The Therapeutic Effects of Psychedelics: 2A or Not 2A? – Part 1

Psychedelics have taken the world by storm with research focused on treating neuropsychiatric disorders like depression and anxiety. While it is understood that psychedelics cause hallucinations and changes in perception through activation in the serotonin 2A receptor (5-HT_2AR) in humans and rodents,^1,2 the mechanisms behind their potential therapeutic effects still remain a mystery.

This article will dive into some of the therapeutic effects of psychedelics and how they are dependent on 5-HT_2AR activation, as reported through clinical and preclinical peer-reviewed articles. However, the studies highlighted here aren’t the only part of the story. Part 2 of this series will examine some of the evidence indicating that 5-HT_2AR may not be necessary for some of these potential therapeutic effects.

Effects on Neuroplasticity

Neuroplasticity refers to changes in brain cells that make connections and allow us to think, feel and do. It’s been shown that psychedelics promote growth in neurons in the frontal cortex, which is an area important for cognitive processing. In people diagnosed with depression, it is thought that a maladaptive plasticity occurs, resulting in the persistence of depressive symptoms.³ So, by promoting neuroplasticity, psychedelics may help treat depressive symptoms. Multiple groups have attempted to determine what mechanisms underlie this plasticity in rodent models. 

One study by Ly et al. 2018 highlights common methodology used to assess neuroplasticity following psychedelic treatment.⁴ In this study, they discovered that multiple psychedelic compounds (DOI*, DMT**, LSD***) induced neuroplasticity at the synaptic level. To further assess whether the 5-HT_2AR played any role in the plasticity-promoting effects of these compounds, they co-treated cells with ketanserin, a commonly used selective 5-HT_2AR antagonist. This completely blocked the ability of these compounds to promote neuroplasticity, suggesting overall that these effects are dependent on the 5-HT_2AR.

*2,5-dimethoxy-4-iodoamphetamine

**N,N-dimethyltryptamine

***Lysergic acid diethylamide

Anti-Depressant Effects

Several clinical and preclinical studies have demonstrated psychedelics’ ability to alleviate depressive symptoms, but few have focused on whether these effects are dependent on  5-HT_2AR activation.

A clinical study using healthy volunteers focused on how psilocybin can alter mood states using multiple tests to assess emotional processing, including a commonly used emotional facial recognition task.⁵ The authors report that psilocybin enhanced positive mood and reduced recognition of negative facial expressions. Psilocybin also increased goal-directed behavior toward positive cues. This suggests that psilocybin may be useful in increasing mood and motivation in humans. Furthermore, when given ketanserin the psilocybin-induced mood enhancement and decreased recognition of negative facial expression was blocked, suggesting these effects are dependent on the 5-HT_2AR. More work needs to be done to specifically identify mechanisms of psychedelics in models of depression.

Anxiolytic Effects 

Psychedelics are being tested for their ability to relieve anxiety, as well as treat post-traumatic stress disorder (PTSD). Preclinical studies have demonstrated that the anxiolytic effects of psychedelics may be dependent on 5-HT_2AR activation. 

There are many ways to model anxiety-like behaviors in rodent models. One way is the four-plate test, which allows researchers to assess how different anxiety medications can alleviate stress in animals who have received a foot shock. The shock is given to deter animals from normal exploration and the anxiolytic effect of the drug is measured by the rescue of exploratory behavior the day following shock. A 2006 study by Ripoll et al. compared the anxiolytic effects of DOI with an anxiety medication (valium) using this model.⁷ They found that DOI exerted anxiolytic effects that were similar to diazepam. These therapeutic effects were found to be blocked with a ketanserin, but not 5-HT2CR or 5-HT_2BR antagonists. These results suggest that the anti-anxiety effects of DOI are 5-HT_2AR dependent.⁸

Conclusion

There seems to be clear evidence across different groups that the 5-HT_2AR is necessary for psychedelics’ therapeutic effects. This article highlighted multiple studies focused on different measures of therapeutic effects of psychedelics, as it relates to depression and anxiety. Although these studies are convincing, there is a lot more work to be done to really figure out the mechanisms behind this interesting drug class.

The second article in this series will focus on the other side of the psychedelic coin: research showing these effects may be independent of 5-HT_2AR activation.

Alaina M. Jaster, BS

Alaina is a PhD student in pharmacology at Virginia Commonwealth University. Her research focuses on behavioral changes and circuitry of psychedelics involved in preclinical models of addiction and depression.

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