Ketamine Assisted Psychotherapy

Ketamine Assisted Psychotherapy (KAP): Demographics, Data and Outcomes

By now you’ve probably heard a bit about the potential benefits of ketamine assisted psychotherapy. Read on as Frshminds’ Emily Frewster takes you behind the curtain to explore a bit of the research into ketamine assisted psychotherapy.

Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy

The article below is part of Frshmind’s “Psychedelic Science Snapshot Series” where Frshminds reviews the latest in psychedelic research.

Original authors: Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss & Phil Wolfson
Summarized by: Emily Fewster


Recently, groundbreaking clinical research on the therapeutic use of psychedelic substances such as psilocybin, MDMA, and ketamine has been gaining interest. Currently, ketamine, alongside cannabis, is the only legal psychedelic medication. Originating as an anesthetic drug in the 1960s, Ketamine was preferred over its analog phencyclidine (PCP) due to fewer adverse effects, and it was during these early explorations of the drug that a peculiar side effect was noted; patients would experience a dissociative/hallucinatory state, and oftentimes be disturbed by it due to the lack of preparation for such a jarring experience. Thus, It was dubbed a “dissociative anesthetic” by the wife of Edward Domino, the primary research clinician (Matthew and Zarate 2016). It wasn’t until a decade later that the therapeutic potential of ketamine shifted from physical to psychological ailments, where it was reported in Khorramzadeh and Lofty (1973), and in Argentina as an adjunct for antidepressant psychotherapy (Fontana 1974). Overseas reports came from Russia exploring ketamine to help treat addictions as well (Krupitsky and Grinenko 1997). After the intense legal crackdown on drugs during the 70s, it wasn’t until the late 1990s that investigators at the National Institute of Mental Health began to again explore the antidepressant potential of ketamine while searching for alternatives to SSRIs and SNRIs(Krystal et al. 1994). In recent years, ketamine has also been explored for the treatment of post-traumatic stress disorder (PTSD), Bipolar I and II depressive phases, obsessive-compulsive disorder (OCD), psychological reactions to physical illness, personality disorders, life-threatening illnesses, and substance use co-occurring with a primary psychiatric disorder.

Historical Psychedelic Research

In the past, investigators aimed to eliminate the psychedelic effects of the drug but retain its antidepressant effects. It was found that after a single session of IV ketamine, there was remission of treatment resistant depression (TRD) and a reduction of suicidality (Krystal 2007). However, these benefits were short lived, and further studies from the IV researchers actually indicated enhanced benefit from the presence of psychedelic experiences (Luckenbaugh et al. 2014). These findings parallel the relationship between mystical experience and treatment outcome in the psilocybin studies (Griffiths et al. 2011), and suggests that profound psychedelic experiences, regardless of the medicine facilitating them, may improve mental health and overall well-being (Sullivan 2018). Ketamine is available in two enantiomers, molecules that are mirror images of each other: the S (+) and the R (−) configurations. The S isomer is estimated to be approximately twice as powerful as the R (Weber et al. 2004), and has recently gained FDA approval as an antidepressant nasal spray for in-office psychiatric use. Current preparations usually contain equal concentrations of both enantiomers. The anti depressant effects may be explained by ketamines primary method of action, NMDA receptor antagonism in the glutamate system. It also induces a substantial presynaptic release of glutamate by increasing the firing rate of glutamatergic neurons. (Moghaddam, Adams, Verma, & Daly, 1997). This increase in glutamate release then favors another type of glutamate receptor, called AMPA receptors, over NMDA receptors because the latter are blocked by ketamine, causing a greater throughput through the former and AMPA mediated synapse strengthening. Unsurprisingly, alterations in the glutamatergic system have been observed in the central nervous system (CNS, CSF, and brain tissue) as well as the periphery in subjects with MDD (Sanacora et al., 2008). Further, Ketamine also impacts other neurotransmitter systems such as cholinergic, monoaminergic, kappa opioid, and GABAergic functions, though most likely as downstream indirect effects (Wallach 2018).

