Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

No time to lose: the current state of research in rapid-acting psychotherapeutics

Neuropsychopharmacology volume 49, pages 10–14 (2024)Cite this article

Subjects

Abstract

The vast majority of treatments for psychiatric and substance use disorders take weeks to work. Notable exceptions to this rule exist, with some treatments such as intravenous ketamine resolving symptoms in minutes to hours. Current research is focused on identifying novel approaches to rapid-acting psychotherapeutics. Promising results from studies of novel classes of drugs and innovative brain stimulation therapies are currently being studied through both clinical and pre-clinical research, as described here. Research focused on understanding neurobiological mechanisms, effective therapeutic context, and implementation approaches are needed to maximize the potential reach of these therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Post RM, Uhde TW, Rubinow DR, Huggins T. Differential time course of antidepressant effects after sleep deprivation, ECT, and carbamazepine: clinical and theoretical implications. Psychiatry Res. 1987;22:11–9.

    CAS  PubMed  Google Scholar 

  2. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60.

    CAS  PubMed  Google Scholar 

  3. Rodger CR, Scott AI, Whalley LJ. Is there a delay in the onset of the antidepressant effect of electroconvulsive therapy? Br J Psychiatry. 1994;164:106–9.

    CAS  PubMed  Google Scholar 

  4. Schlaepfer TE, Bewernick BH, Kayser S, Madler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73:1204–12.

    PubMed  Google Scholar 

  5. Yavi M, Lee H, Henter ID, Park LT, Zarate CA Jr. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2:9.

    PubMed  PubMed Central  Google Scholar 

  6. Kanes S, Colquhoun H, Gunduz-Bruce H, Raines S, Arnold R, Schacterle A, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390:480–89.

    CAS  PubMed  Google Scholar 

  7. Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315:531–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hermida AP, Glass OM, Shafi H, McDonald WM. Electroconvulsive therapy in depression: current practice and future direction. Psychiatr Clin North Am. 2018;41:341–53.

    PubMed  Google Scholar 

  9. Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177:716–26.

    PubMed  Google Scholar 

  10. Gaynes BN, Lloyd SW, Lux L, Gartlehner G, Hansen RA, Brode S, et al. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Ont Health Technol Assess Ser. 2016;16:1–66.

  11. Figee M, Riva-Posse P, Choi KS, Bederson L, Mayberg HS, Kopell BH. Deep brain stimulation for depression. Neurotherapeutics. 2022;19:1229–45.

    PubMed  PubMed Central  Google Scholar 

  12. Bach P, Luderer M, Müller UJ, Jakobs M, Baldermann JC, Voges J, et al. Deep brain stimulation of the nucleus accumbens in treatment-resistant alcohol use disorder: a double-blind randomized controlled multi-center trial. Transl Psychiatry. 2023;13:49.

    PubMed  PubMed Central  Google Scholar 

  13. Zangen A, Moshe H, Martinez D, Barnea-Ygael N, Vapnik T, Bystritsky A, et al. Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial. World Psychiatry. 2021;20:397–404.

    PubMed  PubMed Central  Google Scholar 

  14. Iqbal SZ, Mathew SJ. Ketamine for depression clinical issues. Adv Pharm. 2020;89:131–62.

    CAS  Google Scholar 

  15. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27:1025–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387:1637–48.

    CAS  PubMed  Google Scholar 

  17. Gunduz-Bruce H, Silber C, Kaul I, Rothschild AJ, Riesenberg R, Sankoh AJ, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019;381:903–11.

    CAS  PubMed  Google Scholar 

  18. Iosifescu DV, Jones A, O’Gorman C, Streicher C, Feliz S, Fava M, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83:21m14345.

  19. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208–16.

    PubMed  Google Scholar 

  20. Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. 2021;27:1696–700.

    CAS  PubMed  Google Scholar 

  21. Shivacharan RS, Rolle CE, Barbosa DAN, Cunningham TN, Feng A, Johnson ND, et al. Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating. Nat Med. 2022;28:1791–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28:983–92.

    PubMed  PubMed Central  Google Scholar 

  23. Jones JL, Mateus CF, Malcolm RJ, Brady KT, Back SE. Efficacy of ketamine in the treatment of substance use disorders: a systematic review. Front Psychiatry. 2018;9:277.

    PubMed  PubMed Central  Google Scholar 

  24. Mash DC, Duque L, Page B, Allen-Ferdinand K. Ibogaine detoxification transitions opioid and cocaine abusers between dependence and abstinence: clinical observations and treatment outcomes. Front Pharm. 2018;9:529.

    Google Scholar 

  25. Luba R, Martinez S, Jones J, Pravetoni M, Comer SD. Immunotherapeutic strategies for treating opioid use disorder and overdose. Expert Opin Investig Drugs. 2023;32:77–87.

    CAS  PubMed  Google Scholar 

  26. Belgers M, Van Eijndhoven P, Markus W, Schene AH, Schellekens A. rTMS reduces craving and alcohol use in patients with alcohol use disorder: results of a randomized, sham-controlled clinical trial. J Clin Med. 2022;11:951.

  27. Gay A, Cabe J, De Chazeron I, Lambert C, Defour M, Bhoowabul V, et al. Repetitive transcranial magnetic stimulation (rTMS) as a promising treatment for craving in stimulant drugs and behavioral addiction: a meta-analysis. J Clin Med. 2022;11:624.

  28. Qin J, Chen J, Wang Y, Zou Z. Effects of psychoeducation combined with transcranial direct current stimulation on reducing cigarette craving and consumption in male smokers. Addict Behav. 2023;141:107643.

