This study (2017) reviews the clinical and preclinical data concerning cannabinoids and ketamine as they relate to possible reconsolidation processes of maladaptive memories.
Abstract
“Rationale: Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.
Objective: Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.
Results: We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.
Conclusions: Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.”
Authors: Liana Fattore, Alessandro Piva, Mary Tresa Zanda, Guido Fumagalli & Cristiano Chiamulera
Summary
Clinical studies with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD).
Introduction
Recently, clinical trials with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorders (PTSD) have shown significant effects similar to the standard prolonged exposure therapy. These findings have contributed to a growing interest on the potential use of psychedelic drugs for the treatment of disorders characterized by maladaptive memories.
Although it was thought that memory is stored and stable forever, it was shown that memories can undergo upon retrieval to a process of update called reconsolidation. This has been proposed as an intervention for maladaptive memory disorders such as PTSD and SUD.
Although there is still an open debate about the potential use of MDMA in PTSD and SUD, the rationale for its use is being extended to a broader beneficial Bpsychedelic effect. The proposed mechanism of MDMA effects in PTSD is the modulation of memory reconsolidation.
In this manuscript, we review the preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes that could be related to the reconsolidation of maladaptive memories.
The memory reconsolidation process and the underlying mechanisms
Under traumatic conditions, or rewarding drug effects, the emotional learning can go awry. Extinction or exposure therapy may reduce the conditioned response, but does not modify the original memory trace.
Several reports showed that it is possible to disrupt emotional and appetitive memories by inhibiting the reconsolidation process during a temporal window up to 6 h immediately following retrieval. However, the main critical issue about studies on memory reconsolidation is the way under which memory is reactivated.
Time duration, schedule of reactivation, conditions of reconsolidation inhibition, and modalities under which its occurrence is assessed play a significant role in determining the degree of memory-induced lability after recovery.
Memory reconsolidation is a protein synthesis-dependent process that can be blocked by inhibitors of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) activity, N-methyl-D-aspartate glutamate receptor (NMDARs), -adrenergic receptor, and many others.
The amygdala is involved in memory reconsolidation, and mTORC1 inhibition, followed by reduction of downstream ribosomal protein 6 (rpS6) phosphorylation, is associated with alcohol-related memories and conditioned fear reconsolidation.
Pharmacological studies have shown that glutamate receptor antagonism blocks reconsolidation of maladaptive memories, but not before memory reactivation. Extinction sessions can be used to prevent relapse to drug use, but boundary conditions limit their use.
Drugs acting on memory reconsolidation may modulate the neurobiological mechanisms, neural circuits, and behavioral responses described above as a stand-alone therapy or possibly combined with psycho-behavioral therapy.
Cannabinoid system, receptors, ligands, and modulators: a premise for PTSD?
Studies have shown that the endocannabinoid system regulates memory encoding, retrieval, and consolidation, and that increased levels of the endocannabinoid anandamide facilitate conditioned fear memory extinction and that increased anandamide signaling through inhibition of its primary catabolic enzyme, FAAH, enhances reconsolidation of aversive memories. The endocannabinoid 2-arachidonoylglycerol in the hippocampus mediates the effect of stress on memory retrieval, and the effects of corticosterone on memory retrieval can be prevented by blocking CB1 receptors in the hippocampus.
CB1 receptors have been found to play an important role in memory reconsolidation, with some studies showing that activation of CB1 receptors after memory reactivation disrupts reconsolidation, while others show that CB1 receptors do not affect memory reconsolidation. Fear memory acquisition, consolidation, retrieval, and extinction appear to be regulated differentially by CB1 receptor located in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC).
Delta-9-tetrahydrocannabinol (THC) was found to disrupt contextual fear memory reconsolidation through a CB1 receptor-mediated mechanism. The role of the endocannabinoid system in modulating the emotional memories depends on important variables, such as the nature of the memories (i.e., appetitive or aversive) and the different stages of the memory process.
