Psychopharmacology (2020) 237:1171–1182 https://doi.org/10.1007/s00213-019-05446-2 ORIGINAL INVESTIGATION Therapeutic potential of ayahuasca in grief: a prospective, observational study Débora González 1,2 & Jordi Cantillo 1,2 & Irene Pérez 1 & Magí Farré 3,4 & Amanda Feilding 5 & Jordi E. Obiols 6 & José Carlos Bouso 1 Received: 24 July 2019 / Accepted: 27 December 2019 / Published online: 14 January 2020 # The Author(s) 2020 Abstract Rationale Recent studies have assessed the therapeutic potential of ayahuasca for the treatment of depression with promising preliminary results. Objectives Here, we examine the course of grief over 1 year of follow-up in a bereaved sample that attended a center in Peru to participate in indigenous Shipibo ayahuasca ceremonies. We also explore the roles of experiential avoidance and decentering as mechanisms of change. Methods Bereaved participants who attended the ayahuasca center responded to an online survey that included the Texas Revised Inventory of Grief, Symptom Assessment-45, WHO Quality of Life-Bref, Acceptance and Action Questionnaire, and Decentering. Baseline assessment was completed by 50 individuals (T0). Of these, 39 completed the post-assessment at 15 days (T1), 31 at 3 months (T2), 29 at 6 months (T3), and 27 at 12 months (T4) after leaving the retreat. Pearson’s analysis was performed to examine the relationship between the severity of grief and mechanisms of change during the period of T0 and T1. Results A significant decrease in Texas Revised Inventory was observed at all time points (T1: Cohen’s d = 0.84; T2: Cohen’s d = 1.38; T3: Cohen’s d = 1.16; T4: Cohen’s d = 1.39). We found a relationship between experiential avoidance (r = 0.55; p < .01), decentering (r = − 0.47; p < .01), and a reduction in the severity of grief. Conclusions Our results suggest that the ceremonial use of ayahuasca has therapeutic value by reducing the severity of grief. Acceptance and decentering are both psychological processes that mediate the improvement of grief symptoms. Keywords Ayahuasca . Shipibo . Death . Bereavement . Grief . Psychopathology . Quality of life . Experiential avoidance . Acceptance . Decentering Introduction means “rope or vine” (Metzner, 2005). Ayahuasca is a natural plant concoction used by indigenous groups throughout the The word “ayahuasca” is derived from the Quechua language, Amazon Basin in traditional medicine and spiritual rituals aya means “dead person, spirit, soul, or ancestor” and huasca (Schultes and Hofmann, 1992). The concoction is usually Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-019-05446-2) contains supplementary material, which is available to authorized users. * Débora González 4 Department of Pharmacology, Therapeutics and Toxicoloy, deboragonzalez@iceers.org Universitat, Autònoma de Barcelona, Avinguda de Can Doménech, 08193 Cerdanyola del Vallés, Spain 1 International Center for Ethnobotanical Education, Research and 5 Services (ICEERS), Carrer de Sepúlveda, 65, Office 2, The Beckley Foundation, Beckley Park, Oxford OX3 9SY, UK 08015 Barcelona, Spain 6 2 PHI Asociation, Passeig del Calvell 35-37, 08005 Barcelona, Spain Department of Clinical and Health Psychology, Universitat Autònoma de Barcelona, Bellaterra Campus, Building B, Office B5/ 3 Clinical Pharmacology Unit, Hospital Universitari Germans Trias i 016b, 08193 Cerdanyola del Vallés, Spain Pujol and Institut de Recerca Germans Trias i Pujol (IGTP), Ctra. de Can Ruti s/n, 08916 Badalona, Spain 1172 Psychopharmacology (2020) 237:1171–1182 prepared by boiling the stems of the Banisteriopsis caapi vine even more in people who drink ayahuasca regularly with the leaves of the Psychotria viridis shrub, or Diplopterys (Franquesa et al. 2018), as long as they do not possess border- cabrerana leaves (Schultes and Hofmann, 1992). B. caapi is line personality traits (Domínguez-Clavé et al., 2019). Other rich in beta-carbolines, which have monoamine oxidase- studies have found improvements in other mechanisms of inhibiting properties, the main pharmacological mechanism change that are also classic goals of mindfulness training. of some antidepressants currently used in clinical practice This is the case for positive self (Franquesa et al. 2018), inner (Meister et al. 2016). P. viridis and D. cabrerana contain the reactivity, and the judgmental processing of experiences tryptamine N,N-dimethyltryptamine (DMT) that acts as an (Soler et al. 2016). agonist of 5-HT-2A and sigma-1 receptor sites, which is also Until now, only one exploratory observational study has associated with antidepressant, anxiolytic, and psychoactive found preliminary evidence regarding the therapeutic poten- effects (Fontanilla et al. 2009; Domínguez-Clavé et al. 2016). tial of ayahuasca for grief related to the death of a loved one The evidentiary literature on ayahuasca’s pharmacological (González et al. 2017). Bereavement, defined as the period of safety among healthy volunteers (Dos Santos et al. 2013, grief and mourning after the death of a love one, is a universal 2012; Riba et al. 2003), and the lack of dose tolerance and condition and one of the most painful experiences that humans addictive potential (Fábregas et al. 2010), has triggered exten- face. Feeling stunned or shocked, emotional numbness, mis- sive scientific research into this concoction during the last two trust of others, bitterness over the loss, confusion about one’s decades. Single-photon emission computed tomography role in life, a diminished sense of self, difficulty accepting the (SPECT) techniques have shown ayahuasca to produce an loss, and moving on with life are normal reactions when be- increased blood perfusion in the left nucleus accumbens, right reaved in the aftermath of a death of a love