Introduction

Harmine, a naturally occurring alkaloid found in several plant species, but most notably the Ayahuasca vine (banisteriopsis caapi), has gained attention for its potential therapeutic effects. Understanding the intricate processes of harmine’s action in the body, from binding to the active site of monoamine oxidase-A (MAO-A) to its metabolism and excretion, sheds light on its pharmacological properties. This article aims to provide a detailed exploration of harmine’s journey within the body, including it’s potential to create oxidative stress, and it’s opposing role as a potential antioxidant.

Binding to MAO-A

Harmine exerts its known effects by acting as a reversible inhibitor of MAO-A, an enzyme responsible for the breakdown of neurotransmitters like serotonin. However, very little is known about other effects harmine exerts within the body, particularly as it comes to mineral binding and regulation.

When harmine enters the body, it first acts on the MAO-A enzyme in the digestive tract before being absorbed through the intestine. Once in circulation, it crosses the blood-brain barrier and selectively binds to the active site of MAO-A. The “active site” of an enzyme is the place where the chemical reaction takes place. When harmine binds to the active site of MAO-A it prevents the breakdown of key neurotransmitters, including DMT.

Most of the research on harmine focuses on its effects on MAO-A, which is in line with the prevailing theory that neurotransmitters regulate mood, cognition, digestion, and other aspects of the physiology. While I believe there may be some truth behind this theory, it does not tell the full story. Minerals such as calcium, copper, iron and others also  affect these same processes (including our consciousness and emotions), so I would like to see researchers investigating this angle. Until that time, we are naturally limited to the research being conducted.

Effects of MAO-A Inhibition

The primary narrative goes like this: When harmine binds to the active site of MAO-A, it functions as a monoamine oxidase inhibitor (which means it stops MAO-A from doing it’s enzyme function). This inhibition of MAO-A by harmine leads to increased levels of DMT, serotonin and other neurotransmitters in the brain and elsewhere in the body. When the Ayahuasca brew itself is made with an exogenous source of DMT, this provides yet an additional influx of DMT in addition to that which is being produced endogenously. This enhanced neurotransmitter availability is speculated to have various effects on mood, cognition, and behavior.

Additionally, MAO-A inhibition plays a role in the regulation of other physiological processes beyond neurotransmitter metabolism. As anyone who has ever experienced Ayahuasca will confirm, there are many effects that follow the vagus nerve all the way down the body. Breathing, heart rate, gut motility, bile excretion, and other organ processes are all affected, though it is not clear whether these effects are due to the activation of the nervous system or as a result of other bio-chemical processes, or both.

Metabolism in the Liver

This is where things become interesting. After harmine’s interaction with MAO-A, it eventually becomes unbound from the MAO-A enzyme via not-well-understood processes. For any researchers looking for an interesting project, I’d propose looking into the exact mechanism by which the harmine becomes unbound and what happens to the MAO-A enzyme after the unbinding. Many people believe it returns to normal, but the real-world experience of those who have worked with Ayahuasca tells a different story as the effects of Ayahuasca can often be felt for weeks and sometimes longer. Most explanations are that the elevation in neurotransmitters leads to this after glow period, but that would only make sense if MAO-A was still inhibited in some way, or if the amount or activity of MAO-A was reduced. If it turns out that the amount or activity of MAO-A is affected for long periods, there could be many unintended consequences because this enzyme serves vital functions throughout the body.

Nevertheless, after some process releases harmine from the MAO-A active site, it undergoes metabolism in the liver. The process of metabolism involves the action of enzymes, including the cytochrome P450 (CYP) family, notably CYP1A2 and CYP2D6. These enzymes catalyze the oxidation of harmine, introducing an oxygen atom and leading to the formation of various metabolites.

Oxidation of Harmine and Potential Antioxidant Properties

During the oxidation of harmine mediated by cytochrome P450 enzymes, reactive oxygen species (ROS) are generated as part of their catalytic cycle. These ROS, such as superoxide anion (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH), can induce oxidative stress and potentially cause cellular damage if not adequately controlled. This is where the most potential damage from Ayahuasca and harmine is likely to occur in my opinion.

