Treating Depression with Drugs

By: Helen Beilinson

[I would like to note that Because Science does not endorse the recreational use of drugs, psychedelic or otherwise. Please see your doctor before taking any new medications or changing your current regiment. All of the drugs mentioned below are illegal in the United States and were tested in experimental settings to ensure the safety of the volunteers.]

Refurbishing drugs fashioned for one therapy to treat another illness has been in practice for years. The anti-nausea drug, Thalidomide, was found to be efficacious in treating leprosy and multiple myeloma, and many therapies originally designed to fight tumors are currently being studied for efficacy against autoimmunity. Although many of these studies go under the media radar, an ever-growing group of studies of reusing drugs has raised a fair amount of controversy because the drugs that are being recycled are illegal, psychedelic drugs. The drugs they explore are felonious and their physiological and psychological effects are highly understudied. That being said, new effective and widely used treatments for depression have not been developed since the 1970’s and these studies hold important information in treating this disorder.

Last week, a group at the Imperial College London published a study in The Lancet Psychiatry exploring the effects psilocybin on depression. Psilocybin is the active, hallucinogenic molecule found in many toadstools, including magic mushrooms. Psilocybin is an alkaloid, a class of nitrogen-containing organic compounds found predominantly in plants. It also also includes morphine, a pain-reliving drug, and atropine, the poison found in deadly nightshade, but active as a muscle relaxant to dilate pupils and increase heart rate in small doses. Psilocybin is metabolized by the body to form psilocybin, which stimulates the serotonin receptor Serotonin works in many ways in many places in the body. It is believed to be critical in mood regulation, appetite, and sleep. Serotonin is a neurotransmitter, which is a molecule used by neurons to communicate with each other, relaying information from one end of the body to another. Many current available antidepressants, and other mood related disorders, act to increase the amount of serotonin, which subsequently increases its consequential signaling, lifting mood. Psilocybin acts kind of like serotonin in that it triggers the same receptor as serotonin, which stimulates the same chemical signaling that serotonin does. The biochemistry of psilocybin provides insight into its strong potential in treating depression.

 Although there is evidence that magic mushrooms have been used for religious, spiritual, and recreational purposes since 9000 BCE, they, as well as other psychedelics, only entered the academic and medical field in the late 1950’s. Backlash against the hippie culture of the 60’s and 70’s, however, halted research of hallucinogens. The last decade has brought back studies of these drugs and their effects on various human ailments, triggering molecular studies to elucidate the molecules responsible for hallucinations and changes in mood. 

In the aforementioned study, twelve clinically depressed patients, who were unresponsive to other treatments, were given two doses of psilocybin. The first was a low dose and the second, administered a week later, was higher dose. The patients were then questioned for the next three months and their mean depression severity scores were noted. Before treatment, all patients had scores reflecting severe depression. After the second dose of psilocybin, scores, on average, dropped to scores of mild depression and staying in that range three months after the treatments. Five of the twelve patients were in complete remission after three months, with all patients seeing a notable improvement. The study also noted that all patients experience side effects (including anxiety, confusion, and headaches), which, in all cases were mild and most symptoms passed within two hours of treatment.

 These results are very exciting for the field, as such success in an initial study, particularly for psychiatric disorders, is rare. Interestingly, this isn’t the first time psychedelic drugs have been used as a basis for depression therapy.

In March of 2015, researchers from Brazil published the first clinical trial exploring the potential therapeutic benefit of ayahuasca. Ayahuasca is a botanical hallucinogen used by indigenous groups of the Amazon for ritual and medicinal purposes. The ayahuasca beverage contains two ingredients. The first is a monoamine oxidase inhibitor (MAOI), which inhibits the breakdown of specific neurotransmittors, molecules used by neurons to communicate with each other, such that their effectiveness is increased. The second is dimethyltryptamine, or DMT, a psychedelic compound. Traditionally, the ayahuascan MAOI is from the bark of Banisteriopsis caapi, a jungle vine, and the DMT is from Psychotria viridis, a shrub common in the northwest of the Amazon. These plants are boiled together and concentrated over several hours. Interestingly, other MAOIs have been used for years in treating depression and Parkinson’s disease. For example, many MAOIs prevent serotonin degradation, increasing its signaling capacity. However, available MAOIs are not routinely used as they have a significant risk in interacting with over-the-counter medications and other prescription medicines and require strict diet restrictions, as they can cause high blood pressure.