one (Prigerson insula and left subgenual area, brain regions implicated in the et al. 2009). Prolonged Grief Disorder (PGD) has recently regulation of mood and emotions (Sanches et al. 2016). been included in the latest version of the International Functional magnetic resonance imaging have shown a signif- Classification of Disease (ICD-11) (World Health icant decrease in the activity of the Default Mode Network Organization, 2018), with an estimated prevalence of 9.8% (DMN) (Palanho-Fontes et al. 2015), a brain network that is among bereaved individuals (Lundorff et al. 2017). Core hypperactivated in patients with major depressive disorder PGD symptoms include pervasive yearning for the deceased (MDD), which is associated with maladaptive rumination and persistent preoccupation with the deceased, accompanied and self-referential processes (Hamilton et al. 2011; Sheline by intense emotional pain for, at minimum, 6 months post- et al. 2009). Moreover, ayahuasca enhances creative divergent loss. In addition, PGD is characterized by cognitive, emotion- thinking, a psychological process underlying psychological al, and behavioral symptoms that disrupt the individual’s abil- flexibility that is relevant to the success of cognitive therapy ity to function in different contexts (World Health (Kuypers et al. 2016). Regular ayahuasca ceremony partici- Organization, 2018). Research has found that symptoms of pants have performed well on neuropsychological tests PGD are associated with impairment of the bereaved person’s (Bouso et al. 2012, 2015) and show low levels of psychopath- familiar, social and occupational functioning to a similar ex- ological symptoms (Bouso et al. 2012, 2015; Barbosa et al. tent as found in depression and post-traumatic stress disorder 2009). Rapid anxiolytic and antidepressant effects have been (Prigerson et al. 2009; Jordan and Litz 2014; Maercker et al. demonstrated in animals (Da Silva et al. 2018; Cameron et al. 2013). Drugs alone have not been shown to effectively treat 2018) and human beings (Dos Santos et al. 2007; Palhano- PGD symptoms (Zisook and Shear 2009; Shear et al. 2016). Fontes et al. 2019; Osorio et al. 2015). A recent study The latest meta-analysis of controlled trials found that the supporting these results observed a modulation of salivary mean effect sizes of the current psychotherapeutic interven- cortisol in major depression treatment-resistant patients, tions are smaller than those of treatments for other psychiatric where concentrations similar to those of healthy volunteers disorders (Johannsen et al. 2019; Wittouck et al. 2011). were reached 48 h after a single dose of ayahuasca (Galvão Moreover, the results from grief interventions on non- et al., 2018). pathological grief provide inconsistent support for their effec- Studies about the mediating psychological processes un- tiveness (Wittouck et al. 2011). derpinning ayahuasca’s therapeutic potential are also growing. The present study investigated the long-term effects of aya- A previous study found that 4 ayahuasca sessions could be as huasca in participants who are grieving the death of a loved effective at reducing experiential avoidance (or, formulated one, following a sample of subjects with a history of grief who positively, at promoting the acceptance of negative feelings willingly attended ayahuasca ceremonies at an ayahuasca cen- and thoughts) as 8 weeks of mindfulness-based stress reduc- ter in Peru. The primary outcome variable was the severity of tion (MBSR) (Soler et al. 2018). Decentering, defined as the grief. Secondary variables were psychopathological symp- ability to observe one’s thoughts and feelings in a detached toms, quality of life, experiential avoidance, and decentering. manner (Fresco et al. 2007), also improves 24 h after drinking We hypothezised that the severity of grief would be reduced ayahuasca (Soler et al. 2016). This ability seems to increase after drinking ayahuasca at the center. Second, we Psychopharmacology (2020) 237:1171–1182 1173 hypothezised that psychopathological symptoms, quality of of a loved one; (c) can you understand with ease everything life, and both psychological processes would also improve you read in the English language? Participants were included after drinking ayahuasca. Given that previous studies have in the study if they affirmed feeling grief symptoms related to shown that acceptance and decentering are psychological pro- the death of a loved one (regardless of whether they claim to cesses underlying ayahuasca’s effects, and given that both be going through a period of depression, anxiety, or trauma) constructions play an important protective role in psychopa- and they affirmed having an adequate knowledge of the thology models, we finally hypothesized that the improve- English language. ment of both psychological processes would mediate the re- Once participants were included in the study, assessments duction in the severity of grief. were done 15 days before attending the retreat (T0) and 15 days (T1), 3 months (T2), 6 months (T3), and 12 months (T4) after leaving the retreat. Participants who were included Methods in the study more than 2 months before attending the center were invited to respond to an additional assessment 2 months This study is part of a broader study that aims to prospectively before entering the center (T-1) in order to control for the assess the long-term effects of ayahuasca on well-being and effect of time on outcomes in a subgroup. quality of life, as well as psychopathological symptoms in All questionnaires were administered online using different subsamples with depression, anxiety, post-traumatic LimeSurvey (version 1.92.), which allowed for the collection stress disorder, and grief (data are