My fascination for Monoamine Oxidase (MAO) continues. In the past I’ve explored how MAOA genes may be involved in social hierarchy and evolve in response to chronic generational subordination. MAOA genes may also evolve based on climate as temperature affects MAOA levels. In this article I will explore yet another potential pressure of evolution: environmental oxygen levels and ultimately altitude. Aside from this, an exploration into oxygen related psychoactive effects is presented in this post.
A short recap: in Serotonism I showed how the warrior variant of the monoamine oxidase A (MAOA) gene could facilitate violence by disrupting social defeat mechanisms (dynorphin) that may typically produce withdrawal, anhedonia, submission, learned helplessness, depressive behavior, and psychosis. MAOA normally metabolizes monoamines, especially serotonin. Serotonergic mechanisms appear to attenuate the effects of dynorphin/Kappa Opioid receptors (KOR) and KOR mechanisms also seem to depend on the serotonin transporter (SERT) induction which clears extracellular serotonin, thus preventing the attenuation of its other functions, namely social defeat. In this way, enhancing serotonin appears to facilitate aggression, although it doesn’t seem to be inherent to the effect of serotonin itself but rather it may prevent the normal disengagement signals that prevent extreme escalations during confrontation. The correlations with aggression may reveal that society and the subordinated groups are still in conflict and these genes may disinhibit fight reactions in the face of these events. Confrontation makes one aggressive, these genes just prevent the normal tendency to give up, or inhibit oneself. This book runs through an argument against the violence-MAOA links.
I’ve recently discovered there is a link between hypoxia and upregulated MAO. Of course, I should have suspected a deep running link of MAO and oxygen due to the obvious hint in the name of the molecule: ‘oxidase’. MAO functions largely to metabolize monoamines by catalyzing the oxidization of them. Since oxygen is involved in the process of deamination of the monoamines, it makes sense that chronic hypoxia (low oxygen levels) would lead to a failure of deamination and a subsequent abundence of MAO. This study shows decreased activity of MAO in hypoxia, further supporting this idea.
High altitude environments are not only naturally hypoxic but also often colder in temperature. Heat exposure was shown to decrease MAO activity in the rat brain, while another study found the same results and also tested extreme cold which found no effect on MAO activity. This second study here mentions that cold temperatures induce the activity of an endogenous MAO inhibitor (MAOI) known as tribuline, likely as a compensatory mechanism and perhaps neutralizing an unmeasured increase of MAO, ultimately showing normalized MAO activity in the face of cold. Increased MAO activity would mean increased metabolism of monoamines which would result in potential depressive low energy behaviors. Not only this, but if KOR agonism is left unchecked it could facilitate hypothermia. In this way serotonin may help regulate body temperature through mechanisms of disrupting KOR induced hypothermic effects. Furthermore, since KORs partly function by inducing SERT through MAPK pathways and consequently reducing serotonergic tone (1, 2, 3), it could be that KOR-mediated hypothermia partly functions by reducing serotonin levels, dysregulating temperature stability.
In hypoxic high altitude environments the increased MAO may result in neurodegenerative effects. High altitude may also produce effects that are linked to increased MAO activity such as depression. This fact provides an evolutionary pressure to select for the MAOA ‘warrior-variant’ and other hypo-functioning MAO variants as these individuals would likely have increased survival rates. High altitude may also produce effects that are linked to increased MAO activity such as depression. Initially, high altitude seems to produce euphoria followed by depression. This may mean that initial effects of altitude are low activity of MAO but as MAO levels build up, the effect becomes problematic and strong.
It was very difficult to find information about MAOA and geographical origins and so I could not figure much out about altitude and MAOA prevalence. I did find this somewhat uncomfortable site that lists MAOA variant prevalence by ethnicity. It is notable that the 3 repeat variant of the MAOA gene exists at 60% rate in the Chinese population while on average, most humans have 4 or more repeats according to the link. China is known to have one of the highest average elevations compared to most other countries, averaging almost 2000 meters above sea level. Tibet is a highly elevated location in China where altitude based adaptions have occurred in populations inhabiting the area. It’s worth noting that if these adaptions involve MAO genes then these populations could experience psychoactive effects by relocating closer to sea level that differ from other populations.
Getting High (Or Low)
In the past I’ve claimed that reduced MAO activity induced by heat could account for the apparent psychedelic effects of sweat lodges. Another common sober tripping strategy is what is known as holotropic breathwork or essentially hyperventilation. If hypoxia causes MAO levels to increase due to a reduction in monoamine deamination then it would make sense for hyperoxia (increased oxygen levels) to downregulate MAO (this study mentions hyperoxia and MAO, but isn’t clear about downregulation). Many of the effects of hyperventilation are caused by vasoconstriction due to CO2 levels dropping, reducing blood flow to areas of the brain. This study suggests that acute hyperoxia increases MAO activity, meaning MAO is probably depleted, perhaps then resulting in a low MAO state. It is possible that lowered MAO activity occurs in holotropic breathwork, producing psychedelic-like highs. MAOA is not only known to break down serotonin, but also DMT. In a 2019 study, it was observed that DMT is released at monoamine levels during a cardiac arrest event. This suggests that DMT is endogenous for mammals and is induced in at least one situation naturally. This combined with the fact that heat and possibly hyperoxia both cause notable effects on MAO suggests this could account for psychedelic-like experiences from sweat lodges and holotropic breathwork. It may be perhaps the opposite effect for holotropic breathwork, an enabling of KOR activity by rapid metabolizing of serotonin. Alternatively, MAO activity may be initially enhanced, resulting in a slow depletion and eventually problems metabolizing monoamines and DMT. Since holotropic breathwork sessions are typically long (2 to 3 hours), it may be that some amount of time is needed to deplete MAO, potentially allowing DMT levels to begin building up.
Have you had experiences with holotropic breathwork? What about sweat lodges? Please tell me about your experiences below!