Expert: Ketamine, Other Psychedelic Medicines Could Help Address the Opioid Epidemic

Pharmacy Times spoke with Tiago Reis Marques, MD, PhD, CEO of Pasithea Therapeutics, about how investigative psychedelic-assisted therapy could help address both opioid addiction and chronic pain management.

Aislinn Antrim: Hi, I'm Aislinn Antrim with Pharmacy Times and I'm here with Tiago Marques, CEO at Pasithea Therapeutics, to discuss the potential role for psychedelic medicines in addressing the opioid epidemic. Issues around opioids have largely taken a backseat, especially over the last couple of years with COVID-19, but it's starting to get a little bit more attention again. What are some of the key problems in the opioid epidemic that you see?

Tiago Reis Marques, MD, PhD: So, definitely, it's been a huge problem mainly from an addiction perspective and mainly in the United States. It’s very interested how in the US versus Europe there's a current epidemic running in the US, and the first reason is access to medicine that is easier to be accessed in the US. But we need to identify 2 reasons why patients start to take it: medically and then they start using recreationally. Definitely, opioids have strong addiction potential. And while they're still FDA approved drugs, they should be used carefully. We need to think about all the potential of novel approaches to reduce the use of opioids in other diseases, for example, for pain management, and also how to treat patients currently suffering from addiction disorders using novel approaches in psychiatry.

Aislinn Antrim: Absolutely. How could ketamine or potentially other psychedelic medicines address those problems?

Tiago Reis Marques, MD, PhD: So, regarding ketamine, one of the major reasons patients are taking opioids is that opioids are used and abused for the management of pain—chronic pain disorders or any other pain disorders. Ketamine has shown and has gone a long way from being a drug used for anesthesia purposes towards being a drug used for pain management, and also for the treatment of psychiatric disorders such as treatment resistant depression. What we've seen is that even in those cases where patients are not responding to non-opioid interventions for the management of chronic pain syndrome, ketamine has shown to be an effective approach for the treatment of these chronic pain disorders. So, if we can have a drug that avoids patients jumping from non-opioid pain management towards an opioid and have ketamine be a drug that can provide pain relief, that will be very helpful because it will allow us to have another drug in pain management and control. And what we've seen over the past decade is that in specific types of pain, mostly in neuropathic pain, ketamine provides fast relief for these patients. Of course, ketamine is a drug that has some limitations. It provides short term relief and sometimes patients need to enter maintenance treatment to provide the long-term relief of this pain, but definitely for this type of approach, it could constitute a great alternative for patients before they transition to opioid pain management. On the other side, there's also a lot of research being conducted for the use of psychedelics for the treatment of addictions, and these are still under clinical trials. So, it's still being tested but there's supporting evidence nowadays that some types of psychedelics can actually constitute another approach for the treatment of these patients.

Aislinn Antrim: All right, interesting. How do psychedelics differ from opioids in the context of chronic pain management?

Tiago Reis Marques, MD, PhD: Well, I must first say that there's no indication for the use of psychedelics in chronic pain main management. If we think about psychedelics as 5-HT2A agonist drugs, like psilocybin, LSD, and other drugs, if we can have a broad vision about psychedelics and we include ketamine, that is NMDA receptor antagonists. And if we include ketamine as a psychedelic, then as I mentioned before, it could be a great alternative for patients currently not experiencing relief with non-opioid therapies and can constitute an alternative for these treatment-resistant pain syndromes. I must also say that treating pain is never the product of a single drug, it needs to be a multifactorial approach, where you have in place non-pharmacological approaches. So, it's always very important to integrate other approaches rather than a single drug.

Aislinn Antrim: Absolutely. Can you discuss a little bit of the mechanism of ketamine and how does it work?

Tiago Reis Marques, MD, PhD: So, ketamine blocks a receptor in the brain called NMDA. So, NMDA is part of a major neurotransmitter system—that is the glutamate system—and glutamate is known to be involved in pain. So, simplistically, by managing to modulate the glutamate system, we can manage to have an indirect effect on pain management. Furthermore, what racemic ketamine (and I'm saying racemic because there's different variations of the ketamine molecule from esketamine to arketamine) but racemic ketamine is also known to have an effect on Mu-opioid receptors, so part of the opioid system, and that's also a way that ketamine can modulate pain without having the addictive potential of the strong Mu-opioid drugs that are currently named opioids.

Aislinn Antrim: Absolutely. Can you talk a little bit about current data, and what it does show for the efficacy of ketamine potentially for chronic pain management?

