The History of Antidepressants: From Plants to Prozac

I first came across the study of depression as a biomedical science student. We discussed mental illness as a consequence or a side effect of the biological diseases that we were attempting to mitigate. I learned that people with chronic illnesses, such as rheumatoid arthritis, often feel depressed because they’re in pain. Any mental symptoms were framed as side effects that doctors shouldn’t be overly concerned with. “That’s for their psychiatrist to deal with,” I was told. The idea that depression could be the result of physical pain makes sense, but it didn’t seem like the complete picture.


That year, I also sat in on the first-year psychology lectures. I wasn’t a psychology student at the time, but I was excited to learn more about the brain and my first neuroscience lecture was months away.


Hearing psychologists talk about how the mind worked was fascinating to me, but I was met with a general unenthusiasm for the biological side of things. “Don’t worry too much if you don’t understand neurobiology. It doesn’t come up too often, unless you really want to focus on neuroscience.”


Here were two scientists, both working towards the goal of improving their patients' lives, both unwilling to operate within the other’s framework and learn from their knowledge. This is what inspired me to study mental health from both perspectives. Now I study cognitive and clinical neuroscience at the University of Westminster in central London. I’m also an incoming placement student at the Institute of Psychology, Psychiatry, and Neuroscience.


Like many others, I was taught the serotonin hypothesis, which is the idea that depression is a result of there being too little serotonin in the brain. Serotonin is a chemical called a neurotransmitter that helps cells in the brain communicate with each other. It regulates processes such as sleep, appetite, and emotion. Antidepressant medication, such as Selective-Serotonin Reuptake-Inhibitors (SSRIs) and tricyclic antidepressants, are thought to work by increasing the amount of serotonin available to cells in the brain to address the neurotransmitter deficit. The serotonin hypothesis is mainly supported by the fact that some people who take antidepressant medication can feel better after a few weeks, suggesting that the medicine gradually increased the serotonin available to the brain.


A Brief History of Antidepressants: The Golden Age of Prozac



I was surprised to find out the first modern antidepressants were not intended to be antidepressants at all, but a tuberculosis treatment.


The breakthrough took place at Seaview Hospital, opened to tackle tuberculosis. When patients took Iproniazid they reported feeling happier, more social, and less tired. Not only did their tuberculosis improve, but their outlook on life became brighter. Patients who had lost their will to live were better again. For the first time, people left Seaview Hospital alive and happy, seemingly cured of both their tuberculosis and the accompanying depression. These findings prompted other pharmaceutical companies to explore precisely why iproniazid had these effects with the goal of developing similar drugs to be used in the treatment of mental illness.


Iproniazid suppresses a chemical called monoamine oxidase, which breaks down neurotransmitters (including serotonin) in the brain. Because iproniazid blocks this chemical, neurotransmitters are broken down more slowly, increasing the amount of serotonin and other neurotransmitters available in the brain. Thus, the mechanism of action of iproniazid should ease depression, and for the patients at Seaview Hospital, it did. With the success of iproniazid, more drugs were developed to inhibit the breakdown of monoamine oxidase enzymes. These were the first pharmaceutical antidepressants, known as MAO inhibitors, which are still in use today (although they’re prescribed less often than SSRIs due to concerns about side effects).



What came next remains one of the most common treatments for depression to this day, SSRIs. The development of SSRIs was based on the same idea: that increasing the amount of serotonin in the brain would decrease symptoms of depression.


The first and probably most well-known SSRI is Prozac, or fluoxetine. Instead of suppressing the breakdown of serotonin, Prozac stops cells from reabsorbing (or reputaking) serotonin, making more serotonin available to the brain. Since the release of Prozac in 1988, many more SSRIs have been invented, but they all work in a similar way.


However, not everyone who takes antidepressants feels better. People with mild depression tend to respond less than people with severe depression and some people don’t improve at all. Approximately one-third of people with major depressive disorder experience treatment resistance, meaning that they’ve tried antidepressants (sometimes more than one) and their symptoms didn’t improve. This suggests that serotonin is a piece of a much bigger puzzle. So, it’s especially important to research treatments that work differently in the hope that they’ll work better in treatment-resistant patients.


So far, I’ve focused on the modern history of depression. But the use of mind-altering plants in the treatment of depression long outdates the use of MAO inhibitors or SSRIs. Indigenous people from all around the world have used psychedelic plants and fungi in healing ceremonies for centuries. Native cultures in North and Central America used a psychedelic cactus called peyote in traditional ceremonies. Archaeological evidence from carbon dating suggests that people consumed these psychedelic cacti over 5,000 years ago in what is now part of Texas and Mexico. However, the earliest evidence of psychedelic plants being used specifically to heal comes from South America.


