- Depression is one of the most common mental health issues people face, and sometimes doctors treat symptoms with medications.
- One pharmaceutical route scientists are studying is using psychedelics such as LSD and psilocybin (magic mushrooms) to treat depression.
- However, psychedelics can cause hallucinations, which can be problematic since they can contribute to psychosis or put someone in an unsafe situation.
- In a new study out of Finland, researchers found that the mechanism that causes antidepressant benefits is separate from the mechanism that causes hallucinations.
While there are many antidepressant medications doctors prescribe to treat clinical depression, not everyone responds to them.
Finding the right medication and dose can be difficult, and sometimes people simply do not respond well to typically prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).
This issue led researchers to look into alternative ways of treating depression, and one avenue researchers have been exploring is psychedelics. Some psychedelics may be able to alleviate depression symptoms, but they can also cause hallucinations.
In a study led by researchers from the University of Helsinki in Finland, scientists explored a way to get the benefit of psychedelics without hallucinations. The study is published in Nature Neuroscience.
LSD and magic mushrooms — without hallucinations
Current research shows that psychedelics can be effective in treating depression, particularly depression that is otherwise treatment-resistant.
The caveat, however, is that psychedelics such as LSD and magic mushrooms can cause people to hallucinate, which is not ideal since that can potentially trigger psychosis and unsafe behaviors.
This drove the researchers in the current study to look into the mechanisms that give psychedelics both their antidepressant and hallucinogenic effects to see if the latter could be blocked.
According to the authors, they learned through a prior study that the antidepressants fluoxetine and ketamine “act by binding to TrkB, the receptor for brain-derived neurotrophic factor (BDNF).”
This contributes to neuroplasticity and antidepressant response, and the National Institutes of Health note that neuroplasticity “is a process that involves adaptive structural and functional changes to the brain.”
“[BDNF] and its receptor TrkB (neurotrophic receptor tyrosine kinase, Ntrk2) are central mediators of plasticity and the therapeutic action of antidepressants,” write the authors.
To see whether the mechanisms that contribute to an antidepressant effect and hallucinations are separate, the researchers’ first step was to conduct experiments by injecting cells into dishes to look into how and where psychedelics bind.
The scientists learned not only the location of the binding site, but that the binding of psychedelics to the TrkB receptors in human, rat, and mouse cells was stronger compared to other antidepressants.
Additionally, the researchers learned that a different mechanism is responsible for the antidepressant and hallucinogenic effects. The next step was to see if it is possible to block the hallucinogenic effect.
Testing psychedelics on mice
The next phase of the research project was to see how mice responded to LSD and if they could block hallucinations in the mice.
The researchers did this by conditioning mice to fear foot shocks — they used this approach to measure depression symptoms. After conditioning the mice, the scientists divided the mice into control and treatment groups.
The study authors said they gave the treatment group LSD along with a serotonin 2A blocker — to potentially block the hallucinogenic effects — and then tried to revert the conditioned mice to not fear foot shocks.
The scientists learned two things from this experiment: First, that the mice on LSD did better than the control group at overcoming the fear response. Second, the pathway for the hallucinogenic effect is distinct from the antidepressant effect.
Hallucinogen-free psychedelics vs. antidepressants
This study shows that psychedelics promote neuroplasticity and that it is possible to achieve this effect without hallucinations.
Since the researchers learned that the mechanisms that help depression and induce hallucinations are separate, they have made a new pathway to work on creating a psychedelic-based antidepressant without the side effects.
Additionally, since the psychedelics proved to be much stronger than the antidepressants tested, psychedelics could one day be the future of treating antidepressant-resistant depression.
“Lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants,” note the authors.
The future of psychedelics without hallucinogens
Dr. Abid Nazeer, a psychiatrist and the founder of Advanced Psych Solutions based in Oak Brook, IL, not involved in the research, spoke about the study with Medical News Today.
While Dr. Nazeer pointed out that research into using psychedelics as antidepressants is not new, he did think the study paves the way for more research.
“I think this is a very defining study in terms of how it’s going to open up a lot more research that will be done with this study as a foundation,” commented Dr. Nazeer. “And further studies will now start looking deeper at this concept of getting antidepressant responses without altering somebody’s state of mind.”
Dr. Nazeer also pointed out that the scientists tested on mice and thus we should take the results with a grain of salt.
“I would say a weakness is that this is an animal model. When you’re studying it in mice, that doesn’t necessarily mean that the human brain will have the same reaction,” noted Dr. Nazeer.
Dr. Daniel F. Kelly, a board certified neurosurgeon and founder and director of the Pacific Neuroscience Institute in Santa Monica, CA, not involved in the study, also spoke with MNT about its takeaways.
“This excellent study by Moliner and colleagues brings into question the long-held assumption by many that the therapeutic effects of the classic psychedelics like LSD and psilocybin are reliant upon the individual having a psychedelic or hallucinogenic experience,” said Dr. Kelly.
Dr. Kelly discussed the “careful design and controls” as strengths of the study and looks forward to what the future holds for utilizing psychedelics in depression treatment.
“We are just beginning to unravel the complex mechanisms and pathways underlying the psychotherapeutic effects of psychedelic medicines. It also raises the possibility that new psychedelic compounds may be developed devoid of hallucinogenic effects that provide safe and lasting antidepressant effects or other positive psychological benefits.”
– Dr. Daniel F. Kelly, neurosurgeon
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