The effect of cannabinoids on memory is dependent on the stage of memory process, and cannabidiol enhances visual fear memory extinction when given immediately after, but not before, extinction.
The endocannabinoid system is involved in the adaptation to aversive memories and the control of negative affect. It is likely that the endocannabinoid system is also involved in the modulation of memory consolidation via the PPARs, the transient receptor potential cation channel subfamily V member 1 and the mu-opioid receptor.
In agreement with animal studies, human studies examining PTSD cohorts found lower concentration of anandamide in the amygdala-hippocampal-cortico-striatal circuit in PTSD patients, whereas other studies reported higher plasma concentrations of both anandamide and 2-arachidonoylglycerol in PTSD patients.
Cannabidiol has been found to enhance consolidation of extinction learning and to disrupt reconsolidation of fear memories in rats, leading to inhibition of fear memories reinstatement or spontaneous recovery in the short-intermediate term.
Nabilone, a CB1 receptor agonist, was found to be effective in treating PTSD-related nightmares in patients and PTSD military patients, and may be useful in treating PTSD patients with poor control of nightmares by conventional pharmacotherapy.
Cannabidiol reduces fear memory over-generalization by enhancing memory destabilization and disrupting fear memory reconsolidation. It is therefore a promising adjunct to psychological therapy for patients with PTSD or other trauma-related disorders.
The multiple-faceted pharmacology of ketamine: more than antidepressant?
Ketamine, an NMDA receptor antagonist, is widely misused as a recreational drug, but is also being used off-label as an antidepressant. Ketamine reduces GABAergic inhibitory activity and disinhibites excitatory glutamate transmission by directly interacting with the GluN2B-NMDA receptor subunit, and by stimulating the synthesis of AMPA receptor subunits. This results in a positive feedback with amplification of synaptic activity.
Ketamine may be able to treat PTSD symptoms through disruption of fear memory reconsolidation. This effect is correlated to Zif268 mRNA and protein down-regulation in CA1 area of the hippocampus, and is inhibited by pre-treatment with the selective AMPA receptors inhibitor NBQX.
Ketamine has been reported to have clinical effects in not depressed patients affected by generalized anxiety disorder or social anxiety disorder. Low doses of ketamine were found to be able to reduce symptoms in major depression and PTSD without inducing typical side effects.
Ketamine enhances the reconsolidation of auditory conditioned fear memories by increasing the activation of GluN2B-NMDA receptors in the basolateral amygdala, which presumably interferes with the destabilization mechanism that is necessary to make the memory liable after reactivation.
Ketamine decreased pain and PTSD symptoms after surgery in burned soldiers, but may cause PTSD symptoms in burn patients and accident victims. Ketamine may also exacerbate PTSD symptoms in patients with a history of trauma.
Preclinical studies have reported controversial findings with respect to the effect of ketamine on memory processes associated with conditioned fear.
Opportunities and open questions
A single treatment (drug + memory retrieval) given acutely in a clinical setting, possibly repeated once a week, should be an effective regimen to reduce the reconsolidation of maladaptive memory (either PTSD or SUD).
The data reviewed in this manuscript suggest that a therapeutic approach based on cannabinoids and endocannabinoid system would be suitable, and that it might also act as an enhancer of behavioral interventions such as the application of post-retrieval extinction interventions. Non-pharmacological interventions (e.g., psychotherapy, counseling, motivational support, nursing, standard healthcare, etc.) are always components of a therapy, and can be used to manipulate maladaptive memory reconsolidation.
The above consideration on manipulation of memory reconsolidation may be extended to ketamine, and the use of ketamine few hours before retrieval may trigger a so-called metaplastic cascade that reduces maladaptive memory reconsolidation.
Ketamine can induce a cascade of molecular events leading to enhanced synaptic activity in brain areas involved in mood, motivation, and emotional memory. This effect could be used to facilitate memory destabilization and make memory vulnerable to non-pharmacological inhibition.
We conclude that metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.