How might psychedelics help?
Most traditional psychiatric medicines are designed to manage symptoms and are usually taken regularly over a long period of time. Psychedelic-assisted therapy is different because it can involve a much more intense but shorter-lasting experience. Psychedelics mainly affect the serotonin 5-HT2A receptor, which can lead to major changes in perception, thinking and brain activity. Research suggests that these drugs may temporarily disrupt established patterns of brain activity and increase the brain's ability to form and reorganise connections. This could create a period where certain thoughts, behaviours and psychological patterns are more open to change.
The treatment is also not simply a case of taking a drug and waiting for it to work. In research settings, psychedelic treatment is normally combined with psychological support. This can include preparation before the drug is taken and discussions afterwards to help the patient understand and process their experience. The aim is to create a controlled and supportive environment where an intense psychological experience can potentially be used in a constructive way.
There has been particular interest in people with treatment-resistant conditions, especially when existing medicines or therapies have not worked. Research is currently looking at ketamine as well as other psychedelic and psychedelic-inspired compounds for the treatment of depression, anxiety, PTSD and substance-use disorders.
However, one of the main difficulties with psychedelics is that their effects can be intense and unpredictable. People may experience hallucinations, major changes in perception, changes in their sense of identity and very strong emotions. While these experiences can sometimes be meaningful, they can also be frightening or overwhelming. Because of this, treatment may require specially controlled environments, trained professionals and significant preparation and follow-up. This could make psychedelic treatment expensive and difficult to provide on a large scale.
There are also concerns about which patients are suitable for these treatments. Certain psychiatric vulnerabilities could increase the risks associated with psychedelic drugs, meaning that patients would need to be carefully screened and monitored. Researchers also still need to understand how long the benefits last, which patients are most likely to respond, how much psychological support is required and how these treatments compare with more established therapies.
Another major question is whether the psychedelic experience itself is necessary for the treatment to work. Some researchers believe that the intense experience is an important part of the psychological changes that can occur. Others are investigating whether the biological effects of psychedelics could be separated from hallucinations and other unwanted effects. At the moment, there is no clear answer to this question.
Redesigning psychedelics to reduce unwanted effects
One of the more interesting developments in this area is the idea of redesigning psychedelic drugs rather than simply using existing substances in their traditional form. The aim is to keep the potentially useful biological effects while reducing problems such as hallucinations, cardiovascular effects and long periods of altered consciousness.
This has led to research into what are sometimes called non-hallucinogenic psychedelic analogues. Scientists are studying how different psychedelic molecules interact with receptors in the brain, particularly the 5-HT2A receptor. Different types of receptor signalling can lead to different effects, so researchers are trying to develop compounds that activate pathways which could be linked to therapeutic benefits without causing the same intense changes in perception.
This is an example of a more targeted approach to drug design. Rather than only asking whether a psychedelic drug works, researchers can investigate which molecular mechanisms are responsible for its positive effects and which are responsible for unwanted effects. Some laboratory studies have already identified compounds that produce antidepressant-like effects in animal models while showing fewer of the hallucinogenic effects associated with traditional psychedelics.
Ibogaine analogues are another example of this approach. Ibogaine has attracted scientific interest because of its possible effects on addiction and depression, but there are significant concerns about its safety and toxicity. Because of this, researchers have looked at structurally modified versions of ibogaine that could potentially maintain useful biological effects while reducing some of its risks. Early animal studies suggest that this approach may be possible, although there is still a long way to go before these findings could be translated into safe and effective treatments for humans.
Why could redesigning psychedelics matter?
If scientists are able to separate the therapeutic effects of psychedelics from their more unwanted effects, it could have a major impact on how these drugs are used. A medicine that causes little or no hallucination could potentially be given in more conventional healthcare environments. Patients may not need to spend several hours under constant supervision, which could make treatment cheaper and easier to provide to larger numbers of people.
It could also make these treatments more appealing to patients who want the potential benefits of a rapid or longer-lasting treatment but do not want to experience an intense altered state of consciousness. In addition, redesigned drugs could help scientists understand whether changes in neuroplasticity and emotional processing can produce therapeutic benefits without the subjective psychedelic experience.
On the other hand, removing the psychedelic experience might also remove something important. Some human studies have found links between aspects of the psychedelic experience and improvements in mental health. At the same time, laboratory research has shown that some non-hallucinogenic compounds can produce certain biological effects associated with psychedelics. Understanding how these findings fit together is therefore one of the key questions in current psychedelic research.
Conclusion
Psychedelic substances could become an important new area of mental health treatment, particularly for people who have not benefited from existing therapies. Their potential may come from their unusual ability to temporarily change brain activity and create conditions in which psychological and behavioural patterns can be altered. However, promising research does not necessarily mean that these treatments are ready for widespread clinical use.
The future of psychedelic medicine could involve two different but related approaches. One would involve carefully supervised treatments where the psychedelic experience is considered part of the therapy. The other would focus on developing redesigned medicines that keep the useful biological effects while reducing hallucinations and other unwanted effects. Advances in our understanding of receptors and drug design are making this second approach increasingly possible, but much more research is needed before its safety and effectiveness can be established in humans.
Ultimately, the aim should not simply be to make psychedelic drugs stronger. Instead, researchers should focus on making them safer, more predictable, accessible and specifically targeted to the needs of patients. If scientists can identify which mechanisms are responsible for therapeutic benefits and separate them from unnecessary risks, psychedelic research could contribute to a new generation of treatments for some of the most difficult mental health conditions.
References
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Carhart-Harris, R.L., et al. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384, 1402–1411.
Vargas, M.V., et al. (2020). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589, 474–479.
Dong, C., et al. (2021). Structure-based discovery of no hallucinogenic psychedelic analogues. Science, Vol 375, Issue 6579, 403–411.
Wang, J., et al. (2023). Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants. Chemical Reviews, 124 (1): 124–163.
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