This systematic review (2016; 28 articles) concludes that ayahuasca seems to have low toxicity, but that the myriad reported therapeutic benefits stand in need of replication.
Abstract
“Rationale: In recent decades, the use of ayahuasca (AYA) – a β-carboline- and dimethyltryptamine-rich hallucinogenic botanical preparation traditionally used by Northwestern Amazonian tribes for ritual and therapeutic purposes – has spread from South America to Europe and the USA, raising concerns about its possible toxicity and hopes of its therapeutic potential. Thus, it is important to analyze the acute, subacute, and long-term effects of AYA to assess its safety and toxicity. Objectives: The purpose of this study was to conduct a systematic review of human studies assessing AYA effects on psychiatric symptoms, neuropsychological functioning, and neuroimaging. Methods: Papers published until 16 December 2015 were included from PubMed, LILACS and SciELO databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Results: The review included 28 full-text articles. Acute AYA administration was well tolerated, increased introspection and positive mood, altered visual perceptions, activated frontal and paralimbic regions and decreased default mode network activity. It also improved planning and inhibitory control and impaired working memory, and showed antidepressive and antiaddictive potentials. Long-term AYA use was associated with increased cortical thickness of the anterior cingulate cortex and cortical thinning of the posterior cingulate cortex, which was inversely correlated to age of onset, intensity of prior AYA use, and spirituality. Subacute and long-term AYA use was not associated with increased psychopathology or cognitive deficits, being associated with enhanced mood and cognition, increased spirituality, and reduced impulsivity. Conclusions: Acute, subacute, and long-term AYA use seems to have low toxicity. Preliminary studies about potential therapeutic effects of AYA need replication due to their methodological limitations.”
Authors: Rafael G. dos Santos, Fermanda M. Balthazar, José C. Bouso & Jaime E. C. Hallak
Summary
Introduction
Ayahuasca is a botanical hallucinogen used in ritual contexts by Amazonian indigenous groups in Brazil, Peru, Colombia and Ecuador. It is estimated that nearly 20,000 people worldwide are members of some of the Brazilian AYA religions.
AYA is obtained by boiling the pounded stalks of the vine Banisteriopsis caapi and the leaves of the bush Psychotria viridis. The -carbolines in B. caapi and DMT in P. viridis inhibit MAO-A, allowing DMT to reach the central nervous system.
In recent decades, the use of ayahuasca has spread from South America to Europe and the USA, raising concerns about its possible toxicity.
AYA produces significant psychoactive effects, with the peak occurring around 1.5 – 2 h after administration. Nausea and vomiting are the main side-effects observed in ritual and experimental settings.
Some studies suggest that AYA consumption is safe and does not cause psychopathology or neuropsychological deficits, but these studies were performed among long-time members of AYA religions.
Although previous reviews suggest that acute AYA administration in the experimental setting and long-term ritual consumption of the brew are relatively safe, this review extends previous reviews by assessing the acute, subacute, and long-term effects of AYA on psychiatric symptoms, neuropsychological functioning and neuroimaging.
Search strategy
Ayahuasca and subjective effects, psychological effects, psychiatry, psychiatric symptoms, psychopathology, cognition, neuropsychology, neuropsychological tests, neuroimaging, single-photon emission computed tomography, SPECT, functional magnetic resonance imaging, and reference lists were searched.
Eligibility criteria
This review included experimental studies in healthy volunteers, observational studies of experienced AYA consumers, and clinical trials published in peer-reviewed journals.
A review was conducted of experimental studies, observational studies, and clinical trials involving AYA administration to healthy volunteers, AYA consumers, and patients with a diagnosis based on a structured diagnostic interview.
Data extraction
All studies were screened by two independent reviewers with discrepancies resolved by a third reviewer. The sample was divided into studies assessing psychiatric symptoms, neuropsychological functioning, and neuroimaging parameters.
Study selection
Although there are few studies, the results show that acute administration of AYA to healthy volunteers or patients with depression or substance dependence in a controlled environment is safe, and does not appear to cause psychopathologies or neuropsychological deficits.
Psychiatric symptoms/status: personality, psychopathology and other psychological measures
Grob and co-workers (1996) measured the subjective effects of a 2 mL/kg oral AYA dose (0.24 mg DMT/mL) in 15 long-term members of the UDV. The results were mild and comparable to a 0.1 – 0.2 mg/kg intravenous DMT dose.
Six healthy volunteers were given three increasing doses of encapsulated freeze-dried AYA, which produced significant dose-dependent increases in five of the six HRS subscales and in the morphine-benzedrine, lysergic acid diethylamide, and amphetamine scales of the Addiction Research Center Inventory.
Nine members of the Santo Daime experienced significant reduction in hopelessness and panic symptoms after ingesting AYA. However, all subjects experienced transient increases in psychotic and mania symptoms following AYA ingestion.
