Nonhallucinogenic psychedelics can help manage mental health

Psychedelic medicines are signaling a potential shift in the approach to mental health treatment, with opportunities not only to treat but also to cure complex mental illnesses such as depression and PTSD.

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Mental illnesses are among the most common health conditions in the United States.1 Notably, more than 1 in 5 adults in the United States live with a mental illness, and more than 1 in 5 young people (ages 13 to 18) currently or previously had a severely debilitating mental illness.1 Additionally, about 1 in 25 adults in the United States has a serious mental illness such as schizophrenia, bipolar disorder, or major depression.1 Mental health encompasses emotional, psychological and social well-being. It affects how people think, feel and act, as well as determining how they handle stress, relate to others and make healthy choices. Mental health is important at every stage of life, from childhood and adolescence through adulthood. It’s important to remember that mental health changes over time. When the demands placed on an individual exceed their resources and coping skills, their mental health can suffer. For example, if an individual works long hours, cares for a relative, or is experiencing financial hardship, they may experience a decline in their mental health.


Psychedelic drugs are powerful psychoactive substances that alter perception and mood. They can influence numerous cognitive processes. Generally considered physiologically safe, they are non-addictive or habit-forming and have been employed by early cultures in many sociocultural and ritual contexts.2 The use of psychedelic drugs in psychiatry is exciting because they appear to produce rapid and sustained therapeutic effects on a variety of complex and difficult-to-manage psychiatric disorders, including depression, anxiety, PTSD, and substance use disorder, in addition to from end of life. life care.2 Psychedelic drugs such as lysergic acid diethylamide (LSD) and mushroom-derived psilocybin bind to serotonin 2A receptors (5-HT2AR).3 Numerous studies have demonstrated significant efficacy, such as a 2021 study published in New England Journal of Medicine, which found that patients with moderate to severe major depressive disorder who received 2 doses of psilocybin had equally strong or even better results than patients who received daily doses. of escitalopram.4 Similarly, a 2021 study published in JAMA Psychiatry found that psilocybin-assisted therapy produced large, rapid, and sustained antidepressant effects in patients with major depressive disorder.5 This binding to 5-HT2AR has significant and well established antidepressant effects. However, despite these data, the hallucinatory effects of these drugs complicate their more widespread use as therapeutics.3


Safety concerns and toxicity have limited the therapeutic use of psychedelics. However, the identification of key structural elements of a potentially therapeutic compound has allowed the molecule to be manipulated in such a way as to produce an analogue with more beneficial properties and fewer adverse effects.3 Recent study results have shown that, through careful chemical design, it is possible to modify a psychedelic drug to produce a safer, non-hallucinogenic analog with therapeutic potential.6 Researchers demonstrated this by using a nonhallucinogenic LSD analog called 2-bromo-LSD (2-Br-LSD) for depression. They found that LSD is nearly a full agonist in 5-HT2A and 5-HT2B subtypes, whereas 2-Br-LSD is a partial agonist in 5-HT2A and a potent antagonist in 5-HT2B. Furthermore, LSD interacts with a wide range of other G protein-coupled amine receptors, resulting in adverse effects, while 2-Br-LSD has less off-target activity.6 Another LSD analogue is lysuride (Dopergin). This drug is a dopamine agonist and a partial 5-HT2A agonist. This is used as an anti-Parkinsonian agent and can be repurposed for use in Dravet syndrome.


Many nonhallucinogenic psychedelics fall into a relatively new class of fast-acting therapies called psychoplastogens, which are capable of rapidly promoting structural and functional neural plasticity.2 Neural plasticity refers to the ability to change and adapt in response to stimuli and is an important part of healthy brain function. Nonhallucinogenic psychedelics are specifically designed to maximize the effects of this ability present in psychedelics. Therapeutically, these analogs could be used to promote recovery from many neuropsychiatric disorders, including mood disorders, anxiety, and substance use disorder.2 An example is the analogue tabernanthalog, which is derived from ibogaine. It has demonstrated efficacy in the treatment of substance use disorder and depression. The researchers also studied the effect of tabernanthalog on mild unpredictable stress in mice. Not only did 1 dose of tabernanthalog reduce the anxiety produced by mild unpredictable stress, it also restored the neuronal deficits resulting from the stress.2


Clinical studies will be needed to determine whether psychoplastogenic analogs of psychedelics can produce therapeutic effects in humans without inducing hallucinations and other toxicities associated with traditional psychedelics. More experiments can be done to determine the roles of subjective effects and increased neural plasticity in the therapeutic properties of psychedelics. Some of this research is already underway, as seen in the recent FDA approval of 3,4-methylenedioxymethamphetamine for use in clinical trials in schizophrenia.8 In this study, to be conducted at UCLA, the researchers plan to evaluate the use of the drug to treat reduced social motivation, which can cause significant functional impairment in individuals with schizophrenia and currently has no effective treatment.8 Despite promising therapeutic responses to psychedelic-assisted therapy, the hallucinogenic effects of these drugs make it unlikely that they will be widely used therapeutically. On the other hand, analogues without hallucinogenic effects used to rewire pathological neural circuits have enormous potential as first-line treatments for patients with a variety of neuropsychiatric disorders.


Pharmacists have a significant role in supporting people with mental illness. However, more work is needed to demonstrate the clinical outcomes and cost-effectiveness of these roles, thereby enabling pharmacists to become a more integrated part of mental health care teams in various practice settings.

In addition, all pharmacists should have standardized and mandatory training in mental health and crisis first aid to ensure they are able to safely and appropriately care for patients with mental illness experiencing crises.

About the author

Kathleen Kenny, PharmD, RPh, has more than 25 years of experience as a community pharmacist. She is a clinical medical writer based in Homosassa, Florida.


  1. About mental health. CENTER FOR DISEASE CONTROL AND PREVENTION. Updated April 25, 2023. Accessed June 12, 2023.
  2. Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE. Psychedelics and other psychoplastogens for the treatment of mental illnesses. Frontal psychiatry. 2021;12:727117. doi:10.3389/fpsyt.2021.727117
  3. Cao D, Yu J, Wang H, et al. Discovery based on the structure of non-hallucinogenic psychedelic analogues. Science. 2022;375(6579):403-411. doi:10.1126/science.abl8615
  4. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escit-alopram for depression. N English J Med. 2021;384(15):1402-1411. doi:10.1056/NEJMoa2032994
  5. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder. JAMA Psychiatry. 2021;78(5):1-9. doi:10.1001/jamapsychiatry.2020.3285
  6. Lewis V, Bonniwell EM, Lanham JK. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cellular representative 2023;42(3):112203. doi:10.1016/j.celrep.2023.112203
  7. Sourbron J, Partoens M, Scheldeman C, Zhang Y, Lagae L, de Witte P. Dravet syndrome drug repurposing in scn1Lab-/- mutant zebrafish. Epilepsy. 2019;60(2):e8-e13. doi:10.1111/epi.14647
  8. Hippensteele A. FDA approves MDMA for use in schizophrenia clinical trials. Pharmacy times. June 9, 2023. Accessed June 16, 2023.

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