CATR: Dr. Trujillo, you have done research and have published widely on the pharmacology of ketamine. Before we discuss the addiction risks, can you run us through some of the evidence for ketamine’s therapeutic effects?

Dr. Trujillo: It’s helpful to start with its origins. Ketamine was FDA approved for use in anesthesia in 1970, so we have 50 years of experience with it in medicine. Work on depression began more than 30 years ago in animal models (Trullas R and Skolnick P, Eur J Pharmacol 1990;185(1):1–10; Pilc A et al, Biol Psychiatry 2013;73(12):1125–1132). Jumping forward 10 years, the first human data on ketamine for depression appeared in 2000 with a small double-blind study showing significant improvement in depression just four hours after an IV ketamine infusion with effects lasting 72 hours (Berman RM et al, Biol Psychiatry 2000;47(4):351–354). Subsequent studies have showed significant therapeutic effects at 24 hours that last as long as 7–14 days (Walsh Z et al, BJPsych Open 2021;8(1):e19). Ketamine is clearly different than traditional antidepressants. It works in hours instead of weeks with benefits lasting long enough for intermittent dosing. Perhaps most importantly, it can help patients for whom other antidepressants have been ineffective, such as patients with treatment-resistant depression (TRD).

CATR: What was the rationale for looking at ketamine as an antidepressant? 

Dr. Trujillo: There was a gradual accumulation of findings pointing to the central role of glutamate in depression. The thought was that ketamine, as a glutamate receptor antagonist, might be able to modulate depression in a novel way. But ketamine acts on a variety of receptor targets and has multiple bioactive metabolites, so we still have questions on whether its antidepressant effects are purely due to glutamate antagonism or something else. And it seems glutamate plays a central role in other psychiatric disorders as well. There is work on potential ketamine treatment for bipolar disorder, OCD, PTSD, anxiety, anorexia, and—perhaps paradoxically—substance use disorders (SUDs).

CATR: That does seem paradoxical. Ketamine itself can be addictive, and misuse can have serious medical consequences.

Dr. Trujillo: That’s true. In the United States, we see relatively low ketamine misuse, about 1% of the US population (Van Amsterdam J and Van Den Brink W, Expert Opin Drug Saf 2022;21(1):83–94). I think that has to do with its subjective effects. Ketamine tends to produce a mix of rewarding and aversive effects that, for most people, balance each other out and limit high dose or frequent use. This is very different than other illicit drugs like opioids and stimulants, which are powerfully reinforcing. When we’re looking at long-term adverse effects, the keys are dose and interval. The higher the dose and the more frequently the drug is taken, the higher the risk. Relative to anesthetic and recreational doses, antidepressant doses are quite low. And the interval is intermittent, so when used properly, we expect low rates of addiction and long-term adverse effects. 

CATR: What is “proper” dosing for ketamine in depression?

Dr. Trujillo: Recommended IV ketamine dosing is 0.5 mg/kg given over 40 minutes or so (McIntyre RS et al, Am J Psychiatry 2021;178(5):383–399). It should be given in a closely monitored medical setting. There is a lot yet to be determined, but treatment frequency is typically one to three times a week to determine if a patient will respond. Response after four to six infusions is considered successful treatment. Frequency is then usually decreased for maintenance therapy. 

CATR: And rates of adverse effects are low when it’s dosed this way?

Dr. Trujillo: Yes, we see higher rates of complications with heavy use. A recent analysis found that those who use recreationally had more than 90 times the cumulative exposure to ketamine than those treated for depression; for some, the exposure was as much as a thousand-fold more (Van Amsterdam and Van Den Brink, 2022). Some people use ketamine very occasionally, in party settings at doses that provide mild effects. The risk there is probably low. But others use in binges—they’ll buy ketamine, perhaps to use at a party, but then they can’t stop until their supply runs out. Ketamine has a short duration of action, so it encourages repeat use. People who use it in this manner are at a substantially elevated risk. The other group at high risk consists of individuals referred to as “psychonauts”—people seeking the deep dissociative effects, known as a “k-hole,” that are seen with very high doses. People report near-death experiences, rebirth experiences, losing themselves to become one with the universe, having conversations with God. Some seek that sort of effect, but most are afraid of it; the loss of ego can be very frightening. 

CATR: What are the risks of developing ketamine use disorder?

