Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies

This review (2016) investigated the claim that harmine can have neuroprotective and cognitive-enhancing effects by reviewing animal and cell-based studies. The results point towards an effect and the authors recommend (more) conducting preclinical and human studies.

Abstract

“Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.“

Authors: Rafael G. dos Santos & Jaime E. C. Hallak

Summary

experience

Serotoninergic psychedelics include mescaline, DMT, psilocybin, and LSD, and share a common mechanism of action that consists in agonism at different serotonin receptors.

Drugs that affect the 5-HT2A receptor produce profound modifications in affect, perception, and cognition. These effects can range from blissful mystical-type experiences with positive mood to unpleasant experiences of fear, panic, dysphoria, and psychotic-like effects. Natural serotoninergic hallucinogens, such as mescaline, DMT and psilocybin, are used by indigenous groups in the Americas to induce states of consciousness resembling mystical experiences. Scientists discovered psilocybin and LSD in the late 1800s and early 1900s, and performed experimental studies on healthy volunteers and patients with neurosis, OCD, substance dependence, and existential anxiety and depression. Human hallucinogen research resumed in the early 1990s with studies in healthy volunteers using mescaline and DMT. Since then, the number of studies involving the administration of serotoninergic psychedelics has increased, including studies on the antidepressive and anxiolytic effects of these drugs and on their beneficial effects for treating substance-related disorders. This work summarizes disparate reviews on the therapeutic uses of serotoninergic hallucinogens, with an emphasis on the studies performed by USP and UFRN. LSD and psilocybin have been used to treat anxiety and depression related to cancer and other life-threatening diseases. Between 1960 and 2000, 11 clinical trials were performed assessing the effects of serotoninergic hallucinogens in patients with symptoms of depression and anxiety associated with life threatening diseases. The results showed that both psychedelics were well tolerated and reduced anxiety and depression and increased quality of life. A recent open-label feasibility trial with 12 volunteers with treatment-resistant major depression disorder (MDD) reported that two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) administered with psychological support produced rapid and sustained decreases in depression and anxiety symptoms. In October 2018, the FDA designated psilocybin as a breakthrough therapy for treatment-resistant MDD. Large-scale, multicenter, controlled trials are planned to take place in the next year. In the 1960s, serotoninergic hallucinogens were administered to patients with opioid and alcohol dependence. These studies showed significant decreases in alcohol misuse and increases in alcohol abstinence from one to 12 months after drug intake.

Psilocybin administration resulted in significant reductions in alcohol and nicotine use, and these effects remained significant after six months. The early investigations with serotoninergic hallucinogens in the 1960s involved cancer-related pain and other difficult-to-treat pain syndromes. Psilocybin was used in a clinical trial to treat symptoms of OCD, but further trials should be performed with different doses of psilocybin and other serotoninergic hallucinogens. Some observational and clinical studies suggest that serotonergic psychedelics may improve personality. Future controlled trials should try to replicate these results and further investigate the role of personality changes on the therapeutic effects of serotonergic hallucinogens. Since the 1960s and 1970s, LSD, psilocybin and mescaline have been used recreationally, but the ritual and religious uses of these drugs continue, but in specific areas of Mexico.

Ayahuasca is a botanical hallucinogenic beverage traditionally used for ritual and therapeutic purposes by several indigenous groups from the Northwestern Amazon. It is often prepared by boiling the stems of the liana Banisteriopsis caapi with the leaves of the shrub Psychotria viridis. Ayahuasca is made by mixing B. caapi vine with P. viridis and D. cabrerana leaves. The -carbolines inhibit peripheral MAO-A, which allows DMT to reach the systemic circulation and the brain. The identification of B. caapi was made by Richard Spruce in 1852 in Brazil, but the use of P. viridis as ayahuasca was described by William Burroughs in the 1950s. The book The Yage Letters was published in 1964 and was one of the first descriptions of the effects of ayahuasca to be more available to the public.

Ayahuasca is a plant used in ritual and religious use by indigenous and mestizo populations in the near cities in the Brazilian border with Peru, Colombia and Bolivia. Since the late 1980s, ayahuasca has been allowed in Brazil and is used by 20.000 regular ritual ayahuasca users in 23 countries. The first study to report that ritual ayahuasca use was not associated with psychiatric or cognitive deficits found that ayahuasca users had better scores on psychiatric, personality, and cognitive measures. In the last 15 years, several studies have been performed on ayahuasca, including uncontrolled and controlled trials in healthy volunteers. These studies have reported that acute administration of single ayahuasca doses in controlled experimental contexts is well tolerated, and induces typical psychedelic effects.

The evidence from observational and controlled studies suggesting safety and antidepressive and anxiolytic potentials for ayahuasca use motivated our group to investigate these therapeutic properties. We conducted several animal studies that showed harmine to induce behavioral and neurochemical antidepressive effects. Regarding DMT, the first evidence that this tryptamine could have anxiolytic-like effects came from a 1974 open-label trial.

