Corrigendum: Ayahuasca-assisted meaning reconstruction therapy for grief: a non-randomized clinical trial protocol.

A three-arm, non-randomized controlled trial protocol compares Ayahuasca-assisted Meaning Reconstruction therapy (A-MR) with Meaning Reconstruction therapy alone and a no-treatment control for people who lost a first-degree relative within the prior 12 months. The authors hypothesize that A-MR will produce greater reductions in normal and pathological grief symptoms, and greater improvements in quality of life and posttraumatic growth, than either control condition. The rationale draws on neurobiological evidence that ayahuasca stimulates neuroplasticity and on psychological evidence that psychedelic experiences can facilitate meaning reconstruction and cognitive reappraisal. No controlled studies have tested psychedelic-assisted therapy for prolonged grief disorder.

Study at a glance

Abstract

1 IntroductionGrieving the death of a loved one is a nearly universal experience, and one which may be experienced multiple times over the course of a lifetime. Recent studies have shown that, for each death, approximately nine relatives are directly affected (1). The loss of a first-degree family member significantly increases the risk of mortality, disease, and suicide for the mourner (2–6). Although grief is a natural process, and serves a key existential purpose (7), this psychological process can go awry. Over the last century, different theories have explored how grief itself can become complicated or pathological.Prolonged Grief Disorder (PGD) has been recently incorporated as a diagnosis into the ICD (ICD-11; 8) and the DSM (DSM-5-TR; 9). PGD is characterized by (1) separation distress (i.e. a persistent grief response involving intense longing and preoccupation), (2) intense emotional reactivity (e.g. anger, denial, blame, emotional numbness, meaninglessness, avoidance), and (3) significant functional impairment (10, 11) according to the mourner’s sociocultural context. This reaction should persist to a marked degree for a minimum of 6 months, following the ICD-11 (8), or 12, months following the DSM-5-TR (9).The inclusion of PGD in the psychiatric diagnostic system is not without controversy. Besides the difficulties of distinguishing normal from prolonged grief, and the arbitrariness involved in categorizing continuous variables such as distress or time (10), it has been argued that the requirement for these diagnoses may lead to people experiencing acute grief not receiving appropriate healthcare (12). On the other hand, people in Western countries are rapidly losing the cultural knowledge, tradition, and rites to cope with the death of a loved one (13). In this social context, imposing a 6-to-12-month wait for receiving evidence-based psychological support can leave bereaved people abandoned in the most vulnerable state, especially for those at moderate or high health risk.Despite the WHO’s emphasis on the importance of preventive strategies for addressing the global burden of mental health issues (14), and on loneliness as a significant public health issue (15), evidence-based approaches to prevent PGD are still scarce. Moreover, meta-analyses have shown that preventive therapies for PGD are not currently effective (16, 17). Innovation is therefore necessary to provide effective psychotherapeutic and community support to people in the acute period of grief (18).1.1 Psychedelic-assisted grief therapyPsychedelic-assisted psychotherapy (PAP), a therapeutic approach augmenting talking therapy with psychedelic substances, has been recently classified as a potential breakthrough treatment for psychiatric illness (19). PAP is demonstrating promising outcomes in treating a wide range of mental health issues, ranging from depression to post-traumatic stress disorder, suggesting this efficacy may be transdiagnostic (20, 21). Controlled studies to date have been primarily focused on MDMA-assisted therapy for PTSD (22) and psilocybin-assisted therapy for treatment-resistant depression (23), but it has been proposed that psychedelics could also serve as a prophylactic or preventive intervention with the potential to improve quality of life, well-being, creativity, and personal and spiritual growth (24, 25).Ayahuasca, a traditional indigenous medicine, has been investigated as a potential treatment for treatment-resistant depression (26). Several studies have evidenced that individuals who regularly use ayahuasca in a communal setting exhibit a higher level of general well-being, increased physical activity, and balanced diet than the general population (27–29). While ayahuasca may not