Psychedelic Drugs As Inspiration for Safer Antidepressants
Depression is one of the most common mental health illnesses in America. It is characterized by feelings of low self-esteem, unhealthy alterations in sleep or eating patterns, fatigue, difficulty concentrating, etc. According to the National Institute of Mental Health, approximately 8.4% of the U.S. population experienced at least one major depressive episode in 2020.
Current treatment plans include talk-based therapy or prescribed antidepressants, such as serotonin-reuptake inhibitors (SSRIs), which function by increasing serotonin levels in the brain—a hormone that positively regulates emotions. Although SSRIs are adequately effective, they can have undesirable side effects. Even worse, people with depression are statistically more likely to rely on substance abuse instead for instant gratification. Therefore, researchers are constantly trying to find more effective ways to regulate serotonin levels by targeting serotonin receptors--proteins that allow for cellular communication.
Consequently, Dr. Bryan L. Roth and other members of various research teams attempted to create a drug that would target 5-HT2AR, one of many serotonin receptors that have been researched in the past for treating various mental health conditions. They figured that if individuals used illegal hallucinatory drugs to improve their depression symptoms, perhaps they can make a healthier medication that activated 5-HT2AR in a similar manner to ketamine or psilocybin (also known as shrooms), but without the illegal “trip” effect, so that it would be a useful antidepressant!
Current treatment plans include talk-based therapy or prescribed antidepressants, such as serotonin-reuptake inhibitors (SSRIs), which function by increasing serotonin levels in the brain—a hormone that positively regulates emotions. Although SSRIs are adequately effective, they can have undesirable side effects. Even worse, people with depression are statistically more likely to rely on substance abuse instead for instant gratification. Therefore, researchers are constantly trying to find more effective ways to regulate serotonin levels by targeting serotonin receptors--proteins that allow for cellular communication.
Consequently, Dr. Bryan L. Roth and other members of various research teams attempted to create a drug that would target 5-HT2AR, one of many serotonin receptors that have been researched in the past for treating various mental health conditions. They figured that if individuals used illegal hallucinatory drugs to improve their depression symptoms, perhaps they can make a healthier medication that activated 5-HT2AR in a similar manner to ketamine or psilocybin (also known as shrooms), but without the illegal “trip” effect, so that it would be a useful antidepressant!
Image Source: Tumisu
In the first stage of their research via a process known as docking, they scanned millions of known compounds in a pharmacy database in order to determine which chemicals could possibly interact with 5-HT2AR. The researchers narrowed down their search to two molecules known as R-(69) and R-(70) and visualized what they look like when binding to 5-HT2AR in comparison to LSD. As desired, the compounds activated the serotonin receptor but did not interact in the same way as LSD to produce hallucinogenic effects.
Finally, after the visualizations confirmed useful drug templates, they decided to test the effects of R-(69) and R-(70) for antidepressant activity in mice. In these experiments, the mice are repeatedly forced into stressful situations until they “give up” trying to escape the circumstance at hand, simulating the psychological helplessness experienced with depression. They also created genetically engineered mice known as VMAT2HET to have decreased motor abilities and increased stress hormone levels to represent the depressed group. Using these tests, the mobility of normal mice, VMAT2HET mice, and VMAT2HET mice treated with R-(69) and R-(70) drugs were measured and compared at 30-minute and 24-hour intervals. They found that the depressed mice, when treated with R-(69) or R-(70) had the same mobility levels as normal mice just 24 hours later! Since the mobility of depressed mice improved after treatment, this means that the drugs demonstrate antidepressant potential. Further antidepressant experiments were conducted with varying concentrations of R-(70), ketamine, and psilocybin, in which mice were subject to consistent foot shocks to induce psychological stress. Then, their sucrose preferences, escape behaviors, and anxiety symptoms were measured before and after treatment. The sucrose diets restabilized to normal and mobility levels improved in the R-(70) treated mice to similar levels as the hallucinogen treated mice, providing further evidence for antidepressant activity.
In conclusion, the two compounds that these scientists found via virtual scanning not only lacked the undesirable hallucinogenic effects of illegal drugs, such as psilocybin and ketamine, but they also exhibited antidepressant qualities in mice. Although clinical trials on humans still need to be completed, these results excitingly present the possibility of treating depression with medication.
Finally, after the visualizations confirmed useful drug templates, they decided to test the effects of R-(69) and R-(70) for antidepressant activity in mice. In these experiments, the mice are repeatedly forced into stressful situations until they “give up” trying to escape the circumstance at hand, simulating the psychological helplessness experienced with depression. They also created genetically engineered mice known as VMAT2HET to have decreased motor abilities and increased stress hormone levels to represent the depressed group. Using these tests, the mobility of normal mice, VMAT2HET mice, and VMAT2HET mice treated with R-(69) and R-(70) drugs were measured and compared at 30-minute and 24-hour intervals. They found that the depressed mice, when treated with R-(69) or R-(70) had the same mobility levels as normal mice just 24 hours later! Since the mobility of depressed mice improved after treatment, this means that the drugs demonstrate antidepressant potential. Further antidepressant experiments were conducted with varying concentrations of R-(70), ketamine, and psilocybin, in which mice were subject to consistent foot shocks to induce psychological stress. Then, their sucrose preferences, escape behaviors, and anxiety symptoms were measured before and after treatment. The sucrose diets restabilized to normal and mobility levels improved in the R-(70) treated mice to similar levels as the hallucinogen treated mice, providing further evidence for antidepressant activity.
In conclusion, the two compounds that these scientists found via virtual scanning not only lacked the undesirable hallucinogenic effects of illegal drugs, such as psilocybin and ketamine, but they also exhibited antidepressant qualities in mice. Although clinical trials on humans still need to be completed, these results excitingly present the possibility of treating depression with medication.
Featured Image Source: HASTYWORDS
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