What is prolonged grief disorder?

Prolonged grief disorder (PGD) was added to the DSM-5-TR in 2022 as a formal diagnosis. It describes grief that remains intensely disabling for at least 12 months after a loss (6 months for children), marked by persistent yearning, identity disruption, emotional numbness, difficulty re-engaging with life, and a sense that life has lost meaning. It is distinct from normal grief, which is painful but gradually allows a person to adapt. PGD affects an estimated 7-10% of bereaved adults.

How might ketamine help with grief?

Ketamine promotes neuroplasticity, which is the brain's ability to form new neural connections and reorganize existing ones. In prolonged grief, the brain can become stuck in rigid patterns of rumination and emotional avoidance. By restoring plasticity in the prefrontal cortex and limbic system, ketamine may help the brain process and integrate the loss in ways it has