Ketamine-Assisted Psychotherapy: opportunities and challenges
Main Article Content
Abstract
Ketamine is a dissociative anesthetic with unique pharmacological and psychological properties. Its antidepressant effects are mediated through the glutamatergic system and subsequent neuroplasticity and can be amplified when combined with psychotherapy. The ketamine-induced dissociative state should not be seen as an unwanted side-effect, but as a unique opportunity for psychotherapeutic intervention. When psychotherapy is augmented by subanesthetic doses of ketamine, a synergistic effect is seen that increases and prolongs the effect on depressive symptoms, general well-being and quality of life.
Keywords:
Ketamine, NMDA antagonist, psychotherapy, psychedelic, consciousness
Article Details
How to Cite
KLEINLOOG, Daniel.
Ketamine-Assisted Psychotherapy: opportunities and challenges.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5630>. Date accessed: 05 aug. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5630.
Section
Editorial
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678-684.
doi: 10.1097/ALN.0b013e3181ed09a2
2. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6 (3):279-291. doi: 10.1002/cpt196563279
3. Kohtala S. Ketamine – 50 years in use: from anesthesia to rapid antidepressant effects and neurobioloical mechanisms. Pharmacol Rep. 2021; 73(2):323-345. doi: 10.1007/s43440-021-00232-4
4. Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versitale tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33(5):633-638. doi: 10.1097/ACO.0000000000000916
5. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016; 37(7):865-872. doi: 10.1038/aps.2016.5
6. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70:621-660. doi: 10.1124/pr.117.015198
7. Duman RS. The dazzling promise of ketamine. Cerebrum. 2018:cer-04-18.
8. Krystal JH, Kaye AP, Jefferson S. Ketamine and the neurobiology of depression: toward next-generation rapid-acting antidepressant treatments. Proc Natl Acad Sci U S A. 2023;120(49):e2305772120. doi: 10.1073/pnas.2305772120
9. Jelen LA, Young AH, Stone JM. Ketamine: a tale of two enantiomers. J Psychopharmacol. 2021;35(2):109-123.
doi: 10.1177/0269881120959644
10. Vollenweider FX, Leenders KL, Øye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7(1):25-38. doi: 10.1016/s0924-977x(96)00042-9
11. Dore J, Turnipseed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2): 189-198. doi: 10.1080/02791072.2019.1587556
12. Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute postoperative pain in adults: a systematic review and meta-analysis. J Clin Anesth. 2021;68:110071. doi: 10.1016/j.jclinane.2020.110071
13. Yang Y, Maher DP, Cohen SP. Emerging concepts on the use of ketamine for chronic pain. Expert Rev Clin Pharmacol. 2020;13(2):135-146. doi: 10.1080/17512433.2020.1717947
14. Brinck ECV, Tiippana E, Heesen M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018;12(12):CD012033. doi:10.1002/14651858.CD012033.pub4
15. Mathai DS, Mora V, Garcia-Romeu A. Toward synergies of ketamine and psychotherapy. Front Psychol. 2022;13:868103. doi: 10.3389/fpsyg.2022.868103
16. Jelen LA, Stone JM. Ketamine for depression. Int Rev Psychiatry. 2021;33(3):207-228. doi: 10.1080/09540261.2020.1854194
17. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. doi: 10.1016/s0006-3223(99)00230-9
18. Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
doi: 10.1001/archpsyc.63.8.856
19. Krystal JH, Kavalali ET, Monteggia LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49 (1):41-50. doi: 10.1038/s41386-023-01629-w
20. Lai R, Katalinic N, Glue P, et al. Pilot dose-response trial of i.v. ketamine in treatment-resistant depression. World J Biol Psychiatry. 2014;15:579-584. doi: 10.3109/15622975.2014.922697
21. Loo CK, Gálvez V, O’Keefe E, et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016;134:48-56. doi: 10.111/acps.12572
22. Xu Y, Hackett M, Carter G, et al. Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2016;19:1-15. doi: 10.1093/ijnp/pyv124
23. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yathan LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693-704. doi: 10.1017/S0033291714001603
24. McIntyre RS, Carvalho IP, Lui LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: meta-analysis. J Affect Disord. 2020;276:576-584. doi: 10.1016/j.jad.2020.06.050
25. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383-399. doi: 10.1176/appi.ajp.2020.20081251
26. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychatr Res. 2022;151:693-709. doi: 10.1016/j.jpsychires.2022.04.037
27. Garel N, Drury J, Thibault Lévesque J, et al. The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression. Front Psychiatry. 2023;14:1268832. doi: 10.3389/fpsyt.2023.1268832
28. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023; 388(25):2315-2325. doi: 10.1056/NEJMoa2302399
29. European monitoring centre for drugs and drug addiction (EMDDA). European drug report 2024: trends and developments. www.emcdda.europa.eu, accessed on June 16th, 2024. doi: 10.2810/91693
