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Psychiatrist Muhamad Aly Rifai discusses his article “A psychiatrist’s 20-year journey with ketamine.” Aly recounts his first encounters with ketamine at the National Institute of Mental Health, where its rapid impact on despair reshaped his understanding of depression treatment. He explains the neurobiologic mechanisms, the shift from research to real-world practice, and the FDA’s evolving stance on esketamine and off-label IV ketamine. Aly emphasizes the importance of pairing ketamine with psychotherapy, screening patients carefully, and honoring both the power and limitations of this intervention. He also highlights access challenges, safety concerns, and the need for clinicians to build structured protocols. Listeners will take away a nuanced view of ketamine not as a miracle cure but as a catalyst for healing when embedded in comprehensive, patient-centered care.
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Transcript
Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today we welcome back Muhamad Aly Rifai, a psychiatrist and internal medicine physician, talking about his latest article, “A psychiatrist’s 20-year journey with ketamine.” Muhamad, welcome back to the show.
Muhamad Aly Rifai: Thank you very much for having me today to talk about a very important and timely topic: ketamine treatment.
Kevin Pho: All right, so talk about that article, but before you do, just give us a definition of ketamine to get everyone on the same page, and then tell us your journey with it.
Muhamad Aly Rifai: Sure. So ketamine is a compound that was discovered and FDA-approved in the late sixties as an anesthetic. It was also used as a veterinary medication for anesthesia for animals. It was then approved by the FDA as an anesthetic, and it’s recognized as one that causes very little respiratory depression. So it’s given to individuals in the emergency room or to neonates and kids because it causes a significant calming effect, anterograde amnesia, and it also has a psychedelic-like effect.
It was approved as an anesthetic and was used in anesthesia for the longest time and was very effective. People then started noticing that when it was given for anesthesia, it had this psychedelic effect where it elevated people and caused a dissociative effect. We recognize that it causes a temporary blockade of the NMDA receptors, which triggers a significant biochemical reaction and works on the AMPA receptors. We discovered that it had an antidepressant effect in the late eighties and nineties.
So it became a focus of attention. But in its background, it’s an anesthetic, FDA-approved for anesthesia. We started studying it, and that was part of my journey. I was completing my residency at the University of Virginia in internal medicine and psychiatry in the late nineties. I then did work and a mini-fellowship at the National Institute of Health in Bethesda, Maryland. That was my first exposure to ketamine in a psychiatric realm because they were doing trials on ketamine with an intravenous infusion to see if it can relieve symptoms of depression. The results were amazing, and this was around 2003 to 2006.
Kevin Pho: So we hear about ketamine in the mainstream media. Tell us clinically, how is it being prescribed and used today?
Muhamad Aly Rifai: When we started utilizing ketamine, it was mostly given intravenously. Ketamine, in its FDA-approved formulations in the United States, comes in vials, so it’s approved for intravenous infusion and sometimes can be given intramuscularly. Our work at the National Institute of Mental Health found that an intravenous infusion of ketamine at low doses, which are not the anesthetic doses, had a significant antidepressant effect. The doses were 0.5 milligrams per kilogram up to 1 milligram per kilogram, which is different from the anesthetic doses of around 3 to 4 milligrams per kilogram.
A lot of the colleagues that I worked with at the National Institute of Mental Health went to pharmaceutical companies and isolated the two isomers. Racemic ketamine, which is the compound that’s in the vials, has two compounds: a right-sided isomer and a left-sided isomer, esketamine and arketamine. They focused on esketamine, and Johnson & Johnson’s Janssen Pharmaceutical developed it later on and utilized it as an intranasal formulation. In 2018 or 2019, it was FDA-approved as a treatment for depression under the brand name Spravato as an intranasal treatment.
That was the first FDA-approved indication for ketamine in any form for depression. It was later approved for the treatment of suicidal ideation in the context of depression, and now it has an indication as a monotherapy for major depression. At the same time, a lot of people continued to use intravenous ketamine, the racemic ketamine, and also started utilizing it more in intramuscular injections, which from my research at the National Institute of Mental Health, we found has equal efficacy to intravenous infusions.
Additionally, people and pharmacies started developing other formulations for ketamine, mostly in lozenges and tablets that they utilize. This is all off-label, and these were formulated by compounding pharmacies. We now know that the amount of ketamine that gets into somebody’s bloodstream from these formulations is pretty low. So right now in the United States, what’s approved for the treatment of depression is only the esketamine compound, mostly as an intranasal spray. The use of intravenous ketamine and intramuscular ketamine, as well as the lozenges, is all off-label. So that’s the lay of the land of what’s available right now.
I talked in the article also about some formulations that are gaining momentum in terms of FDA approval. With the administrative changes at the FDA and HHS, there is significant interest in pushing for other formulations of ketamine as an alternative to antidepressants, and because it’s a psychedelic compound as well. So, there are fast-track approvals for intravenous ketamine for the treatment of depression. There are fast-track approvals for intramuscular ketamine for pain management, as well as treatment of depression. And there are also clinical trials for the utilization of arketamine in a tablet form for the treatment of acute depression, either with antidepressants or alone. So there’s a lot of movement right now in the field of ketamine with new products becoming available because of the significant interest and because the focus of the current administration and the FDA is to move away from SSRIs and antidepressants to other helpful compounds.
Kevin Pho: Now talk to us from the patient perspective. What’s it like for them when they’re taking the intranasal esketamine along with the IV version? How often do these medicines have to be given and what can patients expect after taking these medications?