cause physical or psychological dependence, and serious adverse effects are uncommon in healthy individuals (30), some users have reported experiencing psychological distress during its acute effects (31). In a global survey involving 10,836 participants, 2.3% reported requiring medical support following ayahuasca use (32). Additionally, there have been a few documented instances where its consumption has been associated with the emergence of psychotic episodes (33). Nevertheless, most adverse effects can be mitigated by conducting a thorough assessment of participants’ health status prior to administration, ensuring the composition and purity of the ayahuasca preparation, administering an appropriate dosage, and avoiding potential drug interactions (30) (see Section Potential Adverse Effects Management).Despite the promising outcomes reported in the treatment of several mental health issues, no controlled studies have been conducted testing the efficacy of PAP for PGD, nor have any evaluated PAP’s potential in preventing prolonged grief when administered in the early course of bereavement. Previous observational research, however, has suggested that the ceremonial use of ayahuasca has therapeutic value in reducing the severity of grief (34–36). We therefore propose that ayahuasca assisted with an evidence-informed therapeutic approach, the meaning reconstruction model (37, 38), could show greater reduction in grief severity than psychotherapy alone.The rationale behind this hypothesis is grounded in a wide range of neurobiological and psychological evidence. Ayahuasca is an Amazonian concoction, usually prepared from the Banisteriopsis caapi vine and the Psychotria viridis shrub, which has been utilized for healing and ritual purposes since pre-Columbian times (39). Regarding the neurobiological evidence, in vitro, animal and human studies have demonstrated how harmine, tetrahydroharmine, harmaline (all three present in B. caapi) and dimethyltryptamine (present in P. viridis) stimulate adult neurogenesis and neuroplasticity, similarly to other serotoninergic psychedelic substances (40–43). A window for neuroplastic changes would appear to open a few hours after administration, lasting from a few days to a month (44). This period has been related to improvement in grief, depressive mood, stress, mindfulness, acceptance, emotion regulation, social behavior, wellbeing, and quality of life (45). Moreover, elevated peripheral Brain-Derived Neurotropic Factor (BDNF) levels have been observed in healthy volunteers and clinically depressed patients two days following the ayahuasca administration, correlating with clinical improvement in those who were diagnosed with major depression (40). Recent studies have shown that psychedelics reopen a critical period to induce metaplasticity, which dynamically regulates the potential for synaptic plasticity (46, 47). This critical period is context-dependent and has been linked to the ability to induce social reward learning, psychological flexibility, cognitive reappraisal and new patterns of behavior (46, 48, 49). In sum, these studies highlight the importance of the post-treatment integration period to maximize the therapeutic effect of psychedelics.Looking beyond the neurobiological evidence, several studies indicate that the therapeutic effect is experience-dependent (50, 51). Current research points toward specific traits of the psychedelic experience as relevant mediators of the therapeutic outcomes of PAP, such as acceptance-related experiences, the presence of mystical experiences, or the reappraisal of negative emotion (52–55). The altered state of consciousness induced by psychedelics is characterized by high sensitivity to the immediate and previous context, which can help actualize of the person’s belief system with bottom-up information (56). The ayahuasca experience, therefore, could bring new information to the foreground to enrich the therapeutic process, providing an opportunity to transform maladaptive narratives about oneself, other people (including the deceased) or the world (56, 57). The preparatory psychotherapeutic work, moreover, could bring to light potential blockages or resistances, allowing for an appropriate preparation of the patient’s mindset and intention before the administration of ayahuasca. Lastly, psychotherapy following ayahuasca administration (including, but not limited to, psychedelic integration) could likewise help to promote new behavior, in a way that is congruent with reappraised cognitive schemas derived from the assimilation and accommodation of the experience during this critical period.We posit, in sum, that