MAOIs, SSRIs, and Psychedelics

Three mechanisms of action for antidepressant drugs

Arthur Juliani
10 min readApr 13, 2023

Millions of people in the world suffer from depression and anxiety of various causes and manifestations [1]. Since the mid-20th century, biological interventions, typically in the form of pharmaceutical drugs, have been introduced to help treat these issues and improve people’s lives. A key target of these drugs is the neuromodulator systems within the brain and central nervous system. Neuromodulators are a subclass of neurotransmitters which act in a more global way within the nervous system. The neuromodulators that are typically targeted as part of therapeutic treatments include three names most of us are familiar with in one way or another: dopamine, serotonin, and norepinephrine. While almost all drugs approved to treat depression and anxiety disorders act on these neuromodulator systems, they do so in very different ways, with different levels of effectiveness and side-effects as a result. In this article, I will walk through the action of three classes of these drugs: MAOIs such as Marplan, reuptake inhibitors such as Lexapro, and psychedelic upregulators such as psilocybin. Understanding how drugs of the past and present work can provide valuable clues about how future drugs might be designed to work even better.

It is important to point out that none of these drugs are “cures” for the underlying mental health issues. Because of the global action of neuromodulators, some have been tempted to take a biologically reductive approach, and ascribe mental issues simply to a “chemical imbalance.” While there is some truth in it, it is at best an oversimplification, and at worst it sets up a counterproductive model of mental health. It is consistently the case that these drugs paired with psychotherapy or meaningful lifestyle changes are significantly more effective than the drugs alone [2]. This points to a complex interplay between mind and body. Or if you prefer a more physicalist interpretation, a complex interplay between the neuromodulator systems and the broader state of the entire nervous system.

The driving hypothesis behind the three drug interventions I discuss below is that increasing the efficiency of serotonin, dopamine, or norepinephrine signaling in the brain is correlated with decreases in experienced symptoms of anxiety and depression. While the specific nature of why these drugs work is a topic of serious debate, there is a large body of evidence to suggest that they do indeed help people, and they do indeed act on these systems [3]. While some have suggested that there is a weak link between serotonin levels and depression symptoms [4], it is clearly apparent in the acute phenomenological effects of drugs like MDMA or MDAI which cause the brain to release large amounts serotonin and other neuromodulators [5] that these molecules play a very large role in mood and stress levels. Users of MDMA for example describe the experience as extremely joyful and one of the most positive of their lives. On the reverse side, clinical evidence of individuals with damage to the serotonin or dopamine systems suggests sometimes extreme forms of depression or anhedonia [6]. Since the 1950s many drugs of different classes have been developed to attempt to improve the functioning of the serotonin and dopamine systems in individuals with mood disorders. Here I will discuss three high-level mechanisms of action which these drugs have acted through: Monoamine oxidase inhibition, reuptake inhibition, and system upregulation.

Monoamine Oxidase Inhibitors (MAOIs)

Some of the earliest antidepressants developed were MAOIs. This class of drug acts by blocking the action of natural monoamine oxidases (MAOs) in the body. MAOs are enzymes that break down monoamine molecules in the body. It so happens that three of the most common monoamines in the body are serotonin, dopamine, and norepinephrine. MAOs can be thought of as a kind of metabolic janitor, cleaning up molecules after they are no longer needed. As the name suggests, MAOIs prevent the MAOs from doing their job by inhibiting their function. The result is that the monoamines which would have been broken down are kept around longer, thus increasing their levels in the body, as well as the likelihood of their interacting with receptors in the brain. Given the prevalence of serotonin and dopamine, and their role in mood disorders, MAOIs were thought to function as antidepressants because of their ability to increase the amounts of these molecules in the brain [7].

Increased serotonin and dopamine in the brain results in increased signaling at the target neurons for these molecules, which can translate to a reduction in symptoms of anxiety and depression. The downside of using MAOIs however is that MAOs do much more than just regulate the amount of dopamine and serotonin in the brain. There are a number of other monoamines which MAOs typically break down, and by inhibiting the action of MAOs, the levels of these other molecules increase in the body as well. As a result, MAOIs typically induce a wide variety of side effects, including dangerous effects on the function of the heart and liver [8]. Because of this, they fell out of fashion once other more targeted drugs were developed.