Muhamad Aly Rifai: Sure. When we started the intravenous ketamine at the National Institute of Mental Health, it was an infusion over forty-five minutes. The patient prepared like it was a surgical procedure, so they were without food or drink for at least twelve hours prior. The patient was hooked to a monitor, and this is what I do in my office. We monitor them closely; they’re hooked to a blood pressure monitor, a pulse oximetry, and sometimes heart monitoring. They’re monitored for up to two hours and then they go home. They have to have somebody drive them. This is for the intravenous ketamine infusion, and most centers continue to do that, though sometimes the monitoring may be a little bit shorter.
Based on those parameters, the Food and Drug Administration established a REMS (Risk Evaluation and Mitigation Strategies) program for Spravato, the intranasal spray. Patients are enrolled in this program, and clinics that administer the medication are enrolled. The patient is NPO before they receive the intranasal Spravato spray, and then they’re monitored for up to two hours in a clinic with blood pressure monitoring, heart rate monitoring, and continuous monitoring as they receive those doses. Again, somebody has to drive them home.
They may be a little bit sedated, but from the patient’s perspective, a lot of them feel that the medication significantly improves their depressive symptoms. A lot of patients swear by it, that they have a lifting of the veil or the cloud of depression that engulfs them when they receive ketamine treatment. It’s also sometimes used off-label for other psychiatric disorders, such as post-traumatic stress disorder and anxiety. Patients see a lot of benefits from the medication. For Spravato, we have seen that most patients will derive significant benefits, but many will continue to need periodic nasal spray sessions. It varies depending on the severity of the patient’s condition. We’ve seen the same things with intravenous infusions. The effect may plateau, but patients may continue to derive benefits from the continued infusions they get, both intravenous and intranasal. So the benefits are pronounced and significant. We also see significant benefits for individuals who experience suicidal ideation, where intranasal esketamine is approved, and patients derive significant benefits from that because it leads to the complete resolution of suicidal ideation within hours.
What I see is that the administration of ketamine should only be administered in a protective setting. We’ve had in the news the unfortunate situation of actor Matthew Perry, who lost his life after using multiple substances, including ketamine, which he received through lozenges and other formulations, and he combined it with other substances. So the use of ketamine can be dangerous if it’s not in a supervised and monitored clinical setting.
Kevin Pho: Now, how durable are these effects and how often do patients have to come back for repeated treatments?
Muhamad Aly Rifai: It varies with patients, but there are some who will require weekly treatments. The initial protocol that we did at the National Institute of Mental Health for intravenous ketamine required intravenous infusions up to three times a week for two to four weeks. We saw significant improvement in the symptoms of depression within hours and days; the patients were much better. But we’ve also seen that once a patient is stable, they may require maintenance treatments, both with intravenous and intranasal ketamine. There are patients that require monthly, weekly, or biweekly ketamine treatments to maintain the antidepressant effect. We have patients who’ve been on treatment for several years and continue to derive benefit from ketamine.
Kevin Pho: So, in a primary care setting, are there specific types of patients who may be better suited to ketamine versus an SSRI?
Muhamad Aly Rifai: In a primary care setting, I think a referral to a psychiatrist for them to have a discussion about ketamine is best. Ketamine can only be administered in a psychiatric setting. Now, I know there is publicity about freestanding ketamine clinics that are managed by anesthesiologists where it’s only a medical model. A person comes in, they receive intravenous ketamine, and there’s very little psychiatric input. That is usually not recommended because of the complexity of this issue. Though I know throughout the United States, there are many ketamine clinics where it’s only a medical, anesthesia-based model without input from psychiatrists.
But I think input from a psychiatrist, as well as involving a therapist, is important. There should be preparation for the session because it leads to a dissociative effect. People feel like they’re free-floating in the air, and they have a dissociation and catharsis related to trauma or depressive symptoms. Unless there is pre-work for the session, a consultation with a therapist, and after-session work, that benefit could be lost or not maximized if there’s no involvement from a therapist. So I think a referral to a psychiatrist would be the most productive avenue for a patient experiencing severe depressive symptoms. Now with ketamine being FDA-approved in the nasal spray format as a monotherapy for depression, that is an option for a patient who does not want to engage in antidepressant medications.
Kevin Pho: And in terms of complications and potential side effects of ketamine, what do we have to look out for?
Muhamad Aly Rifai: Sedation is the main side effect. Unless there are high dosages, respiratory depression is very unheard of. Elevated blood pressure is one of the main side effects that we monitor for in the clinic, and sometimes tachycardia can happen. But that’s why we monitor for these things; they’re transitory and self-limiting and return to normal after the treatment. Of course, there’s sedation afterwards, and sometimes the dissociative effect can be alarming and frightening to people, and they can have an adverse reaction to that. Preparing the patient for what’s going to happen in the treatment is very important. But we see that most people have the treatment without any significant side effects, and it’s been used long-term and we haven’t seen any significant side effects. The REMS program has good data to show that it is safe and can be administered in a monitored setting.
Kevin Pho: We’re talking to Muhamad Aly Rifai, a psychiatrist and internal medicine physician. Today’s KevinMD article is “A psychiatrist’s 20-year journey with ketamine.” Muhamad, let’s end with some take-home messages for the KevinMD audience.
Muhamad Aly Rifai: Ketamine is an effective treatment for depression. For individuals who have not benefited from antidepressant medications, it has produced a dramatic, rapid, and effective improvement in depressive symptoms. It is coming in the future in other formulations that are going to be available to patients. But now it can be used in an intravenous form off-label and it has a nasal spray form that is available with an FDA approval for the treatment of depression. It is effective, it is helpful for our patients, it relieves depression and suicidal ideation, and it offers great hope to individuals who are struggling with symptoms of depression.
Kevin Pho: Muhamad, thank you so much for sharing your perspective and insight, and thanks again for coming back on the show.
Muhamad Aly Rifai: My pleasure. Thank you.