For any of the 300 million individuals worldwide suffering from depression, a fast-acting, effective treatment can mean the difference between life and death. Yet despite the growing number of pharmaceutical agents advertising relief from sadness, replaced by joy and contentment, their efficacy is often staggeringly slow and poor. In contrast to the promise of immediate happiness, many drugs can leave patients numb, lethargic, fighting unpleasant side-effects, and sometimes even more deeply depressed. A likely reason for the failure of many past anti-depressants is our still incomplete understanding of the neurobiological bases for this debilitating disease. This knowledge gap precludes efforts to ease depression through chemical means. Hence, the search continues for a rapid-acting, reliable therapy. Naturally available treatment options that offer little commercial incentive have remained overlooked by pharmaceutical research. However, mounting research suggests that nature may have provided an effective means to relieve depressive symptoms, in the form of a ceremonial psychedelic brew that’s been appreciated for centuries for its mind-altering and mood-enhancing properties. After early reports that ayahuasca may be a viable alternative to the countless failed pharmaceutical therapies, a team of Brazilian researchers put it to rigorous testing and found promising anti-depressant effects in this age-old spiritual medicine.
A spiritual psychedelic brew
Ayahuasca is an intoxicating brew used by Amazonian cultures for spiritual and medicinal purposes. It combines psychoactive plants containing the psychedelic dimethyltryptamine (DMT), and several monoamine oxidase inhibitors (MAOIs). Effects often last up to six hours, and include altered consciousness, sensory changes, introspection, elevated heart rate and blood pressure, vomiting, and in some cases, intense distress. Because ayahuasca can notably evoke mystical experiences and religious revelations, it has been widely used to promote spiritual awakening.
Ayahuasca the anti-depressant
Ayahuasca has previously been found to attenuate depression severity, but until now, its therapeutic potential had not been rigorously studied in a clinical trial. In their recent double-blind, placebo-controlled trial, Dr. Fernanda Palhano-Fontes, of the Federal University of Rio Grande do Norte, and colleagues tested the drug in 29 patients with treatment-resistant depression. On average, these individuals were moderately to severely depressed and had tried nearly four anti-depressants without success.
Participants consumed a single dose of either ayahuasca or placebo, after which they sat quietly under supervision while the drug took effect. Depression was assessed using two depression scales before the ayahuasca session and one, two and seven days after. Compared to patients who drank placebo, those who ingested the active brew reported fewer depressive symptoms as soon as a day later, with an even stronger reduction a week later (see Figure). By the end of the week, more patients in the ayahuasca group (64%) than the placebo group (27%) responded positively to the treatment. Although remission rates for the ayahuasca group (36%) were on average higher than placebo (7%), this difference was not significant, perhaps due to an unusually high placebo effect. The improvements in mood were not without unpleasant side-effects, notably nausea and vomiting.
The depressed brain on psychedelics
This trial was an important step towards validating ayahuasca as an anti-depressant, a treatment option implicated by only a handful of prior studies. Others found that ayahuasca elicits anti-depressant effects up to three weeks and alters brain blood flow, but these studies were small and not placebo-controlled, the gold-standard for clinical testing. These mood-regulating benefits may not be limited to ayahuasca, as other psychedelics have similarly demonstrated therapeutic efficacy. A small study reported that psilocybin, the psychoactive compound in hallucinogenic mushrooms, alleviated depressive symptoms a week to three months later, though this trial was not placebo-controlled. Several randomized controlled trials have demonstrated that the psychedelic anesthetic ketamine reduces depression symptoms as soon as two hours and up to one week later.
Besides offering hope for fighting depression, the rapid and robust benefits observed from ayahuasca provide valuable insight into the still mysterious neurobiological genesis of depression. To understand the mood-stabilizing powers of ayahuasca, we can look to its array of constituent chemicals. The pool of MAOIs in ayahuasca prevent the degradation of monoamines, a class of neurotransmitters implicated in depression that includes serotonin, dopamine and norepinephrine. The “monoamine hypothesis” of depression–which posits that monoamine deficits play a causal role–is considered inadequate to fully explain the pathogenesis of depression. However, the benefits of ayahuasca support the theory that rebalancing monoamine neurotransmission can at least partly help to combat depression. Moreover, DMT is a serotonin agonist, meaning that it activates the brain’s serotonin receptors. However, existing drugs that act as selective serotonin reuptake inhibitors (e.g., Prozac, Paxil or Zoloft) also increase serotonergic activity through different means, but have relatively limited efficacy. By preventing the breakdown of several monoamines through its MAOI activity, rather than targeting a particular neurotransmitter that may or may not be deficient in the individual patient, ayahuasca may offer a more generalizable therapy than conventional serotonergic drugs.
These effects are likely augmented by DMT’s activation of sigma-1 receptors, which regulate calcium signaling and have been implicated in depression, among other psychiatric conditions. MAOIs and sigma-1 receptors also promote neurogenesis and increase brain growth factors, which may further help to regulate mood.
The road to prescription
Is ayahuasca the miracle drug we’ve long been awaiting to combat depression? Despite the promising evidence supporting its therapeutic potential, many outstanding questions need to be addressed before the psychedelic is prescribed in a clinical setting. The drug’s anti-depressant effects are fast-acting, but further research is needed to determine the duration of these effects and the optimal dosing regimen. Regular supervised, mind-altering trips that consume several hours may be impractical if frequent dosing is required. An equally pressing question is whether the side effects would preclude regular use and patient compliance. Though its non-addictive profile and absence of lasting changes to cognition or personality make ayahuasca an appealing option, the vomiting and hallucinations that often accompany the ayahuasca experience could be deal-breakers for patients desiring a less invasive therapy. Because psychedelic trips can sometimes be accompanied by negative experiences, including sensory or cognitive distortions, additional research is warranted to better characterize their neurobiological properties. Thus, it may be some time before the carefree laughter of an ayahuasca-user infiltrates the mass of TV drug advertisements. But at the very least, ongoing research into its antidepressant properties will bring us closer to understanding how our brain chemistry supports a healthy emotional state.
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Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.