Chronic pain is a major cause of suffering and distress to patients and affects millions of people worldwide (Battaglia et al., 2023). Neuropathic pain is a highly prevalent type of chronic pain caused by diseases or injuries of the somatosensory system. (Attal et al., 2023; IASP, 2021). The pharmacological management of neuropathic pain is challenging, since the drugs currently available in the market induce important side effects and many patients respond poorly to treatments (Attal et al., 2023; Bernetti et al., 2021). To overcome these limitations, novel therapeutic approaches aiming to control refractory pain have been explored. Pioneer studies published in the 1960s and 1970s demonstrate the analgesic effects of psychedelics in patients suffering from cancer-related pain, phantom limb pain, cluster headache, and migraine (Kooijman et al., 2023). In recent years, a revived interest in the study of these drugs has grown, as shown by the increased number of publications on the topic – a phenomenon called the psychedelic renaissance (Hadar et al., 2023).

One of the most emblematic psychedelics is ayahuasca, a ritualistic brew originally used by native peoples of South America (Estrella-Parra et al., 2019). Ayahuasca is most commonly prepared as a decoction of the plants Banisteriopsis caapi and Psychotria viridis, which contain alkaloids that mediate the psychedelic effects of the brew, namely β-carbolines and N,N-dimethyltryptamine (DMT) (Jiménez and Bouso, 2022; McKenna et al., 1984). In addition to B. caapi and P. viridis, other 90 different plant species have been reported to compose ayahuasca samples, including Banisteriopsis inebrians, Lophanthera lactescens, Diplopterys cabrerana, Tetrapterys methystica, Mascagnia psilophylla, among others (Domínguez-Clavé et al., 2016; Ott, 1996). The use of ayahuasca began to expand in the first decades of the 20th century, when ayahuasca was incorporated into new religions that arose in Northern Brazil (Labate, 2012) and can now be found throughout the entire globe (Dos Santos and Hallak, 2021). The traditional use of ayahuasca is intimately related with healing practices. In the cult of Santo Daime, believers often resort to ayahuasca as a sacred medicine for healing ailments of the mind and the body, including pain of various origins (Moreira and MacRae, 2011). The traditional use of ayahuasca in the ritualistic context reduces bodily pain (Barbosa et al., 2009), pain associated with fibromyalgia (Orozco, 2020), and chronic pain (Labate and Cavnar, 2014; Maia et al., 2023).

Despite the reports that ayahuasca improves pain, it is not clear whether that feeling of improvement is due to an analgesic effect per se or rather a result of the subjective psychedelic experience, as patients state that ayahuasca helps them to “understand their bodies” and “find new ways to cope with pain” (Orozco, 2020). It has also been suggested that therapeutic outcomes of ayahuasca ceremonies can be influenced by psychological aspects affected by religiosity and group dynamics (Barbosa et al., 2009; Maia et al., 2023). On the other hand, a preclinical study has provided direct evidence of the antinociceptive effect of ayahuasca in mice (Pires et al., 2018), suggesting that ayahuasca may have intrinsic analgesic properties. However, this study is limited to the evaluation of single treatments in screening assays of acute antinociception and the mechanisms of action behind the effect were not addressed.

Most records of the analgesic effects of ayahuasca come from anecdotal evidence following the ritualistic use of the beverage. Therefore, the analgesic potential of ayahuasca should be investigated aside from the context of religious ceremonies. Considering the major gap in the pharmacological management of neuropathic pain, this work aimed to investigate the antinociceptive effects of ayahuasca and its mechanisms in preclinical models of acute and chronic pain in mice, in particular characterizing the effects and the safety of repeated administrations of ayahuasca during experimental neuropathy. The contribution of the major component harmine to the antinociceptive properties of ayahuasca was also assessed.