Dr. Trujillo: Ketamine is a DEA Schedule III substance, which is defined as having “moderate to low potential for physical and psychological dependence.” Schedule III drugs show less risk than Schedule I or II but do have risk for SUD. And taking large amounts of ketamine, outside of professional supervision, is a risk factor. Indeed, there are several case reports in the medical literature of ketamine use disorder in individuals who used ketamine recreationally, and there is at least one case report of an individual self-medicating with ketamine for bipolar disorder and developing ketamine use disorder after taking large quantities of the drug daily for five years (Liu JX et al, Am J Addict 2015;24(1):7–9). 

CATR: What about physical adverse effects?

Dr. Trujillo: The side effects from frequent use are primarily in two domains. The first is cognitive deficits that manifest as impairments in learning, memory, and attention. In people engaged in recreational ketamine use, imaging studies have noted decreased brain volume affecting both gray matter and white matter (Van Amsterdam and Van Den Brink, 2022). The other area is lower urinary tract symptoms (LUTS). These begin with pain during urination, urgency, and occasional incontinence. Continued ketamine use can develop into permanent incontinence and ulcerative cystitis that manifests as persistent pelvic pain and bleeding. Finally, those who use ketamine frequently can also experience abdominal pain, sometimes called “k-cramps.”

CATR: Are these effects reversible?

Dr. Trujillo: The full answer is that we don’t know, but for most people who use ketamine, the LUTS and the cognitive deficits seem to largely resolve after ketamine is stopped. 

CATR: And how does esketamine play into all this?

Dr. Trujillo: Ketamine is a racemic mixture that includes both S-ketamine and R-ketamine in roughly equal amounts. Esketamine is the purified S-enantiomer of ketamine. So, anyone getting racemic ketamine is also getting esketamine, in a way. But esketamine on its own was approved for use in 2018 under the brand name Spravato on a fast-track designation for TRD. In 2020, it was approved for major depression with suicidal ideation or behavior (Miscel NA and Balon R, J Clin Psychopharmacol 2021;41(3):233–235). It’s normally used intranasally, at 56 or 84 mg. There’s a widely used protocol that starts with the induction phase, with twice-weekly administration for four weeks. This is followed by the maintenance phase, which involves weekly administration for four weeks transitioning to either weekly or once every two weeks, depending on the needs of the patient. 

CATR: How do ketamine and esketamine compare in terms of addictive and misuse potential? How do the potential long-term adverse sequelae compare?

Dr. Trujillo: Subjective effects at therapeutic doses are similar between ketamine and esketamine—dissociation, dizziness, some sedation. A critical difference in terms of addictive potential comes down to the fact that esketamine can only be given in a clinical setting certified with a risk evaluation and mitigation strategy (REMS) program. The potential for misuse is part of the reason the FDA put a REMS program in place. Between the REMS program and the fact that esketamine isn’t available on the illicit market, we don’t see esketamine misuse or addiction. And since esketamine isn’t being used at very high supratherapeutic doses, the risk of long-term LUTS and neurocognitive deficits are low.

CATR: What are your thoughts on the proliferation of private-pay ketamine clinics, many of which are veering outside of typical treatment standards? 

Dr. Trujillo: A quick internet search shows how many of these clinics are out there. Some appear to be legitimate—they have a well-trained psychiatrist on staff, and they offer a broad range of options to patients with TRD. Others appear less legitimate, with websites that tend to be full of flowery language and have a New Age kind of feel. They often speak about personal growth or discovery but not the treatment of a psychiatric disorder.

CATR: Do you have recommendations for patients about how to choose between ketamine clinics?

Dr. Trujillo: When it comes to a serious psychiatric condition like TRD, patients should stick to the experts whenever possible. Academically affiliated clinics are a good place to start. Beyond that, I’d steer clear of places run by doctors without any mental health experience. Clinics should be focused on treating depression, and patients should be presented with a range of options rather than only ketamine. Places that offer oral ketamine should be avoided as well. Some clinics will prescribe oral formulations that come in a lozenge form called a troche (pronounced TRO-key). There’s no documented evidence for this form’s effectiveness in treating depression, and we can’t assume that it is equivalent to the IV form. The bioavailability of oral ketamine is low, around 15%, and first-pass metabolism makes it likely that metabolites are going to be very different between oral and IV delivery. Prescribers offering ketamine troches should get a red flag as going way outside the evidence base. In fact, the FDA recently released an alert concerning the risks of off-label compounded ketamine in which they specifically emphasized the potential dangers of oral formulations (www.tinyurl.com/3a9f59d7).