In the study, six patient volunteers diagnosed with recurrent major depression were given ayahuasca prepared by members of the Santo Daime community in Brazil. Patients’ moods were analyzed for two weeks prior to drug administration, as well as at multiple intervals after drug administration. Three weeks after drinking the ayahuasca, almost all patients had reduced depressive symptoms. Not all patients saw dramatic decreases and throughout the course of the three weeks, and in some, moods did fluctuate from above the initial scores to below the scores seen at the conclusion of the three weeks. Although some patients experienced vomiting that is known to occur after consumption of ayahuasca, no other adverse side effects were noted. It is important to note that the sample size used in this study was very small, but the results are interesting.

 Magic mushrooms and ayahuasca have only recently entered the medical sphere as potential depression treatments. Ketamine is an anesthetic, used to treat chronic pain and has the potential for addiction and abuse. It also can cause severe confusion or hallucinations. It has long been known that ketamine, a club drug commonly referred to as “special K,” acts as an antidepressant at a surprisingly rapid rate, in comparison to other antidepression treatments. Unlike the current available treatments that require several weeks or months that take effect, ketamine has been found to suppress depressive symptoms after a single dose, occurring within hours of drug administration and lasting about a week. It is not approved by the FDA as a treatment, however, due to its side effects, which include blurred or double vision, jerky movements, including muscle tremors, and vomiting, in addition to its addictiveness. The side effects of ketamine are dangerous, but its beneficial actions have prompted it to be used as a last resort in patients with depression that have not responded to other treatments; it has been used to treat suicidal patients in emergency rooms, and there are ketamine clinics that have begun to appear to administer the drug off-label.

As most molecules, ketamine, scientifically known as N-methyl-D-aspartate receptor antagonist (NMDA) (R,S)-ketamine, is metabolized, or broken down into multiple components, by various enzymes once it has been digested. The components into which ketamine is broken down have different effects on the organism, which partially explains the broad set of reactions one can experience after ketamine consumption. NMDA receptors are found on nerve cells and signaling through these receptors is important for synaptic plasticity, which is the ability for synapses (the structure on a neuron that releases and captures neurotransmitters (electrical or chemicals signals, such as serotonin) allowing for neurons to communicate) to get stronger or weaker, changing the speed at which neurons can communicate. NMDA receptor agonists, such as ketamine, block the signaling through these receptors. This allows for anesthetic effects (as pain is felt through neurons), as well as hallucinogenic effects, due to signaling that is offset from baseline. As the signaling balance is complex, and ketamine can be broken down into so many different components, a study published early this month attempted to elucidate whether there were distinct chemicals in ketamine involved in depression suppression and side effect induction. This study was done to understand whether the molecules involved in the former could be isolated for depression treatment without the negative side effects.

 This paper showed that one of the molecules into which ketamine is degraded, specifically (2S,6S;2R,6R)-hydroxynorketamine (HNK) is responsible for the drug’s antidepressant effects. After doing multiple biochemical assays to study the degradation patterns of ketamine, the group assayed the physical, psychological, and behavioral effects of ketamine treatment as a whole versus treatment with its degraded forms, such as HNK, in mice. They found that although ketamine treatment suppressed depressive symptoms, it additionally induced motor incoordination, hyperactive locomotive activity, and other similar side effects that are seen in humans. In comparison, HNK treatment alone similarly suppressed depressive symptoms, but it did not induce the noted side effects.

This study was conducted in mice, meaning it still needs to undergo multiple rounds of testing before it reaches the potential for human treatment. However, the importance of the study lies in that the antidepression molecule of ketamine was separated from the whole of the drug. This molecule, in portions of the study I did not speak to, elucidated nuances of neuronal signaling that were previously unknown, uncovering potential treatment targets of depression. The study of recreational drugs, particularly with human volunteers, is, indeed, controversial. However, research is a step-wise progression. In order to unravel the mechanism by which these drugs affect mood, and subsequently how we can take advantage of these pathways pharmacologically to treat depression, research must start at the top, proving that these drugs truly have a true effect on mood. From there, detailed biochemical work can be done to chemically tease apart the drugs, eventually leading to the discovery of particular molecules that have beneficially effects without negative side effects, as was done with ketamine. From understanding how, biochemically, recreational drugs effect mood, both in positive and negative ways, scientists can develop novel drugs that target the former without inducing the latter.