efficacious for treatment of emotional disorders in different settings”, including by “internet-based settings”, ie telehealth. Trans-diagnositic cognitive behavioral therapy approach, and generalizable, standardized and evidence-based practice was better than nothing at all (being on a “waitlist”), and at least as effective to active treatments for anxiety (medicine) and superior, that is, more effective than “other active treatments for depression”. This generalizable model, even by internet-based means of delivery, was comparable to styles of cognitive behavioral therapy that focus on a particular type of unhealthy negative emotion, feeling or behavior pattern.
Psychotherapy, as engaged by a licensed mental health provider, is not under the direction of the FDA
States and locales around the world currently have accepted licensure and authorizations for psychotherapy to be provided by a number of clinicians including counselors, marriage and family therapists, social workers, psychologists– none of which are medical providers or are responsible for the medical aspects of prescription-based mental healthcare as offered by general medical clinicians and psychiatric specialists such as psychiatric nurse practitioners or psychiatrists. Psychotherapy is the least-invasive approach in the treatment of mental illness, theoretically, and medicines have historically been prescribed in conjunction with working out your stuff with another human.
Escalated level of care traditionally involves adding a medicine. Psychotherapists support what it is the medicine is meant to be doing as it works on some things in your body. Sometimes as it works, there are side effects. In the case of psychedelic medicines like ketamine, these are manageable and transient for most people who also describe the experience of the medicine with words like: loving, mystical, God, to Near Death Experience, terrifying, or shocking. These experiences are frequent and predictable in psychedelic medicines including LSD, MDMA, ayahausca, DMT, psilocybin and the like.
Comparatively, here is the Black Box labeling to consider with sertraline (Zoloft) - a daily pill to be taken for a number of mental health indications, on and off-label, including PTSD:
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
See full prescribing information for complete boxed warning.
•Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1)
•Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors
This is in addition to loss of sex drive, nausea, diarrhea, and the inability to come off of the drugs without risking a physical and psychological withdrawal, with researchers in 2018 finding "Antidepressants should be added to the list of drugs associated with tolerance, dependence and a withdrawal syndrome.” (Perry, 2018)
Whether psychiatric drugs or psychedelic medicines are added to your mental health care plan, a licensed psychotherapist is meant to support you in going on to lead a life without reliance on a daily mental health treatment, an approach dominated by psychiatry and pharmaceutical corporations. Psychotherapy supports clients through the risks and side effects of an antidepressant. Psychotherapy supports clients in the possibility of a personally-meaningful reunion with a sense of Self through the psychedelic-assisted psychotherapy process. Some therapists specialize in certain approaches, methods or medicines, and others provide general ongoing mental health therapy without drugs or medicines. This highlights the necessity in psychedelic research to test their patented compounds against the generic versions, which are all mostly readily available, and against other common, already-approved mental health treatments, of which CBT is one of the current gold standards.
Scopes of Practice vs Scopes of Competency
Licensed psychotherapists work within accepted Scopes of Practices, Standards of Care, and state-licensing board descriptions of legal and ethical practice. Ethically, there is the additional standard of competency in psychotherapy, with and without the addition of drugs or medicines that may affect the psychology of the client, and/or the efficacy of the cognitive behavioral therapeutic intervention. A therapist who may be competent in supporting SSRI + cognitive behavioral therapy may not be competent in supporting a client through the process of psychedelic-assisted psychotherapy if they themselves have never had the experience. A psychiatrist competent in Stan Grof’s form of psychoanalysis, or someone somatic experiencing may be within their Scope of Practice, but not have a scope of competency to provide effective psychotherapy with cognitive behavioral therapy.
Adequate training in cognitive behavioral therapy, with supervised practice is essential. Adequate personal study, research and practice with each medicine is recommended, if not medically or otherwise contraindicated, as well as ongoing continuing education, peer supervision and interdisciplinary collaboration.
On the therapeutic alliance
Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder (Zeifman, et al, 2024):
The present results provide the first preliminary evidence for the relationship between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These findings highlight the important role of psychotherapy, and common psychotherapeutic factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples remain necessary.
