Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Fattore and colleagues open from recent clinical interest in psychedelics sparked by positive results with MDMA in post-traumatic stress disorder (PTSD). They note that MDMA–assisted psychotherapy reduced PTSD symptoms and altered amygdala function, which has stimulated broader interest in using psychedelics to treat disorders characterised by maladaptive emotional memories, including substance use disorders (SUD). The introduction summarises the theoretical shift underpinning these proposals: memories are not immutable but can become labile after retrieval and undergo reconsolidation, a time-limited process during which they may be inhibited, interfered with, or updated. This review sets out to examine whether two classes of psychedelic‑acting substances—cannabinoids (including modulation of the endocannabinoid system) and ketamine—have preclinical and clinical effects that plausibly act via modulation of traumatic or appetitive memory reconsolidation. The authors aim to assemble mechanistic and clinical evidence that supports or contradicts the hypothesis that these agents can therapeutically alter maladaptive memories, and to outline possible translational approaches for testing them in reconsolidation-targeted interventions.

The paper is a narrative, mechanistic review rather than a formal systematic review or meta-analysis. Fattore and colleagues collate and interpret preclinical and clinical studies that examined how cannabinoids (endogenous ligands, phytocannabinoids, synthetic agonists/antagonists and modulators such as FAAH inhibitors) and ketamine/ketamine-like agents influence processes relevant to memory reconsolidation, extinction, retrieval and destabilisation. The extracted text does not provide a formal search strategy, inclusion/exclusion criteria, database list, date range, or risk-of-bias assessment; thus the review appears selective and integrative rather than comprehensive in a methodologically prespecified sense. The authors emphasise mechanistic links: they focus on molecular signalling (for example, NMDAR subunits, AMPA receptors, mTORC1, Zif268), neuroanatomical loci implicated in reconsolidation (amygdala, medial prefrontal cortex, hippocampus) and behavioural paradigms used in animal and human studies (conditioned fear, contextual fear, cue‑induced appetitive memories, clinical symptom change in PTSD). Where available, both animal infusion studies and human experimental or clinical findings are reported and compared. No pooled quantitative synthesis is attempted; instead, the review integrates findings to explore whether observed drug effects plausibly map onto known reconsolidation mechanisms and boundary conditions (memory strength, age, and reactivation parameters).

