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  • 1 Universitat Rovira i Virgili, Spain
  • 2 Independent Researcher
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Background and aims

Pain is the most prevalent symptom of a health condition, and it is inappropriately treated in many cases. Here, we present a case report in which we observe a long-lasting analgesic effect produced by changa, a psychedelic drug that contains the psychoactive N,N-dimethyltryptamine and ground seeds of Peganum harmala, which are rich in β-carbolines.

Methods

We describe the case and offer a brief review of supportive findings.

Results

A long-lasting analgesic effect after the use of changa was reported. Possible analgesic mechanisms are discussed. We suggest that both pharmacological and non-pharmacological factors could be involved.

Conclusion

These findings offer preliminary evidence of the analgesic effect of changa, but due to its complex pharmacological actions, involving many neurotransmitter systems, further research is needed in order to establish the specific mechanisms at work.

Abstract

Background and aims

Pain is the most prevalent symptom of a health condition, and it is inappropriately treated in many cases. Here, we present a case report in which we observe a long-lasting analgesic effect produced by changa, a psychedelic drug that contains the psychoactive N,N-dimethyltryptamine and ground seeds of Peganum harmala, which are rich in β-carbolines.

Methods

We describe the case and offer a brief review of supportive findings.

Results

A long-lasting analgesic effect after the use of changa was reported. Possible analgesic mechanisms are discussed. We suggest that both pharmacological and non-pharmacological factors could be involved.

Conclusion

These findings offer preliminary evidence of the analgesic effect of changa, but due to its complex pharmacological actions, involving many neurotransmitter systems, further research is needed in order to establish the specific mechanisms at work.

Introduction

The treatment of pain is one of the most significant challenges in the history of medicine. At present, there are still many challenges that hamper pain’s appropriate treatment, as recently stated by American Pain Society (Gereau et al., 2014). Paradoxically, while we are presented with analgesic undertreatment (Deandrea, Montanari, Moja, & Apolone, 2008; Greco et al., 2014), the abuse of opioid medications has led to the current opioid crisis that many countries are facing (National Institute on Drug Abuse, 2018).

Pain has several psychological and physical consequences. It is the most prevalent symptom of an underlying health problem, affecting 100 million people in the United States (Institute of Medicine, 2011) and 95 million people in Europe (Boston Scientific, 2013). It is also the most underrecognized and undertreated medical problem of the 21st century (European Pain Federation, 2018).

Changa is a smoking mixture that contains N,N-dimethyltryptamine (DMT; generally extracted from Mimosa hostilis) and β-carbolines (extracted from Banisteriopsis caapi or Peganum harmala). The mechanisms of action for these compounds are quite similar to those found in the ayahuasca beverage (McKenna & Riba, 2015), with possible differences in constituents if P. harmala is used instead of B. caapi. In the case of P. harmala, as mentioned below, ground seeds were used in the case reported. The compounds found in seeds of this plant are β-carbolines (harmaline, harmine, harmalol, tetrahydroharmine, and harmol; Herraiz, González, Ancín-Azpilicueta, Arán, & Guillén, 2010) and quinazolines (mainly vasicine; Herraiz, Guillén, Arán, & Salgado, 2017). The psychoactive effects of ayahuasca usually last between 3 and 5 hr (McKenna & Riba, 2015), but the effects of smoked changa last about 15–30 min (Ott, 1994).

Case Description

JM is a 57-year-old adult male who works as a doctor at a public hospital in Spain. He developed some signs of musculoskeletal pain, especially in his limbs, and fatigue 10 years ago. These symptoms slowly increased and became more extensive until they reached disabling levels. The muscular pain limited him to moderate exercise, as it took him almost 1 week to completely recover from performing physical activity. JM also developed sleep disorders, waking up in the night due to pain. After working a night shift in the hospital’s emergency services, he again needed 1 week to recover physically and in terms of his sleep rhythm. Regarding his sexual life, it took a lot of effort for him to even caress his spouse because of the muscular pain in his arms. After intercourse, he also needed 1 week to recover, and ejaculation was painful, so he experienced decreased sexual desire. Other symptoms included an inability to lift heavy weights, decreased attentiveness, and vision with muted colors.