currently pending publica- and preservation of the data on a secure server that is accessi- tion). In the present article, only the data for the grief subsam- ble only to the researchers via a password. ple has been included and analyzed. Participants and procedure Measures Participant enrollment was carried out between 2015 and Texas Revised Inventory of Grief This questionnaire is a self- 2017. During 2018, the follow-up period of 1 year was con- report measure designed to quantify the severity of grief cluded. Participants were invited to participate in the study (Faschingbauer 1981). In this study, only the Present through the website of the Temple of the Way of Light Feelings Scale was used to measure a person’s emotional state (Temple of the Way of Light 2016), after having booked their at the time of the questionnaire’s completion. The question- stay at the center. This center offered retreats of 9, 12, or naire comprises a total of 13 items scored on a 5-point Likert- 30 days, where participants drank ayahuasca between 4 and type scale (1 = completely false to 5 = completely true). The 9 times in a ceremonial context under the guidance of Shipibo Texas Revised Inventory of Grief (TRIG) is score by calculat- Curanderos (traditional healers). The retreat also offers option- ing the average scores for the subscale. Higher scores indicate al yoga classes, floral and steam baths, and integration circles a greater severity of grief. The scale has been shown to have concerning ayahuasca experiences. Information about the re- adequate psychometric properties with Cronbach’s coefficient treats is available online (Temple of the Way of Light 2016). alpha value of .90 in the present feelings scale. Despite the fact that these programs were not specifically de- veloped to treat grief symptoms, our goal was to reach a suf- Symptom Assessment-45 Questionnaire This questionnaire is ficient number of participants who were suffering from the a self-report clinical measure designed to assess psychiatric loss of a loved one when they attended the retreat. symptoms in 9 different symptom domains, as well as to pro- A total of 50 participants were elegible for the analysis. The vide a general measure of overall psychiatric distress (GSI) screening process involved two stages. First, to be accepted by (Davison et al., 1997). It contains 45 items, which fall into the the center, which requires individuals to be 18 years of age or following scales: Anxiety, Hostility, Obsessive-Compulsive, older. People with previous clinical disorders (i.e., psychosis, Phobic Anxiety, Somatization, Depression, Interpersonal depersonalization, or mania), people who were taking certain Sensitivity, Paranoid Ideation and Psychoticism. Examinees medications (i.e., MAOIs or SSRIs), people with a heart con- are asked to indicate how much the particular problem has dition, those with chronic high blood pressure, and pregnant bothered them during the past 7 days on a 5-point Likert-type women were not accepted (Temple of the Way of Light 2019). scale (0 = not at all to 4 = extremely). The Symptom Second, to respond to a short online questionnaire including Assessment-45 Questionnaire (SA-45) has been normed using the following questions: (a) Please indicate the exact date both non-patient (N = 1621) and clinical samples (N = 13.844) when you will attend to the retreat; (b) please mark “yes,” (Maruish et al. 1998). Each of the samples included norms for “uncertain,” or “no” to the following questions: are you cur- both adolescent and adult males and females. Raw scores are rently going through a period of (b.1) depression; (b.2) anxi- transformed into standard T scores (M = 50, SD = 10). The ety; (b.3) post-traumatic stress; (b.4) grief related to the death scale has been shown to have adequate psychometric 1174 Psychopharmacology (2020) 237:1171–1182 properties with Cronbach’s coefficient alpha values ranging Ayahuasca samples analyses from 0.69 to 0.92. We obtained samples of two different ayahuasca batches World Health Organization Quality of Life-BREF This question- prepared by Shipibo shamans at the Temple of the Way of naire is a shorter version of the original WHOQOL-100 Light along the period of the study. The ayahuasca was (Whoqol Group 1998). This questionnaire was designed to prepared by boiling the stems of B. caapi (rich in assess quality of life in four domains: Physical Health, harmine, tetrahydroharmine, and harmaline) combined Psychological Health, Social Relationships, and with the leaves of P. viridis (rich in N,N-dimethyl-trypt- Environment. For the purpose of this study, only the first three amine) for several hours. Analyses were carried out by scales were used. The questionnaire comprises a total of 24 Energy Control (energycontrol-international.org) using items, scored on a 4–20 scale, with higher scores indicating a liquid chromatography-mass spectrometry (LC-MS). One better quality of life. The scale has been shown to have ade- ayahuasca sample contained 2 mg/ml N, N-DMT, quate psychometric properties with Cronbach’s coefficient al- 2 mg/ml of harmine, 0.37 mg/ml of harmaline, and pha values ranging from 0.68 to 0.82 (Skevington et al. 2004). 