30. Trimbos Institute. National Drug Monitor 2024. www.nationaledrugmonitor.nl, accessed on June 16th, 2024.
31. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65-78. doi: 10.1016/S2215-0366(17)30272-9
32. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249. doi: 10.1038/nm.4050
33. Johnston JN, Kadriu B, Allen J, Gilbert JR, Henter ID, Zarate Jr CA. Ketamine and serotonergic psychedelics: an update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment. Neuropharmacology. 2023;226:109422. doi: 10.1016/j.neuropharm.2023.109422
34. Olsen DE. The subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci. 2021;4:563-567. doi: 10.1021/acsptsci.0c00192
35. Wolfson P, Vaid G. Ketamine-assisted psychotherapy, psychedelic methodologies, and the impregnable value of the subjective – a new and evolving approach. Front Psychiatry. 2024; 15:1209419. doi: 10.3389/fpsyt.2024.1209419
36. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013; 34(4):287-93.
37. Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56-61. doi: 10.1016/j.jad.2014.02.017
38. Lii TR, Smith AE, Flohr JR, et al. Randomized trial of ketamine masked by surgial anesthesia in patients with depression. Nat Ment Health. 2023;1 (11):876-886. doi: 10.1038/s44220-023-00140-x
39. Wolff M, Evens R, Mertens LJ, et al. Learning to let go: a cognitive-behavioral model of how psychedelic therapy promotes acceptance. Front Psychiatry. 2020;11:5. doi: 10.3389/fpsyt.2020.00005
40. Wolf M, Evens R, Mertens LJ, et al. Measuring psychotherapeutic processes in the context of psychedelic experiences: validation of the general change mechanisms questionnaire (GCMW). J Psychopharmacol. 2024;38(5):432-457. doi: 10.1177/02698811241249698
41. Gründer G, Brand M, Mertens LJ et al. Treatment with psychedelics is psychotherapy: beyond reductionism. Lancet Psychiatry. 2024;11 (3):231-236. doi: 10.1016/S2215-0366(23)00363-2
42. Brennan W, Belser AB. Models of psychedelic-assisted psychotherapy: a contemporary assessment and an introduction to EMBARK, a transdiagnostic trans-drug model. Front Psychol. 2022;13:866018. doi:10.3389/fpsyg.2022.866018
43. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177(5):391-410. doi: 10.1176/appi.ajp.2019.19010035
44. Kaelen M, Giribaldi B, Raine J, et al. The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology (Berl). 2018;235(2):505-519. doi: 10.1007/s00213-017-4820-5
45. 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
46. Fonseka LN, Woo BK. Therapeutic role of psilocybin and 3,4-methylenedioxymethamphetamine in trauma: a literature review. World J Psychiatry. 2023;13(5):182-190. doi: 10.5498/wjp.v13.i5.182
47. 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
48. Evans J, Robinson OC, Ketzitzidou Argyri E, et al. Extended difficulties following the use of psychedelic drugs: a mixed methods study. PloS One. 2023;18(10):e0293349. doi: 10.1371/journal.pone.0293349
49. Graziosi M, Singh M, Nayak SM, Yaden DB. Acute subjective effects of psychedelics within and beyond WEIRD contexts. J Psychoactive Drugs. 2023;55(5):558-569. doi: 10.1080/02791072.2023.2255274
doi: 10.1097/ALN.0b013e3181ed09a2
2. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6 (3):279-291. doi: 10.1002/cpt196563279
3. Kohtala S. Ketamine – 50 years in use: from anesthesia to rapid antidepressant effects and neurobioloical mechanisms. Pharmacol Rep. 2021; 73(2):323-345. doi: 10.1007/s43440-021-00232-4
4. Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versitale tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33(5):633-638. doi: 10.1097/ACO.0000000000000916
5. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016; 37(7):865-872. doi: 10.1038/aps.2016.5
6. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70:621-660. doi: 10.1124/pr.117.015198