    PubMed  Google Scholar 

  29. Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment. Am J Drug Alcohol Abus. 2018;44:56–63.

    Google Scholar 

  30. da Costa SC, Oesterle T, Rummans TA, Richelson E, Gold M. Psychedelic drugs for psychiatric disorders. J Neurol Sci. 2022;440:120332.

    PubMed  Google Scholar 

  31. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa P, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29:289–99.

    CAS  PubMed  Google Scholar 

  32. Krebs TS, Johansen P-Ø. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012;26:994–1002.

    PubMed  Google Scholar 

  33. Worrell SD, Gould TJ. Therapeutic potential of ketamine for alcohol use disorder. Neurosci Biobehav Rev. 2021;126:573–89.

    CAS  PubMed  Google Scholar 

  34. Garel N, McAnulty C, Greenway KT, Lesperance P, Miron J-P, Rej S, et al. Efficacy of ketamine intervention to decrease alcohol use, cravings, and withdrawal symptoms in adults with problematic alcohol use or alcohol use disorder: a systematic review and comprehensive analysis of mechanism of actions. Drug Alcohol Depend. 2022;239:109606.

    CAS  PubMed  Google Scholar 

  35. Dakwar E, Levin F, Hart CL, Basaraba C, Choi J, Pavlicova M, et al. A Single ketamine infusion combined with motivational enhancement therapy for alcohol use disorder: a randomized midazolam-controlled pilot trial. Am J Psychiatry. 2020;177:125–33.

    PubMed  Google Scholar 

  36. Grabski M, McAndrew A, Lawn W, Marsh B, Raymen L, Stevens T, et al. Adjunctive ketamine with relapse prevention-based psychological therapy in the treatment of alcohol use disorder. Am J Psychiatry. 2022;179:152–62.

    PubMed  Google Scholar 

  37. Holla B, Biswal J, Ramesh V, Shivakumar V, Bharath RD, Benegal V, et al. Effect of prefrontal tDCS on resting brain fMRI graph measures in alcohol use disorders: a randomized, double-blind, sham-controlled study. Prog Neuro Psychopharmacol Biol Psychiatry. 2020;102:109950.

    Google Scholar 

  38. den Uyl TE, Gladwin TE, Lindenmeyer J, Wiers RW. A clinical trial with combined transcranial direct current stimulation and attentional bias modification in alcohol-dependent patients. Alcohol Clin Exp Res 2018;42:1961–69.

    Google Scholar 

  39. Mahoney JJ 3rd, Hanlon CA, Marshalek PJ, Rezai AR, Krinke L. Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment. J Neurol Sci. 2020;418:117149.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sorkhou M, Stogios N, Sayrafizadeh N, Hahn MK, Agarwal SM, George TP. Non-invasive neuromodulation of dorsolateral prefrontal cortex to reduce craving in alcohol use disorder: a meta-analysis. Drug Alcohol Depend Rep. 2022;4:100076.

    PubMed  PubMed Central  Google Scholar 

  41. Kharbanda KK, Farokhnia M, Deschaine SL, Bhargava R, Rodriguez-Flores M, Casey CA, et al. Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: a narrative review. Alcohol Clin Exp Res. 2022;46:2149–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Melby K, Gråwe RW, Aamo TO, Skovlund E, Spigset O. Efficacy of self-administered intranasal oxytocin on alcohol use and craving after detoxification in patients with alcohol dependence. a double-blind placebo-controlled trial. Alcohol Alcohol. 2020;56:565–72.

    PubMed Central  Google Scholar 

  43. Noël Raby W, Heller M, Milliaressis D, Jean Choi C, Basaraba C, Pavlicova M, et al. Intranasal oxytocin may improve odds of abstinence in cocaine-dependent patients: results from a preliminary study. Drug Alcohol Depend Rep. 2022;2:100016.

    PubMed  Google Scholar 

  44. Van Hedger K, Bershad AK, Lee R, de Wit H. Effects of intranasal oxytocin on stress-induced cigarette craving in daily smokers. Nicotine Tob Res. 2018;22:89–95.

    PubMed Central  Google Scholar 

  45. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150–58.

    PubMed  Google Scholar 

  46. Marseille E, Mitchell JM, Kahn JG. Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial. PLoS One. 2022;17:e0263252.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu W, Zhang Y, Jiang J, Lucas MV, Fonzo GA, Rolle CE, et al. An electroencephalographic signature predicts antidepressant response in major depression. Nat Biotechnol. 2020;38:439–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38.

    CAS  PubMed  Google Scholar 

  49. Aleksandrova LR, Phillips AG. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharm Sci. 2021;42:929–42.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Institute of Mental Health, Bethesda, MD, 20852, USA

    Joshua A. Gordon

  2. National Institute on Drug Abuse, Bethesda, MD, 20852, USA

    Nora D. Volkow

  3. National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20852, USA

    George F. Koob

Authors
  1. Joshua A. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nora D. Volkow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. George F. Koob
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JAG, NDV, and GFK contributed equally to the manuscript. All authors conceived the content, wrote equal parts of the first draft, and edited the manuscript.

Corresponding author

Correspondence to Joshua A. Gordon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gordon, J.A., Volkow, N.D. & Koob, G.F. No time to lose: the current state of research in rapid-acting psychotherapeutics. Neuropsychopharmacol. 49, 10–14 (2024). https://doi.org/10.1038/s41386-023-01627-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01627-y

Search

Advanced search

Quick links