1 mg/ml of tetrahydroharmine. The other sample contained 2 mg/ml N, N-DMT, 2 mg/ml of harmine, 0. Acceptance and Action Questionnaire This is a unidimension- 65 mg/ml of harmaline, and 2 mg/ml of al scale that assesses the construct referred to variously as tetrahydroharmine. No other psychoactive compounds experiential avoidance or, when it is positively formulated, were detected. acceptance (Bond et al. 2011). Experiential avoidance refers to avoidance of the experience of internal events, such as Statistical analysis attempts to suppress or control emotions (Hayes 1987). Participants indicate their response to each question using a Baseline sample characteristics, setting variables, and be- 7-point Likert-type scale (1 = never true to 7 = always true). reavement adjustment over time were analyzed descrip- The Acceptance and Action Questionnaire (AAQ-II) is score tively. Changes in primary and secondary outcome vari- by adding together all the items, with higher scores corre- ables between each time point and baseline were tested sponding to greater experiential avoidance. This questionnaire using Student’s paired two-sided t test or the Wilcoxon has been shown to have adequate psychometric properties paired test, as appropriate. Bonferroni corrections were with a Cronbach’s coefficient alpha value of 0.82. applied to correct for multiple comparisons. A 95% CI for the mean of the primary outcome at all time point EQ-Decenetering This scale assesses decentering, defined as assessments was included to further clarify plausible the ability to observe one’s thoughts and feelings in a detached values. Effect sizes were calculated using Cohen’s d. manner (Fresco et al. 2007). The original scale was called the Effect sizes were defined as large up to 0.8 (d > 0.8) Experiences Questionnaire (EQ), in which participants rate (Cohen 1988). To examine the relationship between expe- items on a 7-point Likert-type scale (1 = never to 7 = all the riential avoidance (AAQ-II), decentering (EQ-D), and the time), assessing decentering and rumination (Fresco et al. severity of grief (TRIG), we used Pearson’s linear corre- 2007). Based on the psychometric characteristics of the orig- lation coefficient. Correlation coefficients between 0.30 inal scale, which showed poor loadings for other items placed and 0.70 were considered moderate. on the rumination factor and a robust structure for the Additional subgroup analysis was performed separate- decentering factor, only the EQ-Decentering scale was used ly for patients who responded to T-1, T0, and T1 as- for the present study. This is an 11-item self-report measure of sessments. We used the chi-square test for categorical decentering. Items are rated on a 5-point Likert scale (1 = variables and Fisher-Snedecor for continuous variables never to 5 = always). The original EQ showed a high reliabil- to evaluate homogeneity between the group who com- ity coefficient with Cronbach’s alpha value of 0.90. pleted the follow-up at T1, and a subgroup that com- pleted an additional assessment at T-1. Subgroup analy- Bereavement adjustment questionnaire An additional ques- ses were conducted using repeated measures analysis of tionnaire was designed to explore bereavement adjustment variance (ANOVAs) with post hoc Bonferroni-correc- during follow-up assessments (Appendix 1). These questions tion, in order to examine differences in primary and covered the following: participants’ subjective perceptions secondary outcomes between the periods of T-1 to T0 about the evolution of their clinical status; the persistent and T1 to T0. long-term harms and benefits derived from ayahuasca intake In this study, p values < 0.05 were considered statisti- during their stay at the center; and participants’ use of ayahua- cally significant. Statistical analysis was performed using sca, medication and psychotherapy to treat grief symptoms Statistical Package for the Social Sciences (SPSS for after leaving the center (at T1, T2, T3, and T4). Windows, version 20). Psychopharmacology (2020) 237:1171–1182 1175 Results Table 1 Demographic and bereavement characteristics of participants Characteristics Total Sample (n = 50) Participants n % Out of 117 participants who were assessed for eligibility, Female 33 66 79.49% participants signed the informed consent form. Age in years* 41.2 (12.1) [24–71] However, 30.1% participants were excluded because baseline Marital status data were not available, 12.91% were excluded because no Single 26 52 follow-ups were available, and 3.23% expressed a desire to Married/partnered 12 24 abandon the study. Finally, 50 participants were elegible for the analysis, having completed the baseline assessment and, at Divorced/separated 11 22 least, one follow-up assessment. Overall, the rate of partici- Widowed 1 2 pants not responding to the assessment at T1 was 22%, at T2, University education 39 78 it was 38%, at T3, it was 42%, and 46% at T4 (Fig. 1). Employed 36 72 Active member of a religious organization 3 6 Caucasian 38 77.6 Baseline sample characteristics First-degree relationship to deceased 39 78 Unnatural death (suicide, homicide, accident) 19 38 Demographic and bereavement characteristics of participants Years since loss are summarized in Table 1. 0 to 3 years 11 22.9 The quality of the relationship with the deceased was pos- 4 to 7 years 19 39.6 itive for 68%, negative for 12%, and ambiguous for 20%. For 82% of participants, the death was considered a traumatic 8 to 15 years 9 18.8 event and 14% were unsure. Among the sample, 68% had lost More than 15 years 9 18.8 an average of 4.11 (SD = 2.15) significant people in the past Previous therapy for grief 27 54 (range 2–10). Previous medication for grief 14 28 The main motivations for attending the retreat were thera- Previous ayahuasca for grief 10 20 peutic (34.1%), spiritual growth (34.1%), and personal devel- *Data are expressed as mean (SD) [range] opment (31.7%). None of the participants affirmed a recrea- tional purpose, such as drug tourism. Among the sample, 76% improve their grief symptoms and 24% were not sure. Of the expected that the ayahuasca ceremonies at the center would overall sample, 70% had never used ayahuasca before. Of the remaining 30% of the sample (n = 15), 40% drank ayahuasca less than 3 times, 40% between 3 and 7 