The Safety of Ketamine

The safety profile of ketamine has also been mapped extensively over the decades from emergency room settings, outpatient pain management clinics, and now psychiatric use (Collins et al. 2010) and has been accepted for use in the office and for prescription use by patients at home. A pooled data study from three different clinical trials of subanesthetic IV ketamine administration in major depressive disorder (MDD) patients found that adverse effects common within the first four hours of administration included dizziness, derealization, and drowsiness (McGirr et al. 2014). However, it remains controversial as to whether these are considered “adverse” or as part of ketamine’s actual effects that result in therapeutic benefit. Further, one third of all patients experienced transient hemodynamic changes, particularly elevated blood pressure. However, there have been no cases of persistent and negative neuropsychiatric or medical effects, nor increased substance abuse in clinical practice. Due to the increase in available data and emphasis on patient self-reports, there has been a subsequent maturation of a dosing strategy into a replicable protocol.

Establishing Ketamine Dosages

Ketamine Assisted Psychotherapy (KAP) utilizes a dosage escalation strategy to achieve different levels of trance increasing to full out-of-body experiences, and it has become clear that ketamine can also be administered using the sublingual, intranasal, or intramuscular routes as opposed to only IV methods (Chilukuri et al. 2014), with these other routes of administration allowing for the entire therapeutic dosing spectrum to occur in a non-medicalized office setting with full psychotherapeutic support (Jaitly 2013; Lara, Bisol, and Munari 2013). The absorption of intramuscular ketamine is similar (93−95%) to IV ketamine, intranasal ketamine absorption is around 15-25%, sublingual ketamine absorption most likely in the range of 15–25%, and oral absorption is the least efficient at 10% or less, and takes more time to have its effect (Wieber et al. 1975).

The Effectiveness of Ketamine Assisted Psychotherapy

The effectiveness of KAP is due to several factors. Dosage is an important one, as subjective effects can vary widely depending on it. For most patients, sublingual induction of the trance state is first investigated to find an individual “sweet spot” with respect to dosage that can be replicated at home under supervision in office sessions. Then, the intramuscular method may be explored in order to produce an out-of-body experience which allows for a unique but related approach to healing. This type of psychotherapy is intensive for both practitioners and their patients. Sessions are long, often up to 3 hours, and likely to be fatiguing. As well, since this form of therapy involves inducing an altered state, set and setting considerations must also be made. The role of the therapist and their ability to bond with patients is especially important, as the breakage or lack of trust is often at the core of trauma persistence (Van Der Kolk 2014). An altered state is a vulnerable state. During ketamines “inward” states, the journey can unfold in different realities that may seem the truth of being, outside of time and space, and/or as if observing our being in different realities. At times, this may be confusing especially if the only observing mind connected to the sense of self is that of the patient. Finally, anchoring the personal elucidation gained from the experience with ketamine, may it be slogans, mantras, visions, internal movies, feelings, metaphors, and/or understandings, to daily life is vital. It can bring new perspective and the direct experience of seeing ourselves in a new way is often the missing link that gives hope to many sufferers of mental illness and others who cannot achieve this critical reframing by other means.

Data from 235 patients from three distinct private general psychiatric practices located in Northern California (Wolfson and Dore) and Austin, Texas (Turnipseed) from 2013–2018 were collected prospectively and analyzed retrospectively. On average, individuals fell in the moderate depression category and moderate anxiety category before treatment, hadtried 2.84 medications for psychiatric complaints at intake such as antidepressants, stimulants, mood stabilizers, antipsychotics, sedatives/anxiolytics, and other medications, and were in therapy for 3-5 years. The average dose range of ketamine during KAP sessions was 200–250 mg for the sublingual route and 80–90 mg for the intramuscular route, which 61.5% of patients received.

Three forms (intake, visit and when applicable, termination) were developed for data collection by the Ketamine Research Foundation (KRF) Ketamine Data Project (KDP), all of which contained demographic, diagnostic, medication, psychoactive history, psychiatric

Reduction in BDI scores with Ketamine based treatment.

history, medical history, and family data. Intake forms included rater views of personality rigidity, recommendations for ketamine administration, and concerns. Self-report data collected before KAP treatment (baseline/intake) included the Beck Depression Inventory (BDI), Hamilton Anxiety Scale (HAM-A), Patient Health Questionnaire–9 (PHQ-9), Childhood Resilience Scale (CRS), and Adverse Childhood Event Score (ACE), and follow-up self-report measures from the last available office visit also included BDI, HAM-A, and PHQ-9, as well as Levine Depression Scale Ratings. Rater view of patient’s symptoms as well as the quality of the KAP session experience was recorded, using Change of State, Mystical Experience Questionnaire (MEQ), and Ego Dissolution Index (EDI) (Nour et al. 2016) to assess the KAP sessions.