Reuptake Inhibitors (RIs)

Reuptake inhibitors (RI) became increasingly popular in the late 20th century. Unlike MAOIs, these drugs are able to more specifically target the action of a given neuromodulator system, such as serotonin. In fact, for the past thirty years selective serotonin reuptake inhibitors (SSRIs) have been the first-line treatment option for anxiety and depressive disorders. In addition to SSRIs there are also equivalent drugs which act on the dopamine (SDRIs) and norepinephrine (SNRIs) systems which have also been developed and marketed as treatments for mood disorders. In each case, these drugs act to increase the amount of a target neuromodulator in the brain, but in a meaningfully different way than MAOIs. Instead of stopping the molecule from being broken down and recycled, reuptake inhibitors, as their name suggests, prevents the molecules from being taken back up into the neuron that released them and be recycled.

The benefit of reuptake inhibitors is that they are capable of being much more targeted, since the signature of each monoamine transporter is different. The latest SSRIs for example are able to target very selectively just the serotonin transporter, meaning that when someone takes an SSRI, they are increasing just the levels of serotonin in the nervous system, and not also dopamine or another molecule [9]. Compared to MAOIs which are less targeted, this results in significantly fewer side-effects. Given the widespread role of serotonin, dopamine, and norepinephrine in the nervous system however, the side-effect profile is not completely eliminated. Serotonin signaling for example is used extensively in the digestive system, which has a complex network of around five hundred million neurons. As such, SSRIs can have side effects related to digestion.

Neuromodulator Signaling

There is another issue with RIs and MAOIs which has less to do with their side-effect profile, and more to do with their actual effectiveness as treatments for anxiety and depression. The role of neurotransmitters and neuromodulators is to communicate information between cells in the nervous system. This happens locally in the case of neurotransmitters, and more diffusely in the case of neuromodulators. In both cases, a signal is being sent from one group of cells to another, and the quality of this signal can vary in a number of ways. Imagine trying to tune in to a radio broadcast. What comes out of the speakers of a radio receiver varies along two dimensions. It can be either clear, noisy, or somewhere in between. Likewise, it can be quiet, loud, or or somewhere inbetween. Ideally, we would like the sound coming out of the speaker to be crystal clear, but neither too quiet nor too loud. Because they simply increase the amount of the neuromodulator in the system, we can think of the action of both MAOIs and RIs as increasing the volume, rather than the clarity of the signal. When we increase the volume, the overall effect might indeed be to enable the signal coming across to be more interpretable, but only up to a certain point, and only if there isn’t too much noise. If the signal is very noisy, then no amount of increased volume will help to make it easier to decipher. What is needed instead is either a more powerful signal, or a more sophisticated antenna which is better able to pick up that signal.

Increasing the quality of the signal rather than the volume is a useful intuition for understanding the action of a third class of antidepressant drugs which act by upregulating neuromodulator systems. To better understand upregulation, we can consider its opposite: downregulation. A classic example of downregulation is the developed tolerance to opioids, both endogenous and exogenous. The opioid system in the brain consists of a network of neurons which release endogenous opioids and neurons with receptors which opioids bind to. The total number of receptors a cell has varies over time based on a kind of equilibrium seeking process. If there is too much signaling happening, then the receptors become downregulated to account for this. If there is too little, then they can become upregulated. In the case of opioid tolerance, the opioid receptors have become significantly downregulated, meaning that more and more of the drug is required to transmit the same signal and elicit the same effect [10]. In the case of opioids this manifests as an increased sensitivity to pain, and a reduced capacity to feel pleasure. Now imagine a drug which could do the opposite, and upregulate the opioid system instead. Such a drug would not only reverse opioid tolerance, but also to return the nervous system to a state where the endogenous opioid signaling was sufficient to prevent pain responses. Perhaps surprisingly, such drugs actually exist.