Alonso et al. (2015) found that a single dose of encapsulated freeze-dried AYA (0.75 mg DMT/kg) increased visionary restructuralization in 10 healthy volunteers and that the intensity of minor psychiatric symptoms decreased one to two weeks after the ayahuasca experience.
A study assessed visual creativity in 40 individuals participating in AYA rituals in Brazil using the visual components of the Torrance Tests of Creative Thinking. AYA administration was associated with significant increases in the number of highly original solutions.
Soler et al. (2015) measured mindfulness-related capacities in a group of 25 individuals with prior experience with AYA, before and 24 h after an AYA intake. The results suggest a non-judgmental approach towards the present experience, thoughts, and emotions.
A recent study performed by our group showed that a single 2.2 mL/kg oral AYA dose (0.8 mg DMT/mL) could reduce depressive scores by up to 82%. The study also showed that AYA could increase psychoactivity and be associated with significant score decreases in several depression scales.
Grob and collaborators (1996) evaluated 15 long-term users of ayahuasca and 15 matched controls with no prior history of AYA ingestion regarding long-term psychological and psychiatric heath. They found that UDV members had less impulsivity, shyness, and were more reflective, confident, gregarious, and optimistic compared to the control group.
Da Silveira et al. (2005) evaluated the mental health of 40 adolescents who had consumed AYA within the UDV context at least 24 times during the last two years prior to the assessment. The results showed that the AYA group showed considerable lower frequencies of anxiety symptoms.
32 North American members of the Santo Daime reported remission from a variety of psychiatric disorders, including depression, anxiety, and attentional problems. Five members had a history of alcohol dependence, and one member had a history of bipolar I disorder. Participants presented lower rates of symptomatology, overall complaints, and intensity and severity of complaints compared with the normative scores for the general population.
Barbosa and collaborators (2009) found that continuous AYA intake was significantly associated with lower scores in the Harm Avoidance and Reward Dependence temperament dimensions, a decrease in physical pain, and a decrease in minor psychiatric symptoms.
Fábregas et al. (2010) assessed the addiction potential of experienced members of AYA religions using the Addiction Severity Index (ASI). They found that jungle-based and urban-based AYA users scored significantly lower than rural and urban controls on the ASI.
Bouso et al. (2012) assessed the impact of repeated AYA use on general psychological well-being and mental health in a sample of regular AYA users and controls. AYA users showed higher scores in the Reward Dependence and Self-transcendence temperament dimensions.
Thomas et al. (2013) conducted a preliminary observational study of 12 participants with a problematic substance use pattern who attended a retreat involving alternative treatments such as sweat lodges and AYA ceremonies.
Bouso et al. (2015) assessed personality and psychopathology in 22 Spanish members of the Santo Daime and 22 controls. They found that AYA users scored lower on Harm Avoidance and higher on Self-Transcendence.
Neuropsychological functioning
AYA ingestion was significantly associated with lower scores in the Sternberg working memory test and a significant reduction in response latency time during the Stroop color and word test. However, only occasional AYA users showed significantly increased execution and resolution times and number of movements in the Tower of London test.
In a study conducted by Grob and coworkers (1996), experienced members of the UDV performed significantly better on the 5th learning trial than controls on the World Health Organization/University of California at Los Angeles (WHO/UCLA) Auditory Verbal Learning Test.
Doering-Silveira et al. (2005a) evaluated the neuropsychological functioning of 40 adolescents with UDV and control group using the Trailmaking test, Stroop-Victoria version, Rey – Osterrieth complex figure Test, Conner’s Continuous Performance Test-II, WHO/UCLA Auditory Verbal Learning Test, and WAIS-III.
In a study with regular Brazilian AYA users, Bouso et al. (2012) found no evidence of neuropsychological impairment, and AYA users scored significantly better than controls groups on almost all measures.
In the study evaluating the Spanish sample of experienced AYA users, Bouso et al. (2015) found that AYA users scored significantly better than controls in several variables, including working memory and set-shifting.
Neuroimaging
Ayahuasca administration was associated with activation of the anterior insula/ inferior frontal gyrus, and increased blood perfusion in the frontomedial wall of the right hemisphere, especially in the anterior cingulate/ medial frontal gyrus, areas associated with somatic awareness, subjective feeling states, and emotional arousal.
A study using functional magnetic resonance imaging (fMRI) explored the neural basis of the visual imagery produced by AYA. The study found that AYA administration was associated with increased activation in the precuneus, cuneus, lingual, fusiform, middle occipital, parahippocampal, posterior cingulate, superior temporal, superior middle, and inferior frontal gyri.
AYA may boost imagery to the same level of natural image, even with the eyes shut, and alter fronto-occipital relationships, which may be associated with psychotic symptoms.
In a subsequent study, Palhano-Fontes et al. (2015) used fMRI to assess the acute effects of AYA on the activity of the default mode network (DMN). They found that AYA administration was associated with decreased activation of key hubs of the DMN and decreased functional connectivity within the DMN.
In a study of 17 patients with recurrent depression, AYA administration increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area.