Memory reconsolidation: The review summarises contemporary reconsolidation theory: following retrieval, a consolidated memory may enter a labile period during which protein synthesis–dependent processes reform the memory trace; interventions given in a limited window (commonly up to about 6 hours post‑reactivation) can disrupt or modify reconsolidation. Boundary conditions—such as memory age, strength and the duration/schedule of reactivation—critically determine whether reconsolidation or extinction processes occur. Cannabinoids and endocannabinoid signalling: Preclinical data indicate that the endocannabinoid system regulates multiple memory stages. Enhanced anandamide (AEA) levels have been reported to facilitate conditioned fear extinction in rodents, and AEA infusion after brief reactivation blocked contextual fear reconsolidation in some studies. By contrast, inhibition of FAAH (which raises AEA) has been reported in other work to enhance reconsolidation of aversive memories, so findings are mixed. A dual FAAH/TRPV1 blocker (AA‑5‑HT) inhibited contextual fear retrieval via dorsal hippocampal CB1 receptor activation, and 2‑arachidonoylglycerol (2‑AG) in the hippocampus was implicated in retrieval of stressful spatial memories. Pharmacological manipulations of CB1 receptors show region- and stage-dependent effects. CB1 agonists (including THC, CP55,940, WIN55212‑2, HU210) disrupted reconsolidation when infused into specific regions (infralimbic cortex, dorsal hippocampus, amygdala or retrosplenial cortex) immediately after reactivation. CB1 antagonists produced heterogeneous effects: some studies report no effect on reconsolidation when given after reactivation, whereas others found disruption of aversive memory reconsolidation when antagonists were infused into the amygdala or dorsal hippocampus, and facilitation of reconsolidation when infused into retrosplenial cortex. CB1 signalling also appears necessary for extinction in many paradigms. The authors highlight that effects depend on memory type (aversive versus appetitive) and the precise neural locus of intervention. Cannabidiol (CBD) and clinical cannabinoids: CBD facilitated extinction and, importantly, disrupted reconsolidation of fear memory when administered immediately after retrieval but not in the absence of retrieval or when given 6 hours later. Animal studies implicated dorsal hippocampal CB1/CB2 receptors in CBD’s reconsolidation effects. Clinically, cannabinoids show mixed biomarker signals in PTSD: some cohorts had lower amandamide concentrations in limbic circuits while others had higher plasma AEA and 2‑AG; PET studies reported elevated CB1 receptor availability in PTSD, more so in women. Nabilone, a synthetic CB1 agonist, reduced nightmare intensity and improved subjective sleep in PTSD patients, with some reports of fewer daytime flashbacks. Ketamine and ketamine‑related mechanisms: Ketamine, an NMDAR antagonist, exerts complex synaptic effects through disinhibition of glutamate release, AMPA receptor activation, mTORC1 signalling, BDNF/TrkB pathways and synaptogenesis. These molecular cascades overlap with mechanisms involved in memory reactivation and reconsolidation, prompting investigation of ketamine’s effects on maladaptive memories. Preclinical reports are conflicting. Some studies showed ketamine impairs fear memory reconsolidation and this impairment correlated with down‑regulation of Zif268 mRNA and protein in hippocampal CA1. Other work found that ketamine increased reconsolidation or strengthened conditioned responses; one study linked this to GluN2B‑containing NMDA receptors in the basolateral amygdala, suggesting ketamine may sometimes interfere with the destabilisation step and thereby enhance reconsolidation. Clinical and experimental human findings: Clinical case reports describe transient remission of PTSD symptoms after low‑dose ketamine (35 mg) with benefits lasting around 2 weeks; randomised data include a trial in which a single 0.5 mg/kg ketamine infusion reduced PTSD and depressive symptoms versus active placebo (midazolam) for at least 2 weeks. However, other clinical and translational studies reported that peri‑traumatic or early post‑trauma ketamine administration could exacerbate PTSD symptoms or contribute to later pathology. Experimental human conditioning paradigms reproduced ketamine’s reconsolidation‑strengthening in some appetitive and aversive conditioned settings, with increased galvanic skin responses to previously conditioned cues after ketamine. Overall pattern: Across cannabinoids and ketamine, the evidence is heterogeneous. Cannabinoid manipulations often show region‑ and stage‑specific disruption of reconsolidation or facilitation of extinction, and clinical signals (e.g. nabilone, CBD) are promising but preliminary. Ketamine shows both potential to impair reconsolidation (and hence reduce maladaptive memories) and to strengthen them depending on timing, dose and neural locus; clinical effects on PTSD symptoms have been reported but are transient and inconsistent.

Fattore and colleagues interpret the assembled evidence cautiously. They acknowledge that, aside from a few reports, clinical therapeutic effects of cannabinoids or ketamine have not been definitively linked to reconsolidation changes, and that the existing literature is sparse and sometimes contradictory. Boundary conditions for reconsolidation, such as memory age, strength and reactivation parameters, are emphasised as critical variables that likely account for discrepant results across studies. The authors propose metaplasticity—the modulation of synaptic plasticity itself—as a plausible common process through which cannabinoids and ketamine might alter memory reconsolidation. Ketamine’s cascade of molecular events (mTORC1 activation, AMPA‑mediated synaptogenesis and related signalling) and the endocannabinoid system’s role in regulating synaptic and circuit responsiveness could both represent metaplastic changes that influence whether a retrieved memory destabilises and becomes vulnerable to updating or disruption. Translationally, the review outlines several intervention timing strategies. The canonical approach is a drug administered to coincide with the 1–6‑hour reconsolidation window after retrieval, aiming to inhibit molecular reconsolidation mechanisms. Cannabinoids may be particularly amenable to this strategy and as adjuncts to cognitive behavioural therapy, since some agents (e.g. CBD, THC, FAAH modulators) have shown extinction enhancement or reconsolidation disruption. By contrast, ketamine carries potential risks: if given immediately before or after retrieval it might strengthen reconsolidation or prevent destabilisation, producing unwanted effects. The authors therefore suggest alternative paradigms such as administering a metaplasticity‑inducing pretreatment hours before memory retrieval to favour destabilisation and subsequent non‑pharmacological inhibition (for example, post‑retrieval behavioural interventions), but they emphasise this is speculative and requires empirical testing. Key limitations acknowledged by the authors include the preliminary nature of much of the evidence, inconsistent findings across laboratories and species, and the lack of standardised clinical protocols linking drug action explicitly to reconsolidation outcomes. They call for more detailed mechanistic and behavioural studies that carefully control timing, dose, neural locus and the reconsolidation boundary conditions, and for cautious translation into clinical practice given potential adverse effects when timing is suboptimal.