CATR: What about teleprescribing of ketamine? There have been some horror stories in the lay press (www.tinyurl.com/2ms38f2p).

Dr. Trujillo: Teleprescribing of ketamine took off during COVID, which was a once-in-a-lifetime situation that opened all sorts of avenues that were previously unavailable. Given the nature of ketamine and its mixture of pleasurable and aversive subjective effects that we discussed earlier, I doubt that ketamine is going to lead to an epidemic of addiction like methamphetamine or heroin. On the other hand, our evidence base for ketamine is with IV infusions (or intranasal, in the case of ­Spravato) performed in professional healthcare settings. We have no frame of reference in terms of safety when patients are taking ketamine at home. Could there be a future in which ketamine is given at home, perhaps through teleprescribing? Maybe, but there would have to be an evidence base to support its efficacy and safety before I would ever recommend it, and we’re nowhere close to that in terms of the research.

CATR: Most of our readers won’t be prescribing ketamine themselves. How can they help mitigate some of the risks we’ve discussed here?

Dr. Trujillo: Let’s say you’re seeing a patient who is thinking about starting ketamine. Or maybe you think ketamine might be a good option for a patient you are seeing with TRD. The first thing to ensure, just like with any medication, is that the patient is fully informed of the risks and benefits before starting. That’s just basic prescribing, but with ketamine it’s so important because there are so many cultural narratives floating around out there. Ask what your patient has heard. What is their understanding of ketamine? What are their concerns? And it helps to obtain a consultation if you don’t have experience as a ketamine prescriber yourself; that way you can inform patients about what to expect. For example, there are basics that all ketamine and esketamine prescribers should adhere to: monitoring of vital signs, observation for at least two hours following a dose, no driving until the next day. Patients need to know about these logistical issues beforehand. And patients should be carefully prescreened. Do they have a history of ketamine misuse? What about misuse of other club drugs or hallucinogens? What about addiction in general?

CATR: Is history of addiction a contraindication for ketamine treatment?

Dr. Trujillo: In my opinion, it shouldn’t be. Depression is a potentially fatal disorder. I’d be wary about automatically excluding anybody. I think patients with SUD should be closely monitored, just like any other patient, and the addictive and misuse potential of ketamine should be discussed thoroughly. Withholding treatment from someone who could benefit can have devastating consequences on its own. Not only might depression go untreated, but someone could turn to the streets to buy ketamine. Unfortunately, what they purchase could be adulterated with a potentially lethal drug like fentanyl, or it could be a different drug altogether. And even if one obtains the correct product, there’s no guarantee it’s the correct dose. 

CATR: Any specific suggestions for patients with a history of SUD getting ketamine?

Dr. Trujillo: Opioid contracts are commonly used in pain clinics, and some of those same principles can be applied when starting ketamine. And if treatment needs to be stopped, whether for doctor shopping, buying off the street, or simply inadequate antidepressant effect, make sure patients know about alternative approaches like transcranial magnetic stimulation or ECT. Importantly, have these conversations at the outset. Also, keep in mind that people sometimes use substances because they are depressed. If you can find a good treatment, and that might be ketamine, substance use might decline. And that takes us to the paradox of ketamine as a possible SUD treatment. 

CATR: How might ketamine work to treat SUD? 

Dr. Trujillo: Research in the area is preliminary but promising. Most studies have been done in patients with opioid or alcohol use disorders, and the intervention was often intensive ketamine-assisted psychotherapy (Ezquerra-Romano I et al, Neuropharmacology 2018;142:72–82). It’s not unlike the paradigm being investigated for psilocybin-assisted psychotherapy for SUD. (Editor’s note: See our interview with Dr. Bhatt in this issue.) More work needs to be done to tease out ketamine’s effect versus therapy’s effect versus any synergistic combination of the two. Ketamine can be an important piece of the treatment puzzle, but just like anything else, it needs to be placed in the context of the whole patient.

CATR: Thank you for your time, Dr. Trujillo.

For more on this topic, see the webinar, Ketamine and the Evolving Psychopharmacologic Pipeline for Depression.