Ketamine, a general anesthetic, has been found to rapidly alleviate treatment-resistant unipolar and bipolar depression at low doses. Until fairly recently, we weren’t exactly sure how ketamine worked, but advancing research is shining light on ketamine’s mechanism of action. In this post, I’ll address misunderstandings about ketamine’s mechanism of action, share what ongoing research is elucidating about how ketamine works, and address concerns about long-term use of ketamine.
Is ketamine an opioid? Research suggests it isn’t.
In March of 2019, the United States Food and Drug Administration approved the use of ketamine in the form of a nasal spray to treat depression. Despite this approval, there’s been a lot of reservation surrounding the use of ketamine.
One of the reasons for this is that many people believed that ketamine was an opioid. This is because, in late 2018, researchers at Stanford University and Palo Alto University reported that naltrexone, which we know is a drug that blocks opioid receptors, also prevented the antidepressant effects of ketamine. This led the researchers to conclude that ketamine must accomplish its antidepressant effects by binding to opioid receptors, and therefore, it must be an opioid.
Of course, this belief that ketamine is an opioid led to skepticism, both on the part of healthcare professionals (who were hesitant to recommend treatment with ketamine in treatment-resistant depression patients as a result) and on the part of potential patients (who were reluctant to be treated with a drug that belonged to a class that is involved in a widely-publicized national epidemic).
This continued until the second half of 2019, when researchers out of Johns Hopkins referenced a series of studies and reported that there’s “plenty of evidence” suggesting that ketamine isn’t an opioid.  According to Adam Kaplin, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, the evidence supporting the idea that ketamine does not bind to opiate receptors, but instead binds to an entirely different receptor—the NMDA receptor—and works in an entirely different way is plentiful.
If ketamine isn’t an opioid, why does naltrexone interfere with ketamine’s antidepressant effects?
Kaplin explained that ketamine is an NMDA antagonist. Ketamine’s inhibitory action on the NMDA receptors leads to mammalian target of rapamycin (mTOR) being turned on. This action is required for ketamine’s antidepressant properties.
Low-level opioid receptor activity suppresses cyclic AMP (cAMP). Because naltrexone inhibits opioid receptors, when a person takes naltrexone, cAMP levels increase. This increase in cAMP shuts mTOR down, which explains why ketamine’s antidepressant effects do not occur in the presence of naltrexone.  Naltrexone blocks the antidepressant effects of ketamine through its effects on cAMP, not through direct inhibition via the opioid receptor.
What is recent research showing about how ketamine works in the treatment of depression?
Pre-clinical research has suggested that the antidepressant effects of the NMDA antagonist ketamine is dependent on the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)1B receptor. Furthermore, we know that patients diagnosed with major depressive disorder (MDD) tend to have lower density of 5-HT1B receptors in limbic brain regions.
A recent, randomized, double-blind, placebo-controlled trial involving thirty selective-serotonin reuptake inhibitor-resistant patients who had been diagnosed with MDD is shining light on how the drug exhibits its antidepressant effects. Participants were randomized to double-blind therapy involving either 0.5 mg/kg ketamine or placebo (normal saline) infusion. Participants were given a radioactive marker that binds to serotonin 1B receptors and their brains were imaged with positron emission tomography (PET) cameras both before the infusion and 24-72 hours after.
By the end of the study, researchers reported an inverse correlation between the antidepressant effects of ketamine and baseline 5-HT1B receptor binding in the ventral striatum of patients diagnosed with MDD. Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet, and one of the study authors, was cited as saying the following: “We show for the first time that ketamine treatment increases the number of serotonin 1B receptors.” 
Concerns for long-term use of ketamine
Because the research on ketamine is still developing, we aren’t exactly sure what the implications are for long-term use. A systematic review reported that “after acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depression.” 
Lundberg, the study author most recently cited, was also reported to have stated that the additional knowledge that their study has contributed to the general body of research regarding exactly how ketamine works may be useful in developing novel therapeutics that do not have the adverse effects that can be associated with ketamine use.
In closing, low doses of ketamine have been found to exhibit rapid antidepressant effects in cases of both unipolar and bipolar depression. The mechanism of action of ketamine’s antidepressant effects is still being elucidated; while the research is still developing, at this point, we know that ketamine does not bind to opioid receptors. Instead, it is an NMDA antagonist that likely increases the concentration of serotonin 1B receptors in the deep areas of the brain. This is what the current research shows about how ketamine accomplishes its antidepressant effects.
 Johns Hopkins Medicine. (2019, July 31). Ketamine isn't an opioid and treats depression in a unique way. ScienceDaily. Retrieved November 18, 2020 from www.sciencedaily.com/releases/2019/07/190731102154.htm
 Wang, M., & Kaplin, A. (2019). Explaining Naltrexone's Interference With Ketamine's Antidepressant Effect. The American journal of psychiatry, 176(5), 410–411. https://doi.org/10.1176/appi.ajp.2019.19010044
 Karolinska Institutet. "How ketamine combats depression." ScienceDaily. ScienceDaily, 31 May 2020. <www.sciencedaily.com/releases/2020/05/200531200337.htm>.
 Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K. (2018). Side-effects associated with ketamine use in depression: a systematic review. The lancet. Psychiatry, 5(1), 65–78. https://doi.org/10.1016/S2215-0366(17)30272-9