Ketamine in Pain Management and Psychedelic-Assisted Therapy with Dr. Nick Schiavoni

Ketamine is no longer just an anesthetic confined to the operating room. Clinicians and researchers are now studying how it can help in pain management and mental health treatment. With a growing body of research on its use for chronic pain, depression and existential distress, ketamine has become a distinctive agent in modern medicine. In our recent webinar, Dr. Nick Schiavoni, an anesthesiologist with expertise in pain management and psychedelic medicine, joined Dr. Houman Farzin to discuss ketamine’s potential, its complex mechanisms, and how it can be integrated safely into mental health treatment. Here are some key takeaways.

A Brief History of Ketamine in Medicine

Ketamine was first synthesized in 1962 and gained FDA approval as a general anesthetic in 1970. It quickly became a critical tool, widely used in hospitals, emergency rooms and even on the battlefield, because it can induce anesthesia without suppressing breathing or causing severe drops in blood pressure. This made it especially valuable in resource-limited settings, such as during the Vietnam War, where it was used extensively as a battlefield anesthetic. Over time, doctors and researchers observed its pain-relieving and antidepressant effects. In recent years, research into its use for acute and chronic pain and for mental health has grown, leading to approaches such as ketamine-assisted psychotherapy (KAP). Using racemic ketamine for depression or chronic pain is off-label; the related medicine esketamine (Spravato) is FDA-approved for treatment-resistant depression and for major depressive disorder with acute suicidal thoughts or behavior.

Ketamine as a Multidimensional Pain Management Tool

Beyond its conventional role in anesthesia, ketamine may be a useful tool for addressing the many dimensions of pain, a concept known as ‘total pain’. First introduced by Dame Cicely Saunders, the founder of the modern hospice movement, total pain recognizes that pain is not just a physical sensation. It is an experience with physical, psychological, social and spiritual components, and each person’s pain draws on these dimensions in different ways. For many patients, especially those with chronic conditions or terminal illnesses, unaddressed emotional and existential suffering can amplify physical pain. Dr. Nick described ketamine as unusual in that it may act on all four components of pain at once. In his view, its pharmacology lets clinicians target the interconnected nature of pain, and this ability to work on several levels is what makes ketamine such a versatile tool in whole-person pain care.

By easing physical and psychological pain, ketamine may help patients reconnect with themselves and others, which can lessen social pain. For patients living with spiritual or existential pain, especially near the end of life, ketamine’s psychedelic properties come into play and can offer room for meaning-making in a supported setting. This is why, in Dr. Nick’s view, ketamine can be more than a pain reliever.

Ketamine’s Complex Mechanism of Action

So how does ketamine actually work? Unlike traditional pain medications that act mainly on opioid receptors, ketamine works on several pathways in the brain and body. Dr. Nick described it as “a different animal” and noted that “ketamine works on multiple different receptors.” He broke its therapeutic effect into three main components: “You have your pharmacological component, you have this element of neuroplasticity, and then you have this psychedelic experience. And those three things together contribute to ketamine’s therapeutic benefit.”

NMDA antagonism: “Ketamine’s primary mechanism of action is this NMDA antagonism,” Dr. Nick explains. But what does that mean? NMDA receptors respond to glutamate, the brain’s main excitatory neurotransmitter. An antagonist is a substance that blocks a receptor. At anesthetic doses, blocking NMDA receptors broadly produces sedation and dissociation. At the lower doses used for depression, one leading theory is that ketamine blocks NMDA receptors mostly on inhibitory neurons, the cells that normally act as the brain’s brakes. With those brakes released, excitatory neurons fire more and release a burst of glutamate. That burst activates other receptors (AMPA receptors) and triggers growth signals such as BDNF, which are thought to support the formation of new connections between neurons. This is the neuroplasticity researchers talk about: a period in which the brain may be more able to adapt and strengthen certain pathways.

Dr. Nick compared this state, which seems ripe for learning, to how muscles get stronger with exercise. In his view, the new connections formed during this window may support lasting changes in how a person thinks and copes, which is part of why ketamine can do more than numb pain.

However, ketamine’s effects extend beyond NMDA receptors. It also has weaker effects at opioid receptors, including mu and kappa receptors, influences dopamine and serotonin signaling, and appears to have anti-inflammatory properties. Researchers think these actions may contribute to its effects on pain and mood, though how much each one matters is still being studied.

