Are Nonhallucinogenic Psychedelics a Pharmacy Oxymoron?

Psychedelic drugs, by definition, cause visual stimulation in the form of intense colors and moving patterns by targeting the human serotonin 2A receptor (5-HT2aR).^1-3 The public seems to be transfixed by emerging information that psychedelic compounds (eg, lysergic acid diethylamide [LSD], methylenedioxymethamphetamine [MDMA], psilocybin) may have the potential to treat various mental health conditions safely and effectively when coupled with psychotherapy.^4-7

Image credit: Zim | stock.adobe.com

These drugs appear to have an advantage over traditional medications in that they work rapidly and the response tends to be enduring.² Many individuals who use psychedelics report changes in emotions, perceptions, and thinking after the experience.³ They also report feelings of dissociation from the body, some of which can be frightening.⁸ Hallucinogens’ propensity to cause hallucinations is a limitation to their use for many patients, but chemists have been able to uncover binding sites that may reduce hallucinations.²

For a number of reasons, interest is growing in creating nonhallucinogenic psychedelic analogs—sometimes called next-generation psychedelics—that would not alter consciousness. The Online Table^3,8-11 includes some of the reasons for heightened interest in these medications as well as some barriers. Recent study findings indicate that 61% of individuals who have an interest in using hallucinogens for treatment (N = 1221) would be interested in trying a nonhallucinogenic psychedelic.¹² Therefore, researchers interested in psychedelics are trying to tease out the therapeutic effects associated with psychedelic experiences and look for related components that do not cause hallucinations.⁹

A NEW CLASS OF DRUGS?

Although nonhallucinogenic psychedelics are not currently a class of drugs, they exist and have existed for years. Some analogs and molecules under investigation are 2-bromo-LSD (2-Br-LSD; a brominated version of LSD), Ariadne, the psilocybin analog CYB003, and lisuride.

Animal studies are underway to determine whether 2-Br-LSD, which reportedly does not cause hallucinations in humans, helps depression and anxiety. Originally developed in 1957 as an LSD derivative that could address inflammation and migraines, it sat on the shelf for decades.13 Hallucinogen research stalled in the 1970s when these drugs became closely associated with American counterculture.¹⁰ One advantage to this compound is that it does not agonize the 5-HT2B receptor and seems to have some 5-HT2B antagonist abilities.¹⁴ Cardiac tissue harbors many 5-HT2B receptors, and using 5-HT2B receptor agonists can cause or aggravate cardiac problems.⁸ The most recent work on this drug in humans was an open-label study of 5 patients with cluster headache, which showed good results and few adverse effects.¹⁵

Another older molecule is ariadne. Studied in the 1970s, it was abandoned for strategic and financial reasons. However, it seemed to have possible benefits in mental disorders and neurodegenerative disorders including Parkinson disease. Much of the information about ariadne is older or anecdotal, but interest in its potential is growing.⁹

The psilocybin analog CYB003 is also currently in clinical trials.⁸ It does not require metabolic activation in the liver and intestines. Researchers altered the drug’s pharmacokinetics by replacing some of its hydrogen atoms with the heavier deuterium to deter its metabolic breakdown. The resultant compound creates a shorter, milder psychedelic experience of only 4 to 6 hours, reducing the length of supervision needed. Phase 2 study results indicate CYB003 has a strong antidepressant effect that is more durable than those of selective serotonin reuptake inhibitors.⁸

Finally, lisuride is a nonhallucinogenic psychedelic LSD analog being studied in animal models of depression.^11,16 Lisuride binds to the 5-HT1A, 5-HT2A, and 5-HT2C receptors. Previously, it had been studied in Parkinson disease because it is chemically related to the dopaminergic ergoline Parkinson disease drugs. It is also thought to bind to dopamine receptors.^11,16

IMPLICATIONS IN THE PHARMACY

Patients, especially those with treatment-resistant mental illness or addictions, may have questions about hallucinogens and the possibility that nonhallucinogenic drugs may someday be available. Key talking points include the following^14,17:

• Psychotherapy is a critical companion to psychedelic medicine of any type.
• It is still unclear whether nonhallucinogenic psychedelics will confer the same therapeutic benefit seen with hallucinogenic psychedelics; most research at this time is being undertaken in animals.
• Some of these drugs appear to have no hallucinogenic effects whereas others have milder or shortened effects.
• Adverse effect profiles have not been developed, but drugs that affect the 5-HT2B receptor are likely to have cardiac effects.

CONCLUSION

Despite widespread interest, there are still numerous barriers to the use of psychedelic medicines. The very fact that they are hallucinogens is a barrier to increasing use. Fortunately, reverse engineering hallucinogens and finding new ways to alter their structures may produce better versions and help address unmet medical needs.

REFERENCES

1. Psychedelic. Merriam-Webster. Accessed October 11, 2024. https://www.merriam-webster.com/dictionary/psychedelics

2. Cao D, Yu J, Wang H, et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science. 2022;375(6579):403-411. doi:10.1126/science.abl8615

3. Duan W, Cao D, Wang S, Cheng J. Serotonin 2A receptor (5-HT2AR) agonists: psychedelics and non-hallucinogenic analogues as emerging antidepressants. Chem Rev. 2024;124(1):124-163. doi:10.1021/acs.chemrev.3c00375

4. Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2022;79(10):953-962. doi:10.1001/jamapsychiatry.2022.2096

5. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489. doi:10.1001/jamapsychiatry.2020.3285

6. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med.2022;387(18):1637-1648. doi:10.1056/NEJMoa2206443

7. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033. doi:10.1038/s41591-021-01336-3

8. Peplow M. Next-generation psychedelics: should new agents skip the trip? Nat Biotechnol. 2024;42(6):827-830. doi:10.1038/s41587-024-02285-1

9. Cunningham MJ, Bock HA, Serrano IC, et al. Pharmacological mechanism of the non-hallucinogenic 5-HT2A agonist ariadne and analogs. ACS Chem Neurosci. 2023;14(1):119-135. doi:10.1021/acschemneuro.2c00597

10. Johnson M, Richards W, Griffiths R. Human hallucinogen research:guidelines for safety. J Psychopharmacol. 2008;22(6):603-620.doi:10.1177/0269881108093587

11. Qu Y, Chang L, Ma L, Wan X, Hashimoto K. Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice. Pharmacol Biochem Behav. 2023;222:173500. doi:10.1016/j.pbb.2022.173500

12. Aday JS, Boehnke KF, Herberholz M, Kruger DJ. Attitudes of psychedelic users regarding cost of treatment and non-hallucinogenic alternatives. J Psychedelic Stud. Published online May 30, 2024.doi:10.1556/2054.2024.00354

13. Hofmann A. LSD: My Problem Child. Oxford University Press; 2013.

14. Lewis V, Bonniwell EM, Lanham JK, et al. A non-hallucinogenic

LSD analog with therapeutic potential for mood disorders. Cell Rep.2023;42(3):112203. doi:10.1016/j.celrep.2023.112203

15. Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogenic 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. Cephalalgia.2010;30(9):1140-1144. doi:10.1177/0333102410363490

16. Glatfelter GC, Pottie E, Partilla JS, Stove CP, Baumann MH. Comparative pharmacological effects of lisuride and lysergic acid diethylamide revisited. ACS Pharmacol Transl Sci. 2024;7(3):641-653. doi:10.1021/acsptsci.3c00192

17. Peterson A, Sisti D. Skip the trip? five arguments on the use of nonhallucinogenic psychedelics in psychiatry. Camb Q Healthc Ethics.2022;31(4):472-476. doi:10.1017/S0963180122000081