During treatment, patients received ketamine sublingually, intramuscularly, or both, with sublingual ketamine administered during the initial in-office session to determine sensitivity and dose for the individual. Each practice was individualized based on this and on diagnosis. Sublingual ketamine was prescribed in a limited amount without refills for at-home use with instructions to dose up to but not exceeding six sessions over a two-week period, with less frequency thereafter, depending on severity. It was also instructed that patients replicate the setting and procedure demonstrated by the clinicians in the initial session at home. In-office sessions were usually spaced 2 weeks apart or more frequently depending on progress. It was during these sessions that intramuscular ketamine was administered in order to induce the transformational state described earlier, however not all patients received this route of administration. This was determined based on therapeutic progress and symptom relief and was at the discretion of the provider.

Outcomes of KAP included clinically significant decreases in anxiety and depression as measured by BDI and HAM-A, and further analysis showed that patients with developmental trauma (cPTSD) had the greatest improvement in depression and anxiety scores. The number of ketamine sessions positively correlated with improvements in the Levine Rapid Depression Scale, and improvements in BDI from pre- to post-treatment. Treatment duration positively correlated with Depression Rater View and Anxiety Rater View, showing that those with a longer total duration of treatment also showed greater improvements in depression and anxiety. Patients with more severe symptomatology (including higher BDI at intake, suicidality at intake and within past year, history of psychiatric hospitalization, and higher ACE scores) had more significant improvements with KAP treatment, as demonstrated by greater improvement in anxiety scores, well-being scores, BDI, PTSD scores, and drug and alcohol use scores.

Additionally, increased age was correlated with greater improvement of depression as per rater view, lower HAM-A with treatment, and lower BDI with treatment. This may suggest the mechanism of neuroplastic change and anti-inflammatory effects are at work, since the amount of prior psychotherapy was not significant enough to explain this result.  KAP is thus shown here to be a unique and potentially powerfully treatment model with two main modalities, “trance” states and “transformational” states achieved from varying dosages and routes of administration. It is believed that the psychedelic/dissociative effects are not to be feared or avoided, rather that they play a vital role in the therapeutic effects of KAP, especially so when these experiences are integrated in a psychotherapeutic context. This benefit occurs not only across a range of doses but also for a range of diagnoses as well. The methodology presented here is especially unique in the fact that patients are required to be more engaged and creative with their settings when completing treatment at home.
Current pharmacological treatments for anxiety and depression are not favoured by many due to negative side-effects such as nausea or sexual dysfunction, and the fact that, in the case of antidepressants, must be taken daily. For many, the intermittent use of a medication is much more favourable, and ketamine presents an option for such use. This intermittent use also decreases the likelihood of adverse side effects. A considerable adverse side effect to be aware of in any medication is addiction potential. However, despite the stigma on recreational ketamine and concerns for its addiction/abuse potential, it does not produce a physical dependence when used in the context of KAP. Moreover, no patients from this sample sought ketamine outside of clinical practice or had any indications of addictive behaviour.

Despite the recorded efficacy and safety of KAP, ketamine is not beneficial to everyone. Ketamine can cause nausea or vomiting and a small subset (<5%) cannot tolerate these effects even with preventative medication. For others (1-2%), there is no response to ketamine even at high intramuscular doses. In the case of patients with particularly rigid personality structures, such as those with severe OCD, personality disorders, or even severe PTSD, entering trance states and sustaining the benefits can be difficult or unattainable, even if they have experienced some relief. The use of ketamine in KAP compared to IV practices, though usually more intensive and with longer sessions, is significantly less expensive. With this in mind, as well as the results presented above, KAP is showing promise as an evolving methodology as opposed to a specific protocol. This has been developed into a step-by-step approach that is manualized and taught in training conducted by KRF. Further research is required to refine, validate, and test the components of this protocol, and to compare outcomes of it with those of IV ketamine interventions and with standard of care interventions in mental health treatment.

Figure 1. A​ verage BDI and HAM-A scores at baseline compared with follow-up reveal a statistically significant decrease in anxiety and depression with treatment. Intake BDI scores on average fell in the range of moderate depression (20–28) and decreased an average of 11.24 points to mild depression range. Intake HAM-A scores fell in the moderate anxiety category and decreased on average 5.5 points to the mild anxiety category.

Learn More About Ketamine


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Emily Fewster

About the Author

Passionate about studying the psychedelic/mystical experience from a neuropsychological lens :)

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