While the indigenous people who have worked with Ayahuasca for thousands of years have no apparent issues with the metabolism of Ayahuasca, I have personally experienced and worked with Westerners who have found that their work with Ayahuasca over long periods has contributed to disregulation in their bodies. One theory that I have after reviewing the blood work of hundreds of people is that many Westerners have build-ups of iron in their livers, and depleted stores of copper. Because the anti-oxidant enzymes that would normally be able to mop up the ROS created by the oxidation of harmine are copper-dependent, many people simply don’t have the ability to  deal with the increased ROS. This can lead to further accumulation of iron, metabolic disfunction, and any symptom one can imagine. Oxidative stress is the driver of aging and disease in humans, so increasing this without adequate anti-oxidant enzymes is not such a great thing.

This may also explain why some people have no issues at all with Ayahuasca. For those people with robust metabolic health, iron balance, and copper stores, Ayahuasca may be truly harmless in this regard. Yet, we are not all coming into these experiences from the same place.

Formation of Metabolites

As mentioned, the oxidation of harmine gives rise to different metabolites, including harmol, harmalol, and harmaline. These metabolites may undergo further modifications through processes such as conjugation, where functional groups like glucuronic acid or sulfate are attached, altering their chemical properties. The involvement of copper-dependent enzymes in the formation of harmine metabolites is yet to be fully elucidated, though from my understanding of these processes, copper (and other minerals) is essential.

The Flip-side of Oxidation

Interesting, it is also noteworthy to mention that harmine itself has been reported to possess antioxidant properties, at least in lab settings. Studies have demonstrated its ability to scavenge free radicals and modulate antioxidant defense systems, suggesting a potential role in counteracting oxidative stress. The precise mechanisms underlying harmine’s antioxidant effects and their interplay with its oxidation processes require further investigation, yet it appears that these effects may happen prior to harmine’s oxidation in the liver. If that is the case, harmine truly possess a level of polarity worthy of research.

Excretion

The metabolites of harmine are eliminated from the body through various routes. Some metabolites may undergo renal excretion, being excreted in the urine, while others may undergo biliary excretion and be eliminated in the feces. The specific excretion pathways depend on the nature of the metabolites and their affinity for transporters involved in renal or biliary elimination. All this is to say, eventually the metabolites leave the body via the normal pathways.

Conclusion

Harmine’s journey within the body involves its binding to MAO-A, hepatic metabolism, and subsequent excretion. It’s worth noting that the pro-oxidant effects of harmine, particularly in the context of liver metabolism, have been explored in limited studies, and the exact mechanisms and implications are not yet fully understood. The antioxidant properties of harmine, on the other hand, have been observed in various in vitro and in vivo studies, mainly focusing on its ability to scavenge free radicals and modulate antioxidant defense systems. These are key areas for further research, particularly in Western populations who have been subjected to several generations of iron fortification and copper depletion, which contribute to poor liver function.

Further Research

• Haas, H. L., Sergeeva, O. A., & Selbach, O. (2008). Histamine in the nervous system. Physiological Reviews, 88(3), 1183-1241.
• Yanovsky, Y., Li, S., & Klyuch, B. P. (2012). Differential effects of harmaline, a tremorogenic harmala alkaloid, on histaminergic neurons in comparison with noradrenergic and serotonergic ones. Neuroscience, 218, 243-255.
• Schwartz, J. C., & Arrang, J. M. (1995). Regulation of histaminergic neurotransmission in the CNS by neuronal histamine receptors. European Journal of Pharmacology, 293(1), 1-13.
• Monti, J. M., Monti, D., & Jantos, H. (2007). Effects of the harmine derivative, 13-(2-propyl)pentyl-6, 7, 8, 9-tetrahydro-9-hydroxy-9-methyl-1H-pyrido [3, 4-b] indole (HP-029), on sleep and wakefulness in the rat. Sleep, 30(12), 1692-1698.
• Passani, M. B., Lin, J. S., Hancock, A., & Crochet, S. (2004). Bifurcation of reticular thalamic neurons and 5‐HT‐releasing properties of limbic cortical neurons projecting to the medial septum. European Journal of Neuroscience, 20(9), 241-250.
• Brown, R. E., Stevens, D. R., & Haas, H. L. (2001). The physiology of brain histamine. Progress in Neurobiology, 63(6), 637-672.