LSD-like, non-psychedelic compounds can have antidepressant effects

  • Previous studies have shown that psychedelic drugs such as LSD (acid) and psilocybin (magic mushrooms) can potentially treat depression, but in some cases can cause disturbing hallucinations.
  • Researchers recently developed two new compounds that target the same subtype of serotonin receptors as LSD and psilocybin, but do not produce hallucinations.
  • Like psychedelics, these new compounds showed antidepressant and anxiolytic effects in animal models at lower doses than Prozac.
  • These compounds hold promise for the development of potential treatments for depression and other mental disorders.

In a recent study published in Natureresearchers identified two compounds that activate the same receptor in the brain as lysergic acid diethylamide (LSD) but do not produce hallucinogenic effects.

Experiments with mouse models showed that psychedelic-like substances reduced symptoms of depression and anxiety, suggesting that the compounds or their derivatives could have potential for treating mental disorders.

Dr. David Olson, Ph.D., a professor in the Department of Biochemistry and Molecular Medicine at the University of California, Davis, who is not involved in the study, said Medical News Today:

“This is the third independent group to develop a non-hallucinogenic antidepressant inspired by psychedelics, which is good confirmation that this approach has potential.[..]While psychedelics have the potential to treat disorders such as depression, their hallucinogenic effects require clinic administration, which drastically increases the cost and complexity of treatment. Non-hallucinogenic compounds that produce psychedelic-like antidepressant effects could potentially be administered at home, thereby reducing costs and increasing patient access.”

In this study, the researchers used a computational approach to identify compounds that may have therapeutic effects similar to psychedelic drugs.

Conventional approaches to drug discovery use high-throughput assays that allow researchers to screen a few million compounds simultaneously to identify candidates that may have the desired biological activity. However, this approach can be time-consuming and expensive.

Moreover, due to the focus on efficiency, conventional approaches have generally focused on compounds synthesized using a small number of well-characterized reactions and readily available building blocks. As a result, the number of molecules available for screening using the conventional approach is relatively small compared to the larger pool of compounds that could potentially be synthesized.

Researchers have used computational methods to construct virtual libraries and identify drug candidates to address these shortcomings. These virtual libraries contain not only compounds that have already been synthesized, but also several millions of virtual compounds that could be synthesized.

Computational methods can simulate how the virtual library compounds interact with the biological target and identify drug candidates. This virtual screening process involves calculating the docking scores, which estimate the strength of the interaction between the small molecule and the target protein.

Calculation of docking scores is challenging due to the complex nature of chemical interactions between the three-dimensional structure of the target protein and the small molecule candidate. Furthermore, the candidate molecules are often flexible and can assume multiple conformations.

As a result, after a few candidate compounds are chemically synthesized, they require testing and optimization.

Almost a third of people with depression do not answer to current treatments, and there is a need for safe and effective drugs for treatment-resistant depression.

New evidence suggests that psychedelics are a promising therapeutic option for difficult-to-treat depression.

The antidepressant and anxiolytic effects of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin have been attributed to their ability to activate the serotonin 5-HT2A receptors on the surface of brain cells.

However, psychedelics can produce hallucinogenic side effects by activating the 5-HT2A receptor.

The activation of the 5-HT2A receptor can activate two different signaling pathways inside the cells, which involve β-arrestin-2 and G.Q protein.

Previous studies have shown that the hallucinogenic effects of LSD are largely mediated by the signaling pathway involving the β-arrestin-2 protein. Thus, it is possible that compounds that activate the 5-HT2A receptor without activating the β-arrestin-2 pathway may help treat depression without causing unwanted hallucinogenic side effects.

Such compounds may offer several advantages over psychedelic drugs for the treatment of depression and other psychiatric disorders. Dr. David A. Merrill, Ph.D., psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center at Providence Saint John’s Health Center in Santa Monica, said:

“Non-psychedelic antidepressants also do not require the intensive staffing, space, and security requirements necessary for classic psychedelics. It is easy to imagine non-hallucinogenic psychedelic-like drugs that retain their antidepressant and anxiolytic properties, but which do not have psychedelic properties could be given to patients at home and self-administer or even delivered to the patient’s home without the need to travel in for the longer office-based sessions used with current psychedelic therapies.”

In the current study, the researchers were interested in compounds that share a molecular motif or scaffold called tetrahydropyridine (TPH).

The THP motif is found in several drugs, including LSD and the cancer drugs vinblastine and vincristine. The chemical structure of THP makes molecules containing this motif suitable for binding to the 5-HT2A receptor.

Although current virtual libraries include many molecules, certain compounds, such as those containing the tetrahydropyridine motif, are underrepresented in these libraries. The underrepresentation of tetrahydropyridines is due to the challenges associated with synthesizing derivatives containing this structural motif.

In their previous work, the study’s authors had come up with new chemical reactions for synthesizing THP derivatives using commercially available building blocks. Building on their previous work, the researchers created a virtual library consisting of 75 million low molecular weight THP derivatives.

The researchers first screened the virtual library for THP derivatives that could bind a model of the 5-HT2A receptor. They initially synthesized 17 candidates with high docking scores and tested the ability of these compounds to activate the 5-HT2A receptor in laboratory-grown cells.

After testing these compounds, the researchers found four molecules that weakly activated the 5-HT2A receptor. Using computational methods and further testing, they optimized the design of these compounds to derive two compounds that could strongly bind the 5-HT2A receptor.

In subsequent experiments, the researchers examined the behavioral effects of these compounds in mouse models. Psychedelic drugs such as LSD produce hallucinogenic symptoms such as head twitching and increased locomotor activity in mice.

Unlike LSD, the two new compounds produced low levels of head twitches and did not result in excessive movement. These compounds also did not have rewarding properties commonly associated with drugs of abuse.

Significantly, these new compounds produced antidepressant and anxiolytic effects in mouse models.

These compounds reduced depression-like symptoms at 20 times lower doses than the antidepressant fluoxetine (Prozac). Furthermore, the effects of these compounds on depressive symptoms were long-lasting, with a single dose producing antidepressant effects lasting 14 days.

Jianjun Cheng, Ph.D., a professor at ShanghaiTech University specializing in medicinal chemistry, not involved in the study, said MNT:

“This study is an excellent example of how a combination of new chemistry and ultra-large screening leads to new biologically active molecules. The game-changing trend of psychedelics as new therapeutic agents for mental disorders such as depression and anxiety is gaining a lot of attention.”

“Several new chemical entities (NCEs) with the same overall 5-HT2A agonist activity but distinct transduction efficiency, signaling bias properties, and selectivity profiles will be critical to determine the optimal pharmacological profile of 5-HT2A agonists as therapeutic drugs, ” Prof. Cheng added.

“Advancing non-hallucinogenic 5-HT2A agonists into clinical trials is very important, which could provide safer alternatives to the psychedelic drugs currently in clinical trials.”

LSD-like, non-psychedelic compounds can have antidepressant effects

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