Low dose ketamine infusion for comorbid posttraumatic stress disorder and chronic pain: a randomized double-blind clinical trial

Objective: To date, treatment options (i.e. psychotherapy, antidepressant medications) for patients with posttraumatic stress disorder (PTSD), are relatively few, and considering their limited efficacy, novel therapies have gained interest among researchers and treatment providers alike. Among patients with chronic pain (CP) about one third experience comorbid PTSD, which further complicates their already challenging pharmacological regimens. Low dose ketamine infusion has shown promise in PTSD, and in treatment of CP, however they have not been studied in comorbid population and under rigorous control conditions.

Methods: We compared the effects of a single dose of either ketamine (0.5 mg/kg) or ketorolac (15 mg) over a 40-minute of IV infusion in CP patients with and without PTSD, in double blind, randomized study. Measures were collected before, during, one day and seven days after the infusion. A planned sample size of 40 patients randomly assigned to treatment order was estimated to provide 80% power to detect a hypothesized treatment difference after the infusion.Main Outcome and Measures: The primary outcome measures were change in PTSD symptom severity assessed with the Impact of Event Scale-Revised (IES-R) and Visual Analogue Scale (VAS) for pain administered by a study clinician 24 hours post infusion. Secondary outcome measures included Impact of Event Scale-Revised (IES-R), VAS and Brief Pain Inventory (Short Form) for pain 1 week after the infusion.

Results: Both treatments offered comparable improvement of PTSD and CP symptoms that persisted for 7 days after the infusion. Patients with comorbid PTSD and CP experienced less dissociative side effects compared to the CP group. Surprisingly, ketorolac infusion resulted in dissociative symptoms in CP patients only.

Conclusions: This first prospective study comparing effects of subanesthetic ketamine versus ketorolac infusions for comorbid PTSD and CP, suggests that both ketamine and ketorolac might offer meaningful and durable response for both PTSD and CP symptoms.

KRIYA: Ketamine Research Institute

KRIYA Institute is devoted to understanding the therapeutic properties of ketamine (and related medicines). We provide clinical services directly to patients; we give presentations about therapeutic ketamine in a variety of settings; we offer consultation services to physicians and therapists; and we run KRIYA Conference, which was the first conference in the world devoted to the use of ketamine. Our mission is to bring together the most rigorous Science and an appreciation of Spirit in the study of psychospiritual medicines such as ketamine.

Trends in Drug Use among Electronic Dance Music Party Attendees in New York City, 2016-2019

Objective: Electronic dance music (EDM) party attendees are a high-risk population for drug use and associated adverse effects. We examined trends in past-year drug use within this population to better inform prevention and harm reduction efforts.

Methods: Each summer from 2016 through 2019, we used time-space sampling to survey a cross-section of adults entering EDM parties at randomly selected nightclubs and at dance festivals in New York City. Ns ranged from 504 (2019) to 1,087 (2016). We estimated log-linear trends in past-year use of 16 different synthetic drugs or drug classes.

Results: Between 2016 and 2019, estimated past-year prevalence of use of ketamine increased from 5.9% to 15.3% (a 157.6% relative increase; P=.007), LSD use increased from 9.9% to 16.6% (a 67.7% relative increase, P<.001), powder cocaine use increased from 17.3% to 35.2% (a 103.5% relative increase, P<.001), and GHB use increased from 1.0% to 4.2% (a 311.8% relative increase; P=.002). Past-year use of ≥3 drugs increased from 12.7% to 20.5% (a 61.4% relative increase; P=.013); however, estimated past-year use of unknown powders decreased from 2.0% to 1.1% (a relative 44.7% decrease; P=.038) and ecstasy/MDMA/Molly use was stable across years (at 25.0-28.5%; P=.687). Conclusions: Reports of powder cocaine, LSD, ketamine, and GHB are becoming more prevalent among EDM party attendees. Prevention and harm reduction efforts are needed to address increasing use. Research is also needed to examine whether increasing media coverage of medical use of ketamine and other psychedelics affects prevalence of recreational use.

Serotonergic Psychedelics in Neural Plasticity

Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.

A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial

Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.

A total of 154 adults (ages 18–60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active “automated self-association training” [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT—targeting self-worth through automated “evaluative conditioning” training delivered by computer—or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS).

Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [β]=−1.30, 95% CI=−1.89, −0.70; t=−4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (β=−0.61, 95% CI=−0.95, −0.28; t=−3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: β=0.015, 95% CI=0.003, 0.03; t=2.35, df=568).

After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine’s rapid antidepressant effects.

Ketamine for the treatment of addiction: Evidence and potential mechanisms

Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine’s ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine’s efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.

Do the dissociative side effects of ketamine mediate its antidepressant effects?

Background: The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.
Methods: Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230min and Days 1 and 7.
Results: Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min (r=-0.35, p=0.007) and Day 7 (r=-0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.
Limitations: Secondary data analysis, combined diagnostic groups, potential unblinding.
Conclusions: Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study

Background: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders.
Aims: The purpose of this study was to replicate our earlier report about ketamine’s anxiolytic activity, using a more robust study design.
Methods: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations.
Results: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments.
Conclusions: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

The Ketamine Papers: Science, Therapy, and Transformation

The Ketamine Papers opens the door to a broad understanding of this medicine’s growing use in psychiatry and its decades of history providing transformative personal experiences. Now gaining increasing recognition as a promising approach to the treatment of depression, posttraumatic stress disorder (PTSD), and other psychological conditions, ketamine therapies offer new hope for patients and clinicians alike. With multiple routes of administration and practices ranging from anesthesia to psychotherapy, ketamine medicine is a diverse and rapidly growing field. The Ketamine Papers clarifies the issues and is an inspiring introduction to this powerful tool for healing and transformation—from its early use in the 1960s to its emerging role in the treatment of depression, suicidality, and other conditions. This comprehensive volume is the ideal introduction for patients and clinicians alike, and for anyone interested in the therapeutic and transformative healing power of this revolutionary medicine.

Ketamine: Dreams and Realities

“Karl Jansen’s book Ketamine, Dreams, and Realities is a goldmine of information on this fascinating substance that combines in a unique way the properties of an anesthetic and a psychedelic. It is clearly written, well researched and documented, and presents a balanced and objective view point. The author’s broad perspective that covers all the aspects of Ketamine from pharmacology to its use in raves makes this book interesting for clinicians and researchers, as well as the general public.”- Stan Grof, M.D.