times, and 20% more than 7 times. Setting variables Participants attended an average of 18.1 (SD = 8.7) days at the center (range 9–30), where they participated in an average of 6.62 (SD = 1.37) ayahuasca ceremonies (range 4–9). Of the 39 participants who responded at T1, 53.8% perceived ayahuasca as the most relevant factor in the evolution of their grief symp- toms during their stay at the center, followed by the work of the Shipibo healers (35.9%), being with other guests (5.1%), the experience of being in the jungle (2.6%), and having attended other alternative activities, such as yoga classes (2.6%). Moreover, 78.4% described an ayahuasca experience that directly affected their grief process. Main outcome analyses The results for outcome variables at all assessment points (T0, Fig. 1 Participant flow throughout the study T1, T2, T3, and T4) are presented in Table 2. 1176 Psychopharmacology (2020) 237:1171–1182 TRIG score was significantly reduced from baseline to all point times follow-up assessment (T1, T2, T3, and T4: p < 0.001). This significant improvement in the severity of grief is shown graphically with confidence intervals (95% CI) (Fig. 2). Calculating effect sizes according to Cohen’s method, we found a high effect size at all assessments points (T1 = 0.84, 95% CI = 0.45–1.23; T2 = 1.38, 95% CI = 0.92– 1.80; T3 = 1.16, 95% CI = 0.72–1.64; and T4 = 1.39, 95% CI = 0.93–1.88). Similarly, SA-45 showed a significant improvement on the Global Severity Index (GSI) for all assessments (T1, T2, T3, and T4: p < 0.001), showing a high effect size at T1 = 1.11, 95% CI = 0.77–1.45; T2 = 1.06, 95% CI = 0.73–1.39; T3 = 0.90, 95% CI = 0.59–1.22; and T4 = 1.1, 95% CI = 0.68– 1.52. Almost all of the psychopathological subscales of SA- 45 showed a significant decrease after the retreat (T1: p ≤ 0.003), which were maintained over the follow-up assess- ments (T2: p ≤ 0.018; T3: p ≤ 0.017; and T4: p ≤ 0.005) with the exception of hostility at T3 (p = 0.451) and T4 (p = 0.087). Fig. 2 Graph of the mean values (dots) and confident intervals (CI, 95%) of the severity of grief at baseline (T0) and follow-up (T1, T2, T3, and T4) The only subscale that did not show a significant decrease after the retreat was phobic anxiety (T1: p = 0.062), although Table 2 Outcome of repeated measures at baseline (T0) and each time point during follow-up. Values are given as means (with standard deviations) Measures T0 T1 T2 T3 T4 Mean Mean Mean Mean Mean (SD) (SD)/Sig.a† (SD)/Sig.b† (SD)/Sig.c† (SD)/Sig.d† N = 50 N = 39 N = 31 N = 29 N = 27 TRIG 40.5 (9.6) 31.1 (9.3)*** 29.7 (9.8)*** 31.8 (8.9)*** 29.7 (9.1)*** SA-45 Hostility 59.0 (5.6) 55.2 (4.1)*** 55.9 (4.3)* 57.4 (5.5) 56.8 (4.6) Somatization 62.3 (9.3) 57.5 (6.6)*** 56.0 (8.3)*** 56.9 (7.9)** 57.9 (9.0)*** Depression 62.0 (6.9) 55.3 (8.5)*** 56.0 (6.8)** 57.0 (6.3)* 57.0 (9.0)** Obsess. compulsive 63.9 (8.5) 56.9 (7.4)*** 56.4 (8.0)*** 57.1 (7.8)*** 58.1 (9.2)** Anxiety 63.9 (8.5) 54.1 (6.8)*** 55.7(7.2)*** 56.4 (8.1)** 55.7 (9.7)*** Interp. sensitivity 62.7 (6.7) 55.5 (6.5)*** 56.3 (6.4)*** 55.8 (7.0)*** 55.6 (6.4)*** Phobic anxiety 65.3 (6.4) 63.1 (5.6) 61.6 (4.7)** 61.8 (4.3)* 60.9 (4.9)*** Paranoid ideation 59.0 (7.7) 53.0 (6.7)*** 53.2 (6.8)*** 54.8 (7.5)* 54.1 (7.9)** Psychoticism 63.4 (5.3) 60.5 (3.6)** 59.9 (3.4)*** 60.0 (3.2)** 60.2 (3.5)*** GSI 63.2 (7.7) 54.2 (7.9)*** 53.7 (8.9)*** 54.8 (8.8)*** 55.1 (9.0)*** WHOQoL Physical health 14.7 (2.9) 16.5 (2.8)*** 17.0 (2.2)*** 16.6 (2.2)*** 16.2 (2.6)** Psychological health 12.6 (2.9) 15.6 (2.4)*** 15.5 (2.2)*** 15.6 (1.5)*** 14.7 (2.5)** Social relationships 12.3 (3.2) 15.0 (3.9)*** 14.8 (3.1)** 15.4 (3.1)** 14.1 (3.6)** AAQ-II 27.0 (7.0) 18.8 (5.7)*** 18.7 (5.7)*** 19.4 (5.6)*** 19.4 (6.7)*** EQ-Delefting 35.3 (7.3) 42.5 (6.2)*** 43.3 (5.7)*** 42.6 (4.9)*** 43.3 (6.6)*** † Bonferroni correction is performed a p value calculated by paired sample t test from T0 to T1 (N = 39) b p value calculated by paired sample t test from T0 to T2 (N = 31) c p value calculated by paired sample t test from T0 to T3 (N = 29) d p value calculated by paired sample t test from T0 to T4 (N = 27) Asterisks indicate p values: *p < .05; **p < .01; ***p < .001 in the paired sample t tests Psychopharmacology (2020) 237:1171–1182 1177 a significant reduction in this symptom was observed over Bereavement adjustment over time subsequent assessments (T2: p = 0.002; T3: p = 0.016; and T4: p < 0.001). The ayahuasca experiences at the center had a positive effect on Finally, the Symptom Assessment-45 Questionnaire grief symptoms for 92.3% of the sample, for 5.1%, it had no (WHOQoL-BREF) questionnaire also showed significant influence and 2.6% experienced a negative effect on their grief improvements in physical health, psychological health, process. The bereavement adjustment of the participants at all and social relationship scales after the retreat (T1: follow-up assessments, the uses of therapeutic resources to treat p < 0.001). The improvements in physical health were grief, and the persistent benefits and adverse effects derived from maintained at T2, T3, and T4 (p < 0.001); in psychologi- the ayahuasca experiences at the center are shown in Table 3. cal health at T2, T3, and T4 (p < 0.001); and in social relationships at T2 (p = 0.003), T3 (p = .001), and T4 Correlation analysis between grief and mechanism (p = 0.004). The effect size was larger for the psycholog- of change ical health subscale (T1 = 0.92, 95% CI = 0.056–1.26; T2 = 0.89, 95% CI = 0.54–1.27; T3 = 0.82, 95% CI = The significant decrease in experiential avoidance (AAQ-II) 0.53–1.11; and T4 = 0.73, 95% CI = 0.33–1.08). between T0 and T1 was found to be associated with the sig- Both mechanisms of change, experiential avoidance nificant decrease in the severity of grief (TRIG) between T0 (AAQ-II) and decentering (EQ-Decentering), significantly and T1 (r = 0.55; p < 0.01). In addition, the correlation be- improved after the retreat (T1: p < 0.001), maintaining tween the significant improvement in decentering ability these gains at all follow-up assessments (T2, T3, and (EQ-Decentering) between T0 and T1 and the decrease in T4: p < 0.001). AAQ-II showed a high effect size for all grief symptomatology (TRIG) between T0 and T1 (r = assessments, as T1 = 0.90, 95% CI = 0.62–1.18; T2 = 1.09, −0.47) was also significant (p < 0.01) (Fig. 3). 