Ayahuasca and its major component harmine promote antinociceptive effects in mouse models of acute and chronic pain.

Ayahuasca, a psychedelic brew used in religious ceremonies, reduces pain in mice across several models of acute and chronic pain, including neuropathic pain. Oral doses of 24-3000 μL/kg dose-dependently decreased formalin-induced pain behaviors and mechanical allodynia caused by inflammation, but did not affect paw swelling or tail flick reflexes. In a model of nerve injury, a single dose reduced mechanical allodynia, and daily treatments for 14 days produced sustained pain relief without detectable toxicity. The antinociceptive effect was reversed by blocking GABAA and serotonin receptors, but not by opioid, GABAB, or cannabinoid receptor antagonists. Harmine, a major component of ayahuasca, also produced consistent pain relief in neuropathic mice.

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Abstract

Ayahuasca (AYA) is a psychedelic brew used in religious ceremonies. It is broadly used as a sacred medicine for treating several ailments, including pain of various origins. To investigate the antinociceptive effects of AYA and its mechanisms in preclinical models of acute and chronic pain in mice, in particular during experimental neuropathy. The antinociceptive effects of AYA administered orally were assessed in the following models of pain: formalin test, Complete Freund's Adjuvant (CFA)-induced inflammation, tail flick test, and partial sciatic nerve ligation model of neuropathic pain. Antagonism assays and Fos immunohistochemistry in the brain were performed. AYA-induced toxicity was investigated. AYA was chemically characterized. The antinociceptive effect of harmine, the major component present in AYA, was investigated. AYA (24-3000 μL/kg) dose-dependently reduced formalin-induced pain-like behaviors and CFA-induced mechanical allodynia but did not affect CFA-induced paw edema or tail flick latency. During experimental neuropathy, single treatments with AYA (24-3000 μL/kg) reduced mechanical allodynia; daily treatments once or twice a day for 14 days promoted consistent and sustained antinociception. The antinociceptive effect of AYA (600 μL/kg) was reverted by bicuculline (1 mg/kg) and methysergide (5 mg/kg), but not by naloxone (5 mg/kg), phaclofen (2 mg/kg), and rimonabant (10 mg/kg), suggesting the roles of GABAA and serotonergic receptors. AYA increased Fos expression in the ventrolateral periaqueductal gray and nucleus raphe magnus after 1 h, but not after 6 h or 14 days of daily treatments. AYA (600 μL/kg) twice a day for 14 days did not alter mice's motor function, spontaneous locomotion, body weight, food and water intake, hematological, biochemical, and histopathological parameters. Harmine (3.5 mg/kg) promoted consistent antinociception during experimental neuropathy. AYA promotes consistent antinociceptive effects in different mouse models of pain without inducing detectable toxic effects. Harmine is at least partially accountable for the antinociceptive properties of AYA.