Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction

Abstract

Opioid addiction in the United States currently presents a national crisis despite availability of different treatments. Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with opioid use disorders (OUD) when administered in isolation. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. TIMBER (Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories) therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) and in combination with memoryaltering pharmacotherapy like ketamine infusion. By a combination of extinction and reconsolidation of memory approaches, TIMBER works to not over-flood and/or retraumatize as is seen in other treatment approaches. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction-only approaches) which explains its superior efficacy in PTSD and benefit in substance use disorders.

Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature

“…The findings are described in detail and organized in relation to the specific type of article and order of publication (see Table 1). Studies retrieved were represented by nine case series/case reports [13,[40][41][42][43][44][45][46][47][48], six randomized-controlled trials [49][50][51][52][53][54], ten open-label studies [55][56][57][58][59][60][61][62][63][64][65] and three double blind trials [66][67][68]. Most cases involved adult males (total M/F = 328/160= 2.1).…”

“…Most cases involved adult males (total M/F = 328/160= 2.1). Patients were mostly diagnosed with OCD [13,40,45,47,55,56,[60][61][62][63][64] or a SUD, such as opioid dependence [41,[43][44][45][46][57][58][59], cocaine dependence [49,50,52,[66][67][68] or alcohol dependence [51,54,65]. Only three studies focused on ED [42,46,48].…”

“…Only three studies focused on ED [42,46,48]. Ketamine was mostly intravenously administered [42][43][44][45][47][48][49][50][51][52][53][54][55][56][57][59][60][61][65][66][67], but intranasal [40,62], intramuscular [46,58,68] and oral [13,41] routes of administration were also recorded. Ketamine was administered together with Cognitive Behavioral Therapy (CBT) [40,43], or in the context of ketamine-assisted psychotherapy (KPT) sessions [58,68] or Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories (TIMBER) [59].…”

“…Ketamine was mostly intravenously administered [42][43][44][45][47][48][49][50][51][52][53][54][55][56][57][59][60][61][65][66][67], but intranasal [40,62], intramuscular [46,58,68] and oral [13,41] routes of administration were also recorded. Ketamine was administered together with Cognitive Behavioral Therapy (CBT) [40,43], or in the context of ketamine-assisted psychotherapy (KPT) sessions [58,68] or Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories (TIMBER) [59]. Ketamine was generally well tolerated, with the exception of transient effects, including nausea [42,43], headache [42,46], dry mouth [45], sleepiness [46], feelings of unreality [45], dissociation [46,49,55,56,62], dizziness…”

Subthreshold repetitive transcranial magnetic stimulation suppresses ketamine-induced poly population spikes in rat sensorimotor cortex

“…Due to their overlapping effects, rTMS and subanesthetic ketamine have been combined to treat neuropsychiatric disorders in humans and shown synergetic effects (Best and Griffin, 2015;Pradhan and Rossi, 2020;Davila et al, 2021). However, the interaction of rTMS and anesthetic ketamine on cortical activities including cortical oscillations and neuronal spike firing has not been explored yet.…”