95% CI = 0.72–1.48; T3 = 1.14, 95% CI = 0.80–1.51; and T4 = 1.07, 95% CI = 0.57–1.53. EQ-Decentering also Subgroup analysis showed a high effect size for all assessments, as T1 = 0.96, 95% CI = 0.64–1.28; T2 = 0.99, 95% CI = 0.55– Of the 39 participants who completed the follow-up as- 1.43; T3 = 0.93, 95% CI = 0.46–1.36; and T4 = 1.26, sessment at T1, a subgroup of 9 participants who com- 95% CI = 0.86–1.66. pleted an additional assessment 2 months prior to the Table 3 Bereavement adjustment, adverse effects, and benefits of ayahuasca at each time point during follow-up T1 T2 T3 T4 N = 39 N = 31 N = 29 N = 27 n% n% n% n% Perception in relation to grief I feel worse 1 2.6 0 0.0 0 0.0 1 3.7 I feel the same 2 5.1 2 6.5 1 3.4 0 0.0 I feel better 36 92.3 29 93.5 28 96.6 26 96.3 Persistent adverse effects of ayahuascaa Physical health 0 0.0 0 0.0 0 0.0 0 0.0 Mental health 0 0.0 0 0.0 0 0.0 1 3.7 Social relationships 1 2.6 1 3.2 0 0.0 1 3.7 Spirituality 0 0.0 0 0.0 0 0.0 1 3.7 Persistent benefits of ayahuascaa Physical health 30 76.9 19 61.3 18 62.1 17 63.0 Mental health 34 87.2 26 83.9 24 82.1 24 88.9 Social relationships 26 66.7 17 54.8 19 65.5 18 66.7 Spirituality 33 84.6 26 83.9 26 89.7 24 88.9 Therapy to treat grief 4 12.9 8 27.6 9 33.3 Medication to treat grief 0 0.0 0 0.0 1 3.7 Ayahuasca to treat grief 3 9.7 4 13.8 4 14.8 a Multiple choice responses 1178 Psychopharmacology (2020) 237:1171–1182 Fig. 3 Scatter plot of the relationship between the severity of grief (TRIG) and experiential avoidance (AAQ-II) (a) and decentering (EQ-Decentering) (b) retreat (T-1) were elegible for the subgroup analysis Discussion (ANOVA). The homogeneity of the groups was tested by comparing key variables (baseline characteristics, pri- This is the first study to prospectively assess the long-term mary and secondary outcome measures). No significant effects of ayahuasca in participants grieving the death of a differences were found in baseline sample characteristics loved one. In this observational study, the primary result nor outcome variables (p > 0.05). The average number of showed that the severity of grief significantly decreased after days registered in the subsample between T-1 and T0 drinking ayahuasca, being maintained over 1 year of follow- was 45.0 (SD = 3.87), and between T0 and T1, it was up. The subgroup analysis performed in a representative sub- 47.67 (SD = 8.38). ANOVA revealed a significant main sample allowed us to infer that the significant differences in effect of time on the TRIG [F (2; 16) = 11.18, p = 0.001]. outcomes are due to the effect of their stay at the center and not Post hoc tests showed a significant improvement only the passing of time. The large effect size obtained at all point between T1 and T0 [− 13.26 (SD = 11.17); p = 0.022] assessments on the primary scale clearly exceeds the mean and not between T0 and T-1 [− 1.07 (SD = 5.24); effect size post-intervention (Hedges’s g = 0.41) and at p > 0.999], indicating that the reduction in the severity follow-up (g = 0.45) obtained in the last meta-analysis focused of grief was only observed during participants’ stays at on the effectiveness of current treatments developed to treat the center. complicated grief and prolonged grief disorder (PGD) Similarly, ANOVA revealed a significant main effect (Johannsen et al. 2019). Studies that have obtained higher of time on secondary variables during participants’ stays effects sizes have applied specific protocols of intervention, at the center. This is the case with the GSI of the SA-45 which involved conducting from 12 to 25 psychotherapeutic questionnaire [F (1,4: 10,9) = 10.30; p = 0.006], only be- sessions during periods of 3 to 9 months, or even longer tween T1 and T0 [− 8.78 (SD = 7.74); p = 0.028] and not (Bryant et al., 2014; Rosner et al. 2014; Boelen et al. 2007). between T0 and T-1 [0.33 (SD = 3.08); p > 0.999], and We dutifully note that the Temple of the Way of Light is not with psychological health of the WHOQol-BREF (F conducting a specific program to treat grief symptoms, and (1,2; 9,8) =12.28; p = 0.004), only between T1 and T0 that the maximum duration of the retreat was 1 month, during [2.52 (1.97); p = 0.015] and not between T0 and T-1 which ayahuasca was taken a maximum of 9 times. [0.03 (2.33); p > 0.999]. It is well known that grief symptoms usually present a high Finally, AAQ-II also showed a significant main effect of rate of comorbidity with mood and anxiety disorders, time [F (2,14) = 7.45; p = 0.006], only between T1 and T0 [− influencing the quality of life of bereaved adults (Boelen and 9.88 (SD = 8.59); p = 0.042] and not between T0 and T-1 [3.25 Prigerson 2007). In our sample, almost all the scales in SA-45 (SD = 4.74); p = 0.281], as well as EQ-Decentering [F were above the score of 60 at baseline (percentile of 84) (1,4:10,8) = 7.30; p = 0.015], only between T1 and T0 [7.30 (Davison et al. 1997) suggesting likely problems with soma- (SD = 6.29); p = 0.025] and not between T0 and T-1 [− 1.47 tization, depression, obsessive-compulsiveness, anxiety, inter- (SD = 3.25); p = 0.638]. personal sensitivity, phobic anxiety, and psychoticism. With Psychopharmacology (2020) 237:1171–1182 