He decided to visit a rheumatologist 3 years ago and was diagnosed with fibromyalgia and chronic fatigue. In the following months, JM was prescribed ibuprofen, diclofenac, and dexketoprofen. However, taking these drugs resulted in little or no improvement. His rheumatologist recommended that he attend a workshop that was taking place in an ambulatory clinic setting. The workshop consisted of 2 months of training in cognitive therapy for fibromyalgia patients. JM completed the training, after which his level of pain decreased from 8 to 3 on the numerical rating scale (which ranges from 0 to 10). However, a couple of weeks later, the pain and fatigue had increased again. He was then prescribed ozone therapy and fluoxetine. Ozone therapy relieved his pain but only for a couple of days. Fluoxetine, however, was effective for both pain and fatigue, assisting JM to attain a rating of 3–4 on the pain scale again. Nevertheless, after 6 weeks of treatment, he decided to stop taking fluoxetine, because he developed autolytic ideation and annoying rumination, the symptoms that he had not previously experienced.

His drug history includes only one instance of consuming ayahuasca 5 years ago. JM decided to take changa with an underground therapist 3 months ago. The changa session involves an evening meeting. Approximately 30 min of meditation precedes consumption. Then, each individual presented (generally four or five people participated) smokes one previously prepared cigarette that contains freebase DMT and ground seeds of P. harmala (the content of the cigarette was confirmed through a harm-reduction organization that analyzed a sample using gas chromatography–mass spectrometry). JM has attended five changa sessions so far. In the first session, he was only able to relax, because he did not know how to smoke. In the second session, 1 week later, he could smoke correctly and felt intense psychoactive effects. After this session, his pain disappeared almost completely for a period of 2 weeks. After the third session, which further took place after 2 weeks, his mood had also improved. The autolytic ideation disappeared and he felt much better. According to him, he was able to see colors brightly again. He had the same results after his fourth session, which took place 15 days after the previous one. After that session, he reported greater emotional stability, pain relief, and a slight decrease in fatigue as well. He participated in another changa session 1 month later, after which he confirmed the decrease in pain that lasted up to 15 days.

Discussion

We can suggest various mechanisms through which changa may exert an analgesic effect. In this case, freebase DMT extracted from M. hostilis was used. DMT is an indole alkaloid widely found in plants and in mammals, including humans (Barker, McIlhenny, & Strassman, 2012; Beaton & Christian, 1977; Saavedra & Axelrod, 1972; Servillo, Giovane, Balestrieri, Cautela, & Castaldo, 2012). It is a partial agonist of serotonin (5-HT) receptors (1A,2A and 2C; Keiser et al., 2009) and also an agonist of sigma-1 receptors (σ1R; Fontanilla et al., 2009). It interacts with other receptors indirectly as well (for a review, see Carbonaro & Gatch, 2016).

Regarding the agonism on 5-HT receptors, the relationship between mood and pain is well known (Marsden, 1979), so an elevation of mood produced by DMT could partially explain its analgesic effect. This is also relevant regarding the efficacy of fluoxetine, as was observed in this case. It has been observed that anti-depressant drugs have an analgesic effect that is independent of their effect on mood (Jann & Slade, 2007; Mico, Ardid, Berrocosso, & Eschalier, 2006). However, it seems that tricyclic anti-depressants and serotonin-noradrenaline reuptake inhibitors are more effective than selective serotonin reuptake inhibitors for the treatment of pain (Jann & Slade, 2007; Stahl, Grady, Moret, & Briley, 2005). This suggests that noradrenergic pathways are highly relevant to the management of pain (Benson et al., 2015).