7. Duman RS. The dazzling promise of ketamine. Cerebrum. 2018:cer-04-18.
8. Krystal JH, Kaye AP, Jefferson S. Ketamine and the neurobiology of depression: toward next-generation rapid-acting antidepressant treatments. Proc Natl Acad Sci U S A. 2023;120(49):e2305772120. doi: 10.1073/pnas.2305772120
9. Jelen LA, Young AH, Stone JM. Ketamine: a tale of two enantiomers. J Psychopharmacol. 2021;35(2):109-123.
doi: 10.1177/0269881120959644
10. Vollenweider FX, Leenders KL, Øye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7(1):25-38. doi: 10.1016/s0924-977x(96)00042-9
11. Dore J, Turnipseed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2): 189-198. doi: 10.1080/02791072.2019.1587556
12. Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute postoperative pain in adults: a systematic review and meta-analysis. J Clin Anesth. 2021;68:110071. doi: 10.1016/j.jclinane.2020.110071
13. Yang Y, Maher DP, Cohen SP. Emerging concepts on the use of ketamine for chronic pain. Expert Rev Clin Pharmacol. 2020;13(2):135-146. doi: 10.1080/17512433.2020.1717947
14. Brinck ECV, Tiippana E, Heesen M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018;12(12):CD012033. doi:10.1002/14651858.CD012033.pub4
15. Mathai DS, Mora V, Garcia-Romeu A. Toward synergies of ketamine and psychotherapy. Front Psychol. 2022;13:868103. doi: 10.3389/fpsyg.2022.868103
16. Jelen LA, Stone JM. Ketamine for depression. Int Rev Psychiatry. 2021;33(3):207-228. doi: 10.1080/09540261.2020.1854194
17. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. doi: 10.1016/s0006-3223(99)00230-9
18. Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.
doi: 10.1001/archpsyc.63.8.856
19. Krystal JH, Kavalali ET, Monteggia LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49 (1):41-50. doi: 10.1038/s41386-023-01629-w
20. Lai R, Katalinic N, Glue P, et al. Pilot dose-response trial of i.v. ketamine in treatment-resistant depression. World J Biol Psychiatry. 2014;15:579-584. doi: 10.3109/15622975.2014.922697
21. Loo CK, Gálvez V, O’Keefe E, et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016;134:48-56. doi: 10.111/acps.12572
22. Xu Y, Hackett M, Carter G, et al. Effects of low-dose and very low-dose ketamine among patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2016;19:1-15. doi: 10.1093/ijnp/pyv124
23. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yathan LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693-704. doi: 10.1017/S0033291714001603
24. McIntyre RS, Carvalho IP, Lui LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: meta-analysis. J Affect Disord. 2020;276:576-584. doi: 10.1016/j.jad.2020.06.050
25. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383-399. doi: 10.1176/appi.ajp.2020.20081251
26. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychatr Res. 2022;151:693-709. doi: 10.1016/j.jpsychires.2022.04.037
27. Garel N, Drury J, Thibault Lévesque J, et al. The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression. Front Psychiatry. 2023;14:1268832. doi: 10.3389/fpsyt.2023.1268832
28. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023; 388(25):2315-2325. doi: 10.1056/NEJMoa2302399
29. European monitoring centre for drugs and drug addiction (EMDDA). European drug report 2024: trends and developments. www.emcdda.europa.eu, accessed on June 16th, 2024. doi: 10.2810/91693