1179 the exception of phobic anxiety, all of these symptoms de- Although the content analysis of participants’ ayahuasca ex- creased significantly at all time points over follow-up to a periences is pending publication, a previous study described level that is considered within the normal range in a non- emotional confrontations with the reality of the death, the patient normative sample (Davison et al. 1997). These results reviewing of biographical memories, and a reencounter with are in line with previous studies that found lower levels of the deceased, as common ayahuasca experiences among psychopathology after drinking ayahuasca in first-time aya- grievers (González et al. 2017). The pharmacological effects huasca ceremony participants (Barbosa et al. 2009), as well of ayahuasca have been described extensively (Dos Santos as in long-term users as compared with control groups (Bouso et al. 2012, 2013; Riba et al. 2001, 2011), including a dose- et al. 2012; Dos Santos et al. 2016). Given that phobic anxiety dependent curve with a slow onset during the first 45 min, a is expressed through symptoms of uneasiness when in open peak in the experience at around 90 min, and slow decrease in spaces and crowds, the fact that we did not find significant the effects from 150 to 250 min. Under the effects of a medi- differences in this scale after the retreat, but found differences um or high dose, the peak of the experience could be similar to throughout later follow-up assessments (T2, T3, and T4), the immersion used in virtual reality exposure therapy could indicate a need for a period of time to adapt to the city (VRET), which allows individuals to bypass symptoms of environment after being in the jungle. However, phobic anx- experiential avoidance (Gonçalves et al. 2012). Other studies iety and psychoticism are on the threshold of being considered have compared acute ayahuasca effects with a controlled ex- problematic areas, according to the follow-up assessments. As posure to autobiographical material (Domínguez-Clavé et al. far as we know, this is the first article to look deeply into these 2016). This acute confrontation with difficult memories, psychopathological symptoms among a sample of grievers, so thoughts, and feelings could promote increased acceptance, we cannot compare many of these subscales with other stud- leading to psychological modifications that are observable ies. Only one previous study has assessed a few of these psy- beyond the time frame of the acute inebriation (Soler et al. chopathological symptoms after participants received 2018). Although this is the only study that has assessed the prolonged grief-specific cognitive-behavioral therapy modulation of acceptance (or experiential avoidance) after an (Rosner et al. 2014), an integrative cognitive-behavioral ap- ayahuasca experience over the course of 1 year, our results are proach that includes structured exposures and cognitive in line with other studies that have found an increase in accep- restructuring. In this study, there were no differences in terms tance to result from an ayahuasca experience (Domínguez- of phobic anxiety, somatization, and anxiety when participants Clavé et al. 2016; Soler et al. 2018). Nevertheless, around were compared with a waiting list group. 150 min after ayahuasca intake, the intensity of the effects The significant long-term improvements on all the scales of begins to decrease, allowing a healthy distance from the psy- quality of life in our sample offer a broader picture of the chological material and leading to a reflective phase impact of ayahuasca on the evolution of grief. Previous stud- (Kjellgren et al. 2009). During this phase, decentering could ies have found similar results in first-time ayahuasca ceremo- improve (Fresco et al. 2007). Gains in the ability to decenter ny participants (Barbosa et al. 2009), as well as improvement are in line with other studies that have found an increase in in psychosocial well-being in regular participants (Bouso et al. decentering abilities following ayahuasca intake (Domínguez- 2012; Dos Santos et al. 2016). However, last meta-analysis on Clavé et al. 2016; Soler et al. 2016; Sampedro et al. 2017), and psychological interventions for grief did not find statistically in those with more than 15 ayahuasca experiences compared significant effects on health-related quality of life (Johannsen with those with non or few experiences (Franquesa et al. et al. 2019). 2018). However, contrary to a previous study (Sampedro Although subjective responses about the persistent harms et al. 2017), the gains in decentering in our sample persisted and benefits of ayahuasca experiences at the retreat support over a year of follow-up. the overall outcomes, we must bear in mind that a large pro- These results are also in line with previous studies that portion of the participants expected that ayahuasca ceremonies show a positive relationship between high levels of acceptance would improve their grief symptoms, which could promote and high levels of decentering (Hayes et al. 2017). In our suggestibility and enhance positive outcomes. The fact that sample, we observe that increased acceptance and decentering most of them affirmed that ayahuasca had a positive effect in following the retreat have a significant correlation with im- terms of mental health and spirituality led us to ponder the role provements in the severity of grief. Acceptance is considered a that spiritual coping played in the adjustment of bereavement key mechanism of change in complicated grief treatment in our sample. Previous studies have shown that spirituality (Glickman et al. 2017), a form of cognitive-behavior therapy can play a centrally important role in helping individuals