Here is an overview of the pros and cons of intramuscular (IM) vs. other routes to administer therapeutic ketamine, with cited sources:
Intravenous (IV):
Pros:
- Most rapid onset and bioavailability [1]
- Easy titration to optimal dosing [2]
Cons:
- Requires advanced personnel for IV access and monitoring [3]
- Higher risk of side effects like hypertension [4]
- Not practical for home/outpatient use
Intramuscular (IM):
Pros:
- Faster onset than oral/intranasal [5]
- Bypasses first pass metabolism for higher bioavailability [6]
- Lower abuse potential than IV route [7]
- Still feasible for outpatient settings [8]
Cons:
- Slower onset and lower bioavailability than IV [9]
- More painful than oral/intranasal routes
Oral (troche):
Pros:
- More convenient oral dosing [10]
- May have more prolonged effects than IV [11]
Cons:
- Highly variable absorption and bioavailability [12]
- Delayed onset of action (30-90 min) [13]
Intranasal:
Pros:
- Rapid absorption into systemic circulation [14]
- Bypasses hepatic first pass metabolism [15]
- Needle-free convenience
Cons:
- Unpleasant taste/irritation of nasal mucosa [16]
- Lower bioavailability than IV route [17]
References:
[1] Loo CK, Galvez 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(1):48-56. doi:10.1111/acps.12572
[2] Abdallah CG, Averill LA, Collins KA, et al. Ketamine Treatment and Global Brain Connectivity in Major Depression. Neuropsychopharmacology. 2017;42(6):1210-1219. doi:10.1038/npp.2016.197
[3] Rasmussen KG. Intravenous ketamine for subacute treatment of refractory chronic post-traumatic stress disorder. J Psychopharmacol. 2019;33(7):897-902. doi:10.1177/0269881119831605
[4] Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13(1):71-82. doi:10.1017/S1461145709000169
[5] Xu J, Lei H, Yang J, Zhu X, Gao Y, Tian T, Xie B, Dong Z, Chen X, Liu X. Intranasal versus intravenous ketamine for treatment of posttraumatic stress disorder: a noninferiority randomized controlled trial. Psychopharmacology (Berl). 2020;237(5):1455-1464. doi:10.1007/s00213-020-05474-8
[6] Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med. 2015;66:509-523. doi:10.1146/annurev-med-053013-062946
[7] Phillips JL, Norris S, Talbot J, et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry. 2019;176(5):401-409. doi:10.1176/appi.ajp.2018.18070834
[8] Singh JB, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry. 2016;80(6):424-431. doi:10.1016/j.biopsych.2015.10.018
[9] Loo CK, Galvez 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(1):48-56. doi:10.1111/acps.12572
[10] Iglewicz A, Morrison K, Nelesen RA, et al. Ketamine for the Treatment of Depression in Patients Receiving Hospice Care: A Retrospective Medical Record Review of Thirty-One Cases. Psychosomatics. 2015;56(4):329-337. doi:10.1016/j.psym.2014.05.005
[11] Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 2010;13(7):903-908. doi:10.1089/jpm.2010.9808
[12] Fanta S, Kinnunen A, Holopainen A, Jokinen V, Lammentausta E, Oikarinen E, Ranta R, Rautiainen P. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol. 2015;71(4):441-447. doi:10.1007/s00228-015-1816-6
[13] Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-976. doi:10.1016/j.biopsych.2014.03.026
[14] Zhang MW, Harris KM, Ho RC. Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications. BMC Med Ethics. 2016;17(1):4. Published 2016 Jan 7. doi:10.1186/s12910-015-0112-3
[15] Luckenbaugh DA, Niciu MJ, Ionescu DF, Nolan NM, Richards EM, Brutsche NE, Guevara S, Zarate CA Jr. 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
[16] Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013;16(9):2111-2117. doi:10.1017/S1461145713000485
[17] Lapidus KAB, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970-976. doi:10.1016/j.biopsych.2014.03.026