Dr. Nick also discussed research on the opioid system’s role in ketamine’s acute antidepressant effect. “When you combine ketamine with naltrexone, which blocks the opioid receptors, the acute antidepressant effects disappear,” he said, describing a small 2018 Stanford study. This finding is contested: later studies did not find the same effect, and researchers still disagree about how much the opioid system matters. What most clinicians agree on is that the longer-lasting benefits seem to depend on what happens after a session, including therapy and the changes a person makes during the period of heightened neuroplasticity.

Ketamine’s Psychedelic Effects in Therapy

Ketamine is often described as a psychedelic, and its dissociative and hallucinogenic effects are frequently highlighted in pop culture and media. While anesthesia settings usually aim to suppress these experiences, ketamine-assisted psychotherapy works with them. “In the hospital, we’re trained to minimize ketamine’s psychedelic effects because they can be disorienting,” Dr. Nick shared. “But in a controlled therapeutic setting, those same effects can be profoundly healing.”

Dr. Houman added, “In a psychotherapy setting, we use [ketamine] to unlock the gates to the subconscious, allowing repressed material to emerge and be explored in a controlled and safe manner.” This material, memories and emotions, has often been buried for years, even decades. Bringing it to the surface with a therapist present can open a window into trauma, grief or other emotional wounds, and an opportunity for meaningful therapeutic work.

Dr. Nick described how a ketamine session can feel for patients: “It has a lot of the components of a mystical experience. It brings about these feelings of pure love, joy, happiness. It induces a state of ego dissolution, fostering connectedness to self, to others, to the universe. And often there’s these interactions with the divine and deeply spiritual or religious components.” He pointed out that ketamine may help patients work through the existential questions that often arise near the end of life, such as “Why me? What comes next?”, and may ease fear, emotional suffering and unresolved trauma. Experiences vary, and not everyone has an experience like this.

Dr. Nick noted that ketamine has not been studied for existential distress as much as some other compounds. Psilocybin, which remains investigational and is not FDA-approved in the US, has drawn more research attention in this area, even though ketamine can produce comparable non-ordinary states. Compared with other psychedelics, ketamine offers a more controlled and predictable experience. “We can safely guide patients into a non-ordinary state of consciousness,” Dr. Nick said. He emphasized that many patients who are hesitant about psychedelics may still benefit from ketamine in a structured, medically supervised setting.

Dr. Houman then stressed the importance of a patient-centered approach. “Some patients are really into the more psychedelic oriented outlook, while others prefer it medical. And I think, wherever anyone sits on that spectrum, we should respect that.” He continued, “We can facilitate healing experiences regardless of how it’s done, as long as we’re respecting set and setting and developing the right sort of therapeutic alliance by maintaining awareness of our responsibility in that power dynamic when patients are in these vulnerable states.” Ultimately, the clinician’s responsibility is to create a safe, supportive space where each patient can heal in a way that feels right for them.

Ketamine Therapy Integration and Risks

As promising as ketamine-assisted therapy is, both doctors emphasized the importance of careful integration and responsible use. “Most of the work takes place in the integration phase,” Dr. Houman stressed. He continued, “This altered state experience reveals what work needs to be done, and then you actually have to do the work.” Therapy is just as important as the medicine itself. Ketamine can open a door, but it is through integration, with the help of skilled clinicians, that patients make sense of their experiences and turn them into lasting change.

There are also important risks to consider. Ketamine can temporarily raise blood pressure and heart rate, which makes it unsuitable for some patients with cardiovascular conditions. Concerns about dependency and misuse also highlight the need for careful medical oversight. “One of the things that we’re seeing more now is ketamine being offered at home with minimal oversight,” Dr. Houman cautioned. Ketamine has gone from a medicine always given by an anesthesiologist in a hospital setting to one that is sometimes used remotely without direct supervision.

Ketamine is a versatile medicine that shows promise for pain management and mental health treatment. As with any powerful medicine, it must be used responsibly. Dr. Nick and Dr. Houman believe that when it is given with proper screening, support and integration, ketamine may help relieve chronic pain, ease psychological suffering and even help patients find meaning in life’s most difficult moments. Research is still catching up, and there is much left to learn about what ketamine can and cannot do.