Psychedelics as Upregulators

A class of drugs which seem capable of this kind of neuromodulator upregulation are psychedelics. LSD, Psilocybin, and DMT for example have all been demonstrated to possess the ability to increase dendritic growth in cortical neurons after only a single dose [11]. What this means practically is that the neurons in the cortex grow new dendrites, and these dendrites are covered with receptors for serotonin among other molecules. This new neuronal growth means that the serotonin system is now effectively upregulated, and the signal to noise ratio is functionally improved. It is improved not by turning up the volume (as with MAOIs or SSRIs), but by making the receiver significantly more sensitive to the signal that does exist. The practical result of this is that after a single dose of psilocybin paired with psychotherapy, individuals in clinical trials exhibit significantly reduced symptoms associated with major depressive disorders [12].

What is especially promising is that these psychedelic treatments need to only take place once or twice in order to induce changes which last weeks to months. This is because the upregulation that takes place is a lasting change in the structure of the nervous system itself. In contrast, MAOIs and RIs often need to be taken on a continuous daily basis for their effects to persist, since they are artificially and temporarily increasing the levels of the neuromodulators in the brain. It is also the case that the brain can adapt to MAOIs and SSRIs over time, resulting in antidepressant discontinuation syndrome, which can manifest as increased symptoms of anxiety or depression after stopping long term treatment with an SSRI [13].

Beyond the serotonin system, there are promising psychedelic drugs which act to upregulate other important neuromodulatory systems. One such particularly promising drug is Ibogaine, which may act to upregulate the opioid system after a single full dose in a similar way that DMT or other psychedelics work on the serotonin system [14]. Practically, this means that many individuals who are dealing with opioid addiction problems report an immediate remission of withdrawal systems and a greatly reduced desire to consume opioids after a single full dose of Ibogaine. Like psilocybin, these effects likewise seem to last for months after administration. Compared with classic psychedelics, which are safe to consume, Ibogaine has some dangers associated with it. Because of this there have been a number of different novel drugs created based on Ibogaine which are currently undergoing clinical trials. These new drugs are meant to replicate the opioid upregulating effects of Ibogaine without the negative potentially life threatening side effects.

Are Psychedelics the Future of Antidepressants?

Given their apparent efficacy, why then are psychedelic upregulators not the standard of care across the world for addiction, depression, and anxiety disorders? All of these substances have been known about contemporaneously with the development of MAOIs, and even before the development of most RIs. The likely reason is that unlike MAOIs or RIs, psychedelics cause significant changes in conscious phenomenal experience in the hours after administration. This is what led to their appeal and spread in the 1950s and 1960s counterculture, and is also unfortunately what led to their prohibition in the 70s onwards as part of the war on drugs. Only now, over half a century later are we finally in a position culturally to be able to objectively evaluate the mechanisms of action and effects of these substances in humans. What is being found is more or less what researchers were beginning to discover over half a century ago [15], that these drugs are safe and effective in a way that many other drugs to treat mood disorders are not. With the FDA poised to likely approve MDMA and psilocybin for use in the treatment of PTSD and major depressive disorder later this year, we can perhaps finally begin to make up for 50 years of lost time.

As promising as the potential use of currently known psychedelics is, A greater potential exists to develop novel compounds which may work even better. The current SSRIs for example are much better than the earliest ones in terms of efficacy and side-effect profile, we can likely expect the same to be the case for psychedelics in the coming decades. One prominent current line of research by pharmaceutical companies is to develop so-called non-hallucinogenic psychedelics, which have none of the strong acute phenomenological effects of a classical psychedelic but still serve to upregulate the relevant neuromodulator systems within the brain and produce an antidepressant effect. While promising, this line of work is not without controversy, as some prominent researchers believe that the experiential aspect is essential to the therapeutic effect [16]. In a future article I will take a look at this interesting new line of research, and the arguments for and against such a psychedelic without the psychedelia.

Thank you for reading!



Arthur Juliani

Interested in artificial intelligence, neuroscience, philosophy, psychedelics, and meditation.