Long-term effects
Bouso et al. (2015) found that regular AYA use was significantly associated with cortical thinning in the mesotemporal and inferior frontal gyri, precuneus, superior frontal gyrus, posterior cingulate cortex, and superior occipital gyrus, and increased thickening in the precentral gyrus and anterior cingulate cortex.
Discussion
Studies show that acute administration of AYA to healthy volunteers in controlled settings produces significant subjective effects, similar to those described for other classic hallucinogens that act as 5-HT2A-receptor agonists, such as mescaline, psilocybin, LSD, and DMT.
AYA was administered to volunteers with depression and to patients with drug-related disorders. It was associated with acute and subacute symptom improvement in all three studies, including fast-acting and enduring antidepressive effects and significant reductions in cocaine use.
These preliminary data corroborate the results from non-controlled human studies reporting that regular AYA use is associated with remission of mood and anxiety disorders, as well as drug abuse/dependence. Moreover, AYA inhibits and prevents the onset and recurrence of alcohol-related behaviors in mice.
AYA may reduce the effects of addictive drugs by inhibiting dopamine levels in the mesolimbic pathway, by reducing synaptic plasticity associated with dependence, by improving decision-making, and by facilitating transcendent experiences.
AYA and its alkaloids may have antiaddictive and antidepressive potentials, but controlled trials have not been carried out to separate or distinguish these factors from each other and test them.
AYA and psilocybin increase activity in brain regions implicated in emotional processing, interoception, memory, and the sense of “self”, and reduce activity in key areas of the default mode network (DMN), such as the posterior cingulate cortex.
Acute administration of AYA can induce several effects on cognitive processes, including impairments in working memory, sustained attention, planning, motion perception, visual-spatial attention, context-dependent and sensory information processing, time perception and temporal control, and inhibitory control.
Long-term AYA use was associated with structural alterations in the medial parts of the brain, but no evidence of increased psychopathology or worse neuropsychological functioning among AYA users.
Previous studies suggest that the anterior and posterior cingulate cortices are involved in the acute effects of AYA and other hallucinogens, and that these alterations could be induced by activation of frontocortical glutamate networks secondary to 5-HT2A receptor agonism.
Animal studies have shown that B. caapi alkaloids induce antidepressive-like behaviors in experimental models of depression and increase BDNF levels in the rat hippocampus. Moreover, AYA administration to female Wistar rats was associated with antidepressive-like behaviors and increased neuronal activation in serotoninergic brain areas.
Taken together, these studies suggest that enhanced neuroplasticity and neurogenesis may be involved in the antidepressive, anxiolytic and antiaddictive effects of AYA and other hallucinogens.
Adverse events associated with AYA use
AYA and other hallucinogens have been used as experimental models of psychosis, and the ingestion of AYA may lead to a prolonged psychotic reaction or disorder.
According to the reviewed studies, acute AYA administration in controlled settings is not associated with prolonged psychotic reactions. AYA produced few short-lived side-effects such as transient anxiety, nausea, and vomiting, and no side-effects lasting beyond the acute effects of AYA were reported.
Despite the fact that nearly 20,000 people worldwide are members of some of the Brazilian AYA religions, we are aware of only a few case reports describing adverse psychiatric reactions to AYA.
A young adult male experienced two psychotic paranoid episodes during and after participation in AYA rituals. The psychotic symptoms persisted for a few weeks and only resolved after treatment with risperidone, but it is difficult to establish a direct causal relationship between AYA and the emergence of psychotic symptoms.
A study conducted in the context of the UDV reported 29 cases of psychotic features that were possibly associated with AYA use. However, in only 19 of them AYA seemed to be the main onset factor, and in these cases pre-morbid personality factors could also be associated with the occurrence of psychotic behavior.
Taken together, these results suggest that adverse psychiatric reactions among AYA users are rare, and that a causal relation with AYA is sometimes difficult to establish. Moreover, admixture plants with chemical compounds that may induce psychotic-like reactions should be looked for in cases of reported psychotic outcomes.
The reviewed studies suggest that long-term AYA use by adults and adolescents is not associated with psychiatric disorders or neuropsychological deficits, and may even be associated with improved quality of life and well-being.
These results are in line with a previous study that found that long-term peyote ingestion was not significantly associated with deficits on the Rand Mental Health Inventory and 10 neuropsychological tests of memory and attentional/executive functions.
There is an absence of research in humans to evaluate the effects of AYA in pregnant women and in children, although children of all ages participate in the AYA rituals. It would be important to carry out research with the child population of AYA users for risk assessment.
More research is needed regarding the possible pharmacological interactions between AYA alkaloids and MAO inhibitors, monoaminergic and serotoninergic substances, and antidepressants.
Conclusion
Studies have shown that AYA users have impaired working memory and better performance in other executive functions, such as planning and inhibitory control, compared to occasional users and non-users. However, more studies are needed to determine the long-term effects of AYA and the mechanisms of action responsible for these effects.