Ayahuasca for Depression: A three-pronged approach


Ayahuasca refers to the combination of two Amazonian plants: Banisteriopsis caapi, a vine, and Psychotria viridis, a shrub from the same family as coffee. Traditionally, the leaves of Psychotria viridis are combined with Banisteriopsis caapi and brewed into tea. A recent study suggests that ayahuasca may be able to treat symptoms of depression with a three-pronged approach: increasing serotonin, temporarily blocking the enzyme that breaks down serotonin, and reducing inflammatory activity.


Psychotria viridis contains dimethyltryptamine, known as DMT, which acts on serotonin receptors in the brain, causing hallucinations, time distortion, and out-of-body experiences. DMT is the chemical responsible for the spiritual experience associated with ayahuasca. A very small amount of DMT is found naturally in the brain, but it’s not nearly enough to produce a noticeable effect. When consumed on its own, DMT is quickly broken down by the same enzymes I mentioned earlier, the chemical that is suppressed by MAO inhibitors. In the ayahuasca tea, these enzymes are inhibited by chemicals in Banisteriopsis caapi, so the DMT from Psychotria viridis takes longer to be broken down, prolonging the psychedelic experience to hours instead of minutes.


DMT can also affect sigma-1 receptors, which are responsible for regulating the inflammatory response. Inflammation is the body’s way of sounding the alarm by releasing chemicals called cytokines. Cytokines send a signal to our immune system to attack the invader. In return, the immune system releases more cytokines to send for backup. Sometimes, our own cells can get caught in the crossfire. When this inflammation occurs in the brain, it causes sickness behaviour. We’ve all experienced sickness behaviour, the brain fog and tiredness that comes after a vaccination or at the beginning of a cold.


Sickness behaviour may have evolved to keep us away from members of our family when we’re sick and to help our body conserve energy by making us want to curl up in bed. Some of the symptoms of depression resemble many sickness behaviours, such as social withdrawal, fatigue, and lack of appetite or interest in activities. This has led many scientists to hypothesize that some depression symptoms are the result of increased inflammation.


Psychedelics are complicated chemicals that science doesn’t fully understand yet. These are likely not the only effects that ayahuasca has. While it is possible that some of the antidepressant effects of ayahuasca are attributable to its anti-inflammatory effect, scientists aren’t sure what sigma-1 receptors actually do. It might have something to do with protecting brain cells from dying of oxygen deprivation, but for now, the role of sigma-1 receptors remains unclear.


What comes next?


Psychedelic therapy could be the beginning of a brave new world in psychiatry, but it is not without its flaws. Psychedelics are decriminalized in some parts of the world, particularly for religious use, but they remain illegal in the UK. This prompts many patients seeking psychedelic therapy to travel to countries where psychedelics are legal for medicinal or spiritual purposes. With the increasing popularity of ayahuasca ceremonies comes increased dangers. Ayahuasca tourism can be risky because not every company offering these services is safe or legitimate. Furthermore, there is a great deal of debate about cultural appropriation.


It’s also important to note that these trials are imperfect and often suffer from methodological issues due to the nature of the experiment. Clinical trials have to prove that their new treatment is more effective than a placebo, or a sugar pill, which is difficult to do with psychedelic drugs because the effects are so intense and noticeable, so most participants can tell if they were given the placebo. This makes the results less meaningful because the participant’s knowledge of which drug they got could impact their experience. Some studies try to control for this by only recruiting participants who have never consumed a psychedelic substance before, but drug use is underreported in scientific research due to the stigma and illegality surrounding many of these chemicals. More trials with larger sample sizes are needed to establish psychedelics as an effective treatment for depression.


As with any treatment, safety is a serious consideration. Not everyone is going to benefit from taking psychedelic drugs, even in a therapeutic, clinical setting. The risk of psychosis, particularly in those with a family history of schizophrenia, is not something to be taken lightly. Adverse effects can occur during psychedelic ceremonies, just like with any intervention. These substances have a great potential to heal, but no one treatment is going to work for everyone. Psychedelics must not be thought of as a one-size-fits-all approach to psychiatric disorders.


Depression is a multifaceted, complex disease that likely has multiple causes and mechanisms that differ on an individual level. Each case of depression is unique and our treatments should reflect that. It’s unrealistic to expect any one kind of depression treatment to work for every single person with depression. By better understanding the various mechanisms that underlie depression and other mental illnesses, we can develop treatments that work where our current ones don’t. We have to do better than our current standard of care and develop a variety of treatments to help as many people as possible, not just those who respond to antidepressants. Depression is the single leading cause of disability globally; we have to do better than a one-size-fits-all approach.



Header Image Source: The Conversation