The Therapeutic Alliance: The Fundamental Element of Psychotherapy (Stubbe, 2018) :
There is consistent evidence that the quality of the therapeutic alliance is linked to the success of psychotherapeutic treatment across a broad spectrum of types of patients, treatment modalities used, presenting problems, contexts, and measurements (1–4). Although scholars may differ in how the alliance is conceptualized, most theoretical definitions of the alliance have three themes in common: the collaborative nature of the relationship, the affective bond between patient and therapist, and the patient’s and therapist’s ability to agree on treatment goals and tasks (2, 3). The therapeutic alliance is posited to be a measure of the therapist’s and client’s mutual engagement in the work of therapy—thus representing an important component for achieving treatment success, regardless of the specific treatment modality employed (3). The statistical relationship between alliance and outcome is modest—approximately 7% of the variance and an average effect size of .26. However, this link has proven to be robust across multiple meta-analyses (1–4).
In "Interpersonal factors in internet-based cognitive behavioral therapy for depression: Attachment style and alliance with the program and with the therapist” (Zalaznik, et al, 2024), researchers studied "guided internet-based cognitive behavioural therapy (ICBT) for depression”, finding:
A culturally-adapted version of ICBT for depression showed that alliance with therapist and alliance with programme both can play an important role in its effectiveness: alliance with programme and the therapist drive adherence and dropout and alliance with therapist is related to symptom improvement. Although the focus of treatment is not interpersonal, avoidant attachment style can improve following ICBT.
On cognitive behavioral therapy in psychedelic medicine research
The MAPS-sponsored study MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial (Monson, et al, 2020), researchers write:
Our initial data indicates that MDMA delivered in combination with CBCT for PTSD appears to be safe, does not appear to be treatment-interfering, and may potentiate the treatment effects for PTSD and the larger relationship context in which it exists.
This study obviously includes a review of some literature on cognitive behavioral therapy, its use in PTSD treatment as well as couples (relational) therapy. This was not, however, the study design used for MDMA-assisted psychotherapy for PTSD included in the MAPS/Lykos application presented to the FDA advisory committee.
Also in 2020:
“When combined with specific context factors that are typically present in psychedelic therapy, belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective experiences and become revised accordingly, potentially leading to long-term increases in acceptance and associated reductions in psychopathology. This model shows substantial parallels between psychedelic therapy and CBT that may be harnessed by using CBT as a therapeutic framework for psychedelic interventions.”
The acute subjective effects of psychedelics are responsive to users’ expectations and surroundings (i.e., “set and setting”). Accordingly, a great deal of thought has gone into designing the psychosocial context of psychedelic administration in clinical settings. But what theoretical paradigms inform these considerations about set and setting? Here, we describe several historical, sociological influences on current psychedelic administration in mainstream European and American clinical research settings, including: indigenous practices, new age spirituality from the 1960s, psychodynamic/psychoanalytic approaches, and cognitive-behavioral approaches. We consider each of these paradigms and determine that cognitive-behavioral therapies, including newer branches such as acceptance and commitment therapy (ACT), have the strongest rationale for psychedelic-assisted psychotherapy going forward. Our primary reasons for advocating for cognitive-behavioral approaches include, (1) they avoid issues of cultural insensitivity, (2) they make minimal speculative assumptions about the nature of the mind and reality, (3) they have the largest base of empirical support for their safety and effectiveness outside of psychedelic therapy. We then propose several concepts from cognitive-behavioral therapies such as CBT, DBT, and ACT that can usefully inform the preparation, session, and integration phases of psychedelic psychotherapy. Overall, while there are many sources from which psychedelic psychotherapy could draw, we argue that current gold-standard, evidence-based psychotherapeutic paradigms provide the best starting point in terms of safety and efficacy.