Concerning σ1R, this orphan receptor is distributed throughout the central nervous system, heart, liver, and lungs (Hayashi & Su, 2007), and it has been observed to play a role in several conditions, such as addiction, depression, amnesia, cancer, and pain (Collier, Waterhouse, & Kassiou, 2007). At the endoplasmic reticulum, it acts as a ligand-operated chaperone protein, regulating the flow of Ca2+ via inositol 1,4,5-triphosphate receptors (Hayashi & Su, 2007; Su, Hayashi, Maurice, Buch, & Ruoho, 2010). In the plasma membrane, it can modulate the activity of opioid and N-methyl-D-aspartate receptors, as well as K+ and Ca2+ channels (Zamanillo, Romero, Merlos, & Vela, 2013). Its activity can be modulated by σ1R ligands, which are expressed in areas associated with pain control, such as dorsal root ganglion neurons, dorsal spinal cord, the thalamus, the periaqueductal gray, and the rostroventral medulla (Gundlach, Largent, & Snyder, 1986). There are various genetic and pharmacological findings that provide sufficient evidence to consider σ1R antagonists as part of an innovative approach for the treatment of pain (Vela, Merlos, & Almansa, 2015). In fact, the first phase II, randomized, placebo-controlled clinical trial in which a σ1R antagonist (MR309) was used reported encouraging results (Bruna et al., 2018). However, other studies also reported an analgesic effect of σ1R agonists in terms of neuropathic pain (Ohsawa, Hayashi, & Kamei, 2010; Tomohisa et al., 2015). Thus, the underlying mechanism for the analgesic effects of the agonism/antagonism of σ1R has not yet been fully clarified. Ohsawa et al. (2010) suggested that the anti-nociceptive effect of the σ1R agonist that was used in their study (pentazocine) involves the lowering of nitric oxide metabolites. The effect was likely produced due to a dose effect (the peripheral application of pentazocine may produce the nociceptive response at a lower dose, whereas higher doses, such as those used in the study, produce an inverse effect; Ohsawa et al., 2010). Tomohisa et al. (2015) used σ1R agonist SA-4503 in their study. Interestingly, SA-4503 and not NE-100 (a σ1R antagonist) produced anti-nociceptive effects in terms of chemotherapeutic-induced neuropathic pain. To explain this finding, the authors mention the cytoprotective and neuroprotective effects of σ1R agonists (Griesmaier et al., 2012; Hyrskyluoto et al., 2013; Ono et al., 2014; Tuerxun et al., 2010), which may influence the anti-neuropathic effects. Furthermore, DMT also reduces inflammation via σ1R (Szabo, Kovacs, Frecska, & Rajnavolgyi, 2014). It has been observed that inflammation response can induce pain, and that inflammatory signals can induce changes in neurotransmitter metabolism, neuroendocrine function, and neuroplasticity (Walker, Kavelaars, Heijnen, & Dantzer, 2014). In this respect, DMT can also induce neuronal plasticity (Kourrich, Su, Fujimoto, & Bonci, 2012; Ly et al., 2018; Ruscher et al., 2011; Tsai et al., 2009), which can play a vital role in the treatment of pain (Price, Verne, & Schwartz, 2006; Sibille, Bartsch, Reddy, Fillingim, & Keil, 2016).

The ground seeds of P. harmala are the other constituent of changa. They contain many β-carbolines and quinazolines, with harmaline being the major alkaloid (Mahmoudian, Jalilpour, & Salehian, 2002). It has been observed that these β-carbolines bind with modest affinity to 5-HT2A receptors (Riba, 2003), except in the case of harmine, which expresses high affinity with these receptors (Glennon et al., 2000). They also show affinity for 5-HT2C, 1A, dopamine (Nasehi et al., 2010), gamma-aminobutyric acid (GABA; Glennon et al., 2000), imidazoline (I2; Yu, Idle, Krausz, Küpfer, & Gonzalez, 2003), and adrenergic (α2) receptors (Husbands et al., 2001). These β-carbolines can also interact with opioid receptors (Farouk, Laroubi, Aboufatima, Benharref, & Chait, 2008). However, the most remarkable is their ability to inhibit the enzyme monoamine oxidase (MAO) at concentrations in the micromolar and nanomolar range (Riba, 2003). These substances appear to be more effective at inhibiting MAO-A than at inhibiting MAO-B.

The seeds of P. harmala have been traditionally used (Akhtar, Iqbal, Khan, & Lateef, 2000) for the treatment of various types of pain (Moloudizargari, Mikaili, Aghajanshakeri, Asghari, & Shayegh, 2013). Recent studies have verified the analgesic potential of P. harmala seeds using three different extracts and pain models (Farouk et al., 2008; Monsef, Ghobadi, Iranshahi, & Abdollahi, 2004; Sokmen, Jones, & Erturk, 1999), showing that the butanolic extract had the maximum effect in the writhing test. Pretreatment with naloxone prevented the extracts from having a nociceptive effect, so it was concluded that an opioid-modulated mechanism is involved.