Tiago Reis Marques, MD, PhD: So, there's been many trials and reviews and meta-analyses of data. There are different types of pain arising from neuropathy to complex pain disorder and a narrow set of pain. So, there's different type of pains. The one where we see ketamine to be most effective is definitely in neuropathic pain management. Again, with a multidisciplinary approach together with behavioral therapies, activity-based therapies, rather than as a single intervention, we've seen also a dose response activity, so it's different doses of ketamine providing different relief of pain. But overall, a standard dose of 0.5 mg/kg has shown to be effective in this pain relief. Finally, regarding the way we use ketamine, normally it’s not as a single treatment but it is provided as part of different or multiple infusions across a period of time, so 2 to 3 times a week over a period of several weeks. And efficacy has been shown in the short term within the first weeks, but also with some data on the longer term, so after a period of months, but mostly with acute relief in a period of a few weeks. Unfortunately, all the trials that have been conducted have been done with a small sample size, so we lack still well conducted, big sample size studies that can also select a less heterogeneous group of patients. So, what we've seen in pain management is that a lot of studies include nociceptive, nociplastic, complex pain, neuropathic pain, so we need to be able also to reduce the heterogeneity and identify where ketamine acts the best. So, overall, we need still better studies where methodology is more robust.

Aislinn Antrim: Definitely. You've also been studying in-home ketamine infusions, which is different from the more common kind of in-clinic approach. Can you talk about the benefits or the risks as well of in-home infusions?

Tiago Reis Marques, MD, PhD: Yeah, so that's a great question because one of the major problems regarding ketamine has been the access to this treatment. Ketamine is an anesthetic [so] it needs to be provided under medical supervision. And for that reason, typically a patient needs to go to a clinic to receive this treatment. That can limit access to the patients. For example, for pain, a severe acute, or even a chronic pain, it can be very difficult for the patient even to leave their beds to go to a clinic to receive this treatment. And we think that by providing this treatment at home, we are increasing access of patients to this drug. It is paramount to do this in a safe way. That's why all of our infusions are provided by board certified doctors who are infusion specialists and have experience in using ketamine, so mostly an anesthesiologist. Doctors go to the patient's house carrying not only ketamine, but also a bag with rescue medication in case of any side effects, also with a monitor to monitor vital signs so that we can provide these infusion in a safe environment. Furthermore, the doses that we're talking are sub-anesthetic dose, so the risks are much lower. And we truly believe that we can provide this treatment in a completely safe environment.

Aislinn Antrim: That's very interesting. What are safety data showing around this approach and how can any safety concerns be managed for in-home infusions?

Tiago Reis Marques, MD, PhD: So, we are confident that we can provide this treatment and [as long as we] have rescue medications to manage any side effect, we're confident that what we recreate at the patient's house is exactly similar to what you see in any other clinic administering this drug. So, we recreate at the patient’s house a typical ketamine clinic with the same or similar monitoring approach, treatment, and the rescue medication approach. So, it's only at the patient's home. So, from a safety perspective, it doesn't differ at all from a clinic. We've seen this change, particularly with COVID, of patients more and more being managed at home and having access to different types of medication in the comfort of their house. So, we truly believe, and we have data to support this, that the next wave of medical treatment is going to pass also by the at home administration of drugs. We've seen this in other areas of medicine, from cystic fibrosis, to some sorts of neurologic disorders, and we believe that this constitutes a new trend and we are at the forefront of this trend.

Aislinn Antrim: Absolutely. And finally, what do you predict for the future of ketamine and chronic pain management?

Tiago Reis Marques, MD, PhD: There are still currently studies trying to find out who are the patients who would most benefit from this drug. There's a very simplistic approach from patients and the public thinking that ketamine works for all types of pains but that's not true. So, what we need is clear data and more data arising from well conducted studies to better allow us to identify which type of pain actually benefit from this treatment. So, ketamine more and more, is finding its own space in the treatment algorithm of chronic pain management. And that's what we need, are recommendations as part of treatment algorithms. And I think that ketamine is similar to what we've seen in psychiatric disorders, where ketamine is also finding its own space into treatment algorithm. For that, we need data, we need more evidence. There is already enough evidence to provide us support for the use of ketamine in chronic pain management, but more data will allow us to refine what patient population would benefit the most from this drug.

Aislinn Antrim: Wonderful, thank you for talking with me about this.

Tiago Reis Marques, MD, PhD: Thank you so much.