In 2023, researchers compared the esketamine part of the ketamine molecule with and without cognitive behavioral therapy in "Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: The CBT-ENDURE randomized clinical trial study protocol (Kitay, et al, 2023) writing:
Cognitive behavioral therapy (CBT) effectively augments classic antidepressant medications and is highly effective in relapse prevention, especially among those with previous recurrent episodes of depression (Hollon et al., 2005; Sim et al., 2015). CBT has also been shown to prevent suicide attempts in high-risk populations over longer-term periods (Brown et al., 2005; Rudd et al., 2015). Work by our group demonstrates the feasibility and potential benefit of combining ketamine and CBT to sustain the anti-depressant effects of ketamine in severely ill, TRD patients (Wilkinson et al., 2017). A subsequent small, proof-of-concept trial showed that CBT could improve longer-term outcomes among patients treated with IV ketamine (Wilkinson et al., 2021). Here, we present the protocol for a trial that combines CBT with esketamine in patients with major depression and suicidal ideation.
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Results of the CBT-ENDURE will have important implications for the long-term approach to patients with MDSI who receive therapy with esketamine. These study results are especially relevant for those patients who begin therapy while inpatients under the supplemental indication of esketamine, for those who live in areas remote from clinics, and for individuals for whom repeated treatments are inconvenient, uncomfortable, or cost prohibitive.
This research shows comparison to FDA-approved medicine, racemic ketamine, off label, as well as the less-effective esketamine used for its on-label indication of depression and suicidality, which many forms of antidepressant drugs have not been able to treat. (This has been labeled treatment-resistant depression.) These articles echo the evidence that cognitive behavioral therapy, with the addition of a medicine is related to positive outcomes over a longer term. In spite of this evidence, cognitive behavioral therapy is not part of the current Spravato (esketamine) plus new antidepressant as approved by the FDA in 2019.
Psychedelic/ psychiatric/ neuroscience research study design should take note - there are brain scans that may indicate what type of treatment for depression and/or anxiety will work best and treatment includes cognitive behavioral therapy, which is also measurable in brain scans. Here is 2024 research that directly compares 3 common antidepressants with cognitive behavioral therapy - based intervention, all reflected in brain circuit scores. The Default Mode Network (DMN) and Salience Network (SN) are well-studied in ketamine and psychedelic literature, as well as the person’s subjective experience as these brain circuits are being treated. “Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety (Tozzi, et al, 2024):
There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or ‘biotypes’ to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.
The established behavioral intervention mentioned was psychotherapy based on the underlying theories of cognitive behavioral therapy (Scott, et al, 2024). Their conclusions reflect earlier work, "New and emerging approaches to treat psychiatric disorders" (Scangos, et al, 2023) in which researchers write:
Psychiatric disorders are highly prevalent, often devastating diseases that negatively impact the lives of millions of people worldwide. Although their etiological and diagnostic heterogeneity has long challenged drug discovery, an emerging circuit-based understanding of psychiatric illness is offering an important alternative to the current reliance on trial and error, both in the development and in the clinical application of treatments. Here we review new and emerging treatment approaches, with a particular emphasis on the revolutionary potential of brain-circuit-based interventions for precision psychiatry.
Cognitive behavioral therapy, with and without psychedelic medicines including ketamine are part of these brain-circuit-based interventions. Consider this 2024 paper "Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review”, (Le, et al, 2024) finding similar brain signatures for ketamine and serotonergic psychedelics (SP’s):
Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD.
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Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.
This is some of the ongoing context of what has been called, “The Psychedelic Renaissance”, “The Psychedelic Hype Bubble”, and “the Wild West”. The FDA advisory committees for MDMA-Assisted Therapy as well as racemic ketamine and other psychedelic New Drug Applications (NDA’s) have access to this information, as do the researchers at MAPS/Lykos and the other psychedelic corporations and stakeholders in the psychedelic space. This review is ongoing.
...the greatest threat to a healthy psychedelic future is the fetishizing of just the drug alone,” adding, “Whether plant, or synthesized compound of one, there is a narrative that all you need to do to change your mind is eat something. I unknowingly contributed to that narrative.
— Rosalind Watts, psychedelic researcher, as quoted in "Some psychedelic medicine developers want to ditch the therapy aspect. What could go wrong?” (Salon, 2024).
Part of an ongoing series and literature review of psychedelic-assisted psychotherapy, focusing on ketamine and cognitive behavioral therapy. For ongoing citations or works-cited, check out https://psychedelictherapy.institute or Mastodon : https://toad.social/@PsychedelicInstitute | This information does not constitute or replace direct medical or mental health care from your providers.