Apart from the possible synergy with DMT’s effects on 5-HT release, and therefore the aforementioned potential analgesic effect, β-carbolines also interact with receptors closely related to pain modulation, such as GABA (Munro, Hansen, & Mirza, 2013), I2 (Bektas, Nemutlu, & Arslan, 2015), α2 (Carroll, Mackey, & Gaeta, 2007), and opioid receptors (Kirkpatrick et al., 2015). Complex interactions between these receptors are also possible, since I2 can potentiate analgesic actions produced by opioid receptor ligands (Bektas et al., 2015). Furthermore, two studies demonstrated the neuroprotective effects of the alkaloids of P. harmala (Herraiz & Guillén, 2011; Splettstoesser, Bonnet, Wiemann, Bingmann, & Büsselberg, 2005), which could also be related to their analgesic effects (Mannelli et al., 2009).

Regarding the ability of β-carbolines to inhibit the MAO-A enzyme, although some authors indicate that MAO inhibitors should not be used in the treatment of pain (Mika, Zychowska, Makuch, Rojewska, & Przewlocka, 2013), MAO inhibitors like phenelzine have been shown to be effective for treating pain associated with depression (Davidson, 1985). Moreover, specific MAO-A inhibitors could have greater analgesic effects (Menkes, Fawcett, Busch, & Jones, 1995), since these specific inhibitors increase norepinephrine, DA, and 5-HT levels in the tissues (da Prada et al., 1990).

The major quinazoline present in P. harmala seeds is vasicine, which has been shown to produce significant anti-inflammatory effects (Singh & Sharma, 2013), which can also be related to its analgesic effects.

As discussed above, we cannot dismiss the possibility that the active constituents in changa produce a direct analgesic effect. However, those compounds have short half-lives (t½λz = 260–532 min; Riba, 2003) that are insufficient to explain the pattern that can be clearly observed in the case: an analgesic effect that endured for over 2 weeks. It is well known that a single administration of a psychedelic drug, such as psilocybin, can produce long-lasting effects (Griffiths et al., 2011). The mechanisms underlying these long-lasting effects are not well understood, but they have been correlated with psychological factors like peak experiences (Bogenschutz et al., 2015; García-Romeu, Griffiths, & Johnson, 2014; Griffiths et al., 2011) or an enhancement of the placebo effect (Hartogsohn, 2016). Regarding the latter, it is well known that psychedelics can increase suggestibility in human subjects (Carhart-Harris et al., 2015; de Rios, Grob, & Baker, 2002), so it is reasonable to think that the variables found in the ritualistic setting in which changa was provided, like expectancy or attentive and respectful listening by caregivers, together with the fact that there could be a real, short-term analgesic effect, probably exert a magnified placebo effect. Furthermore, a recently published review suggests that psychedelic drugs like lysergic acid diethylamide and psilocybin may alleviate malignant and neuropathic pain (Whelan & Johnson, 2018). The authors argue that this effect could be related to the psychedelic experience itself, which can modify the metacognitive interpretation of pain. Some authors have suggested that epigenetic modifications (Schindler, Wallace, Sloshower, & D’souza, 2018), as well as neuroplasticity and neurogenesis (Ezquerra-Romano, Lawn, Krupitsky, & Morgan, 2018; Ly et al., 2018), could trigger long-lasting responses.

Due to the complexity of the pharmacological effects produced by changa’s constituents, more research will be needed in order to clarify the specific mechanisms through which long-lasting analgesic effects can be produced. It will also be significant to describe other indirectly affected systems, such as modifications of opioid receptor density or alterations of 5-HT binding sites, among many other systems that are hypothesized to be affected by changa’s constituents. In addition, the analgesic effect of ayahuasca was reported (Barbosa, Cazorla, Giglio, & Strassman, 2009), suggesting similar mechanisms of action.

Conclusions

The intense psychedelic effects of changa limit its application in clinical contexts. However, the case reported here suggests that changa can produce a long-lasting analgesic effect, involving a combination of mood-enhancing effects; other psychological factors; an interaction with several neurotransmitter systems; and anti-inflammatory, neuroprotective, and plasticity-promoting actions. Remarkably, changa could offer pain treatment that targets multiple monoamine neurotransmitters, as recommended by some authors (Benson et al., 2015).

Further research on the bioavailability of changa constituents based on the smoking procedure that is used is also warranted.

Acknowledgements

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. GO wrote the first draft of the manuscript. GO and ST conceived this case report and interviewed the patient. They also reviewed and approved the final version of the manuscript.

Ethics

This study was conducted following the principles of the Declaration of Helsinki, and the patient’s informed consent was also obtained.

Conflict of interest

The authors declare no conflict of interest.

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