adapt with elements of interpersonal psychotherapy and motivation- to the loss of a loved one (Wortmann and Park 2008; Hays and al interviewing (Shear et al. 2016). On the other hand, Hendrix 2008). decentering is a mediator in the metacognitive approach to In our sample, 78.4% of participants described an ayahua- treating grief (Wenn et al. 2015), a form of psychotherapy that sca experience that directly affected their grief process. uses detached mindfulness to alter dysfunctional thinking 1180 Psychopharmacology (2020) 237:1171–1182 styles by helping individuals to understand their “thoughts conclusions, large controlled cohort studies or randomized, about thoughts.” Accommodation (new learning) is a psycho- placebo-controlled trials conducted with adequate samples of logical process that has been associated with an ability to participants will provide evidence of causality. engage with traumatic experiences when it is combined with more acceptance and decentering (Hayes et al. 2017). Accommodation provides an opportunity for constructive pro- Conclusions cessing and meaning making regarding the experience (Neimeyer 2019). Moreover, other kinds of experiences, such This study offers preliminary findings in support of the long- as having a reencounter with the deceased (González et al. term therapeutic potential of ayahuasca for bereavement. A 2017), could modulate the internal working model of the de- significant improvement in the severity of grief and the high ceased and the attachment style maintained with him or her effect size maintained over a year follow-up are sufficiently after death. Future studies should explore more potential encouraging to warrant further research. Furthermore, the as- mechanisms of change in order to reach a better understanding sessment of experiential avoidance and decentering highlights of the therapeutic potential of ayahuasca among the bereaved. the improvement of these mechanisms of change following The study has some limitations. First, the naturalistic de- drinking ayahuasca and their relation to grief improvement. sign of the study does not allow us to isolate the effects of Therefore, more research is necessary to better understand ayahuasca from the other diverse variables in the setting, ayahuasca’s therapeutic value in terms of relief from grief which include the healing work of the Shipibo shamans during symptoms. the ayahuasca ceremony. In fact, the separation of the effects of ayahuasca from the healer’s work is not conceived of within Acknowledgements The authors wish to thank Matthew Watherston for the Shipibo traditional medicinal framework, in which partic- allow us to conduct the study at the Temple of the Way of Light and Aubrey Marcus for his generous philanthropic contribution. Special ipants drank the ayahuasca. Moreover, without a placebo thanks to all of the volunteers for their participation and contributions to group it is not possible to know if ayahuasca was truly respon- our understanding in this field. sible for the improvement in grief symptoms, as it is not pos- sible to draw conclusions about causality. Second, the lack of Funding information This work was financially supported by the scientific evidence on the stability of ayahuasca alkaloids over ICEERS and the Beckley Foundation. time does not guarantee similar concentrations when partici- pants took ayahuasca in the center and at the time, the samples Compliance with ethical standards were analyzed. Moreover, the lack of knowledge about the The study was approved by the Ethics Committee on Animal and Human doses used throughout the ceremonies by each participant pre- Experimentation of the Autonomous University of Barcelona (UAB- vents us from assessing to relate the improvement in the se- CEEAH Barcelona, Spain) and was conducted in accordance with the verity of grief in relation with the doses of DMT or Declaration of Helsinki. Participants signed an online informed consent and were not financially compensated for their participation. betacarbolinnes ingested. Third, the sample size is relatively small and there were a large number of participants that did Conflict of interest The authors declare that they have no conflict of not complete all the follow-up assessments. This limitation interest. can be extended to the subgroup analysis, which was conduct- ed to control for the effect of time passing. Fourth, nine par- Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, ticipants attended psychotherapy over the year follow-up, four adaptation, distribution and reproduction in any medium or format, as took ayahuasca again to treat grief symptoms, and one partic- long as you give appropriate credit to the original author(s) and the ipant took medication, so we cannot attribute the maintenance source, provide a link to the Creative Commons licence, and indicate if of the improvement in grief symptoms exclusively to the per- changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated sistent benefits of the ayahuasca experiences at the retreat. otherwise in a credit line to the material. If material is not included in the Fifth, we did not assess Prolonged Grief Disorder or article's Creative Commons licence and your intended use is not Persistent Complex Bereavement Disorder, having used self- permitted by statutory regulation or exceeds the permitted use, you will report measures rather than clinical interviews. This, along need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. with the fact that the sample was heterogeneous, in terms of the causes of loss and the amount of time that had passed since the loss, makes the extent to which subgroups profited differ- ently from ayahuasca uncertain. 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