A placebo-controlled study performed 50 years later showed that 0.05 mg/kg of DMT produced relaxation in some participants.8 DMT has been shown to have antidepressive and anxiolytic effects in rodents.56 Brazilian scientists reported that ayahuasca (5-9 mg/kg DMT) has antidepressant effects in rodents, and that a single dose of ayahuasca (1.67 mL/300 g) produced rapid and persistent significant physiological and behavioral improvements in a juvenile non-human primate model of depression.

A clinical trial with 17 patients was published in February 2016 assessing the effects of serotoninergic hallucinogens on patients with MDD. In an inpatient psychiatric unit, depressed patients received a single dose of 2.2 mL/kg oral ayahuasca (0.8 mg/mL DMT). Ayahuasca produced significant reductions in depressive and anxiety symptoms and was well tolerated, with the only adverse reactions being transient nausea and vomiting.

The above-mentioned results show that single ayahuasca doses may have antidepressant and anxiolytic effects, and that observational studies of ayahuasca ritual/religious users and therapeutic communities may also show improvements in substance-related disorders. However, there are no controlled trials that have assessed the antiaddictive effects of ayahuasca.

Observational studies performed among ritual ayahuasca users showed evidence of beneficial changes in some personality traits, including confidence, agreeableness, optimism, openness, and spirituality. These studies were also associated with significant increases in mindfulness-related capacities, and positive self-regulation in people with borderline personality traits.

The mechanisms of action of serotoninergic hallucinogens are still poorly understood, but preclinical and human studies have provided evidence that these drugs increase cortical electrical activity and information processing, and increase neuroplasticity by stimulating c-fos expression in the medial prefrontal and anterior cingulate cortices.

Serotoninergic hallucinogens and ketamine increase neuroplasticity and glutamatergic transmission, which are involved in the antidepressant and anxiolytic effects of these drugs. However, these effects are mediated by different mechanisms, such as the 5-HT2A receptor or the N-methyl-D-aspartate receptor.

Ayahuasca intake is positively correlated with increases in mindfulness-related capacities, and the effects of ayahuasca on BDNF levels are negatively correlated with the antidepressive effects of ayahuasca. 5-HT2A receptors are modulated by serotoninergic hallucinogens, and the effects are produced in brain regions involved in emotion regulation, cognition, memory, introspection, and self-awareness.

Serotoninergic psychedelics affect brain function by disrupting neural hierarchies, increasing bottom-up information transfer, and modifying the emotional expression of pain. These effects are often correlated with “ego dissolutive” and mystical experiences, which appear to mediate the therapeutic effects of these compounds. There is evidence that suggests that 5-HT1A and 5HT2C receptors are involved in the therapeutic effects of psychedelics.

In the 1960-70s, classic hallucinogens were commonly administered in combination with psychotherapy before, during, and after drug intake. However, these studies often used different theoretical models and psychotherapeutic approaches, and there were no placebo, adequate control groups, and standardized criteria for therapeutic outcome.

Recent studies have improved the validity of studies with classic hallucinogens by including placebo, control groups, and standardized instruments to measure and assess therapeutic outcomes. Some studies reported that personality traits, social cognition, mindfulness-related capacities, and mystical experiences are among the most prominent psychological processes behind the therapeutic effects of serotoninergic psychedelics. However, these results are derived from open-label trials and need to be replicated by controlled studies.

Recent studies have shown that classic psychedelics may improve emotion processing and social cognition by reducing the recognition of negative emotions and by increasing empathy, and that psilocybin may improve anhedonia, although this last result should be interpreted with caution due to its open-label design and small sample size.

In psychedelic-assisted therapy studies, psychological interventions are used before, during, and after the experience. It is still not known if the therapeutic effects of these drugs are truly increased by the inclusion of psychotherapy, nor which psychotherapeutic approach would be the most effective. The protocols for our study included trust building before the experiment, a non-directive, supportive approach during the drug session, and follow-up encounters from some days to several weeks after the session. However, the studies were not conducted by psychiatrists or psychologists trained in psychedelic-assisted psychotherapy. More studies should be performed comparing different therapeutic interventions in human hallucinogen research, and the influence of the social, religious and spiritual context in which these substances are used should also be further investigated. Evidence from carefully designed and performed open and controlled trials suggests that serotoninergic hallucinogens have antidepressive, anxiolytic, and antiaddictive properties. Furthermore, evidence from observational studies suggests a low toxicity profile for ritual ayahuasca users.

In 2018 the FDA designated psilocybin as a breakthrough therapy for treatment-resistant MDD. If the trials show positive results, psilocybin could be used off-label for treating depression and anxiety in cancer patients. The use of ayahuasca ritually and therapeutically by indigenous and mestizo communities of the Northwestern Amazon and Brazilian syncretic religions has been evolving for generations. If the clinical trials with ayahuasca continue to show positive results, regulatory agencies worldwide may be faced with the challenge of regulating a plant-based hallucinogen/psychedelic. New drugs with rapid onset of action and sustained effects after single or few doses may be beneficial for many patients. However, long-term studies are lacking on the efficacy and safety of serotoninergic hallucinogens.

Ayahuasca is prepared with stalks and leaves of the Psychotria viridis bush. The resulting brew is brownish and bitter.

Psychedelics affect several targets, including the AMPA receptor, glutamate transporter 1, mTOR, RIMAs, SRI, and TrkB receptor.