30. Trimbos Institute. National Drug Monitor 2024. www.nationaledrugmonitor.nl, accessed on June 16th, 2024.
31. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65-78. doi: 10.1016/S2215-0366(17)30272-9
32. Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249. doi: 10.1038/nm.4050
33. Johnston JN, Kadriu B, Allen J, Gilbert JR, Henter ID, Zarate Jr CA. Ketamine and serotonergic psychedelics: an update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment. Neuropharmacology. 2023;226:109422. doi: 10.1016/j.neuropharm.2023.109422
34. Olsen DE. The subjective effects of psychedelics may not be necessary for their enduring therapeutic effects. ACS Pharmacol Transl Sci. 2021;4:563-567. doi: 10.1021/acsptsci.0c00192
35. Wolfson P, Vaid G. Ketamine-assisted psychotherapy, psychedelic methodologies, and the impregnable value of the subjective – a new and evolving approach. Front Psychiatry. 2024; 15:1209419. doi: 10.3389/fpsyt.2024.1209419
36. Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013; 34(4):287-93.
37. Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56-61. doi: 10.1016/j.jad.2014.02.017
38. Lii TR, Smith AE, Flohr JR, et al. Randomized trial of ketamine masked by surgial anesthesia in patients with depression. Nat Ment Health. 2023;1 (11):876-886. doi: 10.1038/s44220-023-00140-x
39. Wolff M, Evens R, Mertens LJ, et al. Learning to let go: a cognitive-behavioral model of how psychedelic therapy promotes acceptance. Front Psychiatry. 2020;11:5. doi: 10.3389/fpsyt.2020.00005
40. Wolf M, Evens R, Mertens LJ, et al. Measuring psychotherapeutic processes in the context of psychedelic experiences: validation of the general change mechanisms questionnaire (GCMW). J Psychopharmacol. 2024;38(5):432-457. doi: 10.1177/02698811241249698
41. Gründer G, Brand M, Mertens LJ et al. Treatment with psychedelics is psychotherapy: beyond reductionism. Lancet Psychiatry. 2024;11 (3):231-236. doi: 10.1016/S2215-0366(23)00363-2
42. Brennan W, Belser AB. Models of psychedelic-assisted psychotherapy: a contemporary assessment and an introduction to EMBARK, a transdiagnostic trans-drug model. Front Psychol. 2022;13:866018. doi:10.3389/fpsyg.2022.866018
43. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177(5):391-410. doi: 10.1176/appi.ajp.2019.19010035
44. Kaelen M, Giribaldi B, Raine J, et al. The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology (Berl). 2018;235(2):505-519. doi: 10.1007/s00213-017-4820-5
45. 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
46. Fonseka LN, Woo BK. Therapeutic role of psilocybin and 3,4-methylenedioxymethamphetamine in trauma: a literature review. World J Psychiatry. 2023;13(5):182-190. doi: 10.5498/wjp.v13.i5.182
47. 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
48. Evans J, Robinson OC, Ketzitzidou Argyri E, et al. Extended difficulties following the use of psychedelic drugs: a mixed methods study. PloS One. 2023;18(10):e0293349. doi: 10.1371/journal.pone.0293349
49. Graziosi M, Singh M, Nayak SM, Yaden DB. Acute subjective effects of psychedelics within and beyond WEIRD contexts. J Psychoactive Drugs. 2023;55(5):558-569. doi: 10.1080/02791072.2023.2255274