ayahuasca experiences, when taking place within the framework of an appropriate and effective psychotherapeutic intervention, could enrich the clinical treatment of grief. This would allow for the integration of new information evoked from the psychedelic experience, and for this to result in more adaptive behavior and coping. We also hypothesize this would favor grief adaptation through fostering psychological processes such as meaning reconstruction, experiential acceptance, or cognitive reappraisal during a period of heightened meta-plasticity.2 Study protocol2.1 Study design and hypothesesThis three-arm, non-randomized controlled trial investigates the efficacy of Ayahuasca-assisted Meaning Reconstruction therapy (A-MR) in decreasing normal and pathological grief symptoms in people who have lost a first-degree relative within the prior 12 months. Participants are sequentially allocated to the following treatment conditions: (1) a control group receiving Meaning Reconstruction therapy (MR), (2) a control group receiving No Treatment (NT), and (3) an experimental group receiving Ayahuasca-assisted Meaning Reconstruction therapy (A-MR).The objective of this trial is two-fold. First, our aim is to compare the efficacy of A-MR with that of MR and NT by assessing differences in (a) the severity of normal grief symptoms, (b) pathological grief symptoms, (c) quality of life, and (d) posttraumatic growth. Moreover, we are also interested in analyzing how each condition may influence the proposed processes of change: (e) meaning-made (f) psychological flexibility, and (g) self-belief consistency. Additionally, we will explore the participants’ (h) subjective effects of ayahuasca and the (i) acceptance-avoidance promoting effects.The following hypothesis will be tested:Hypothesis 1. The experimental group receiving A-MR will show greater improvement in normal and pathological grief symptoms, quality of life, and post-traumatic growth compared to both control groups (MR and NT), at post-treatment and 3 months follow-up. Moreover, MR group will show greater improvement than the NT group, expecting a medium clinical effect size.Hypothesis 1.1. The experimental group receiving A-MR will show greater improvement in psychological flexibility, meaning-made, and self-believed consistency compared to both control groups (MR and NT), at post-treatment and 3 months follow-up. Furthermore, MR will also show greater improvement than the NT group, expecting a medium clinical effect size.Hypothesis 2. Reductions in the severity of normal and pathological grief symptoms will be principally related to changes in meaning- made, but also to changes in psychological flexibility and self-belief consistency. Moreover, a stronger relationship between changes in the severity of grief symptoms and meaning-made is expected in the A-MR group.2.2 ParticipantsParticipants eligible for this study will be English and Spanish-speaking adults experiencing grief symptoms due to the death of a loved one. Inclusion criteria involve: (1) people aged 18-65; (2) having experienced the loss of a first-degree relative; (3) within the past 12 months; and (4) with a Texas Revised Inventory of Grief score over 39 (TRIG ≥ 40). Exclusion criteria involve: (1) medically and mentally significant health conditions; (2) history of psychotic disorder (Axis I- DSM-IV-TR); (3) pregnant or breastfeeding women; (4) hypertension (SBP > 140 mmHg, DBP > 90 mmHg, HR >100 bpm); (5) substance use disorder, excluding nicotine; (6) alcohol consumption exceeding 40g/day; (7) concurrent psychological or pharmacological treatment for grief. Those who are not eligible will be referred to other mental health professionals specialized in bereavement.2.3 ProcedureParticipants will be recruited through the newsletter, webpage, and social media accounts of the Beckley Foundation, Beckley Med, MIND Foundation and the International Center for Ethnobotanical Education, Research and Service of to psychedelic research and receiving the to in the the will be to a to for inclusion Those who the inclusion criteria will a with the to more about would and to any criteria are will also be about the to range with a general to prevent potential that is before each ayahuasca those who are eligible will provide will be conducted at during treatment and at and at (see in the A-MR and MR group will a psychotherapy process, within after the assessment is those in the A-MR group will in to two ayahuasca the therapeutic process, by an preparation and by a MR integration during the after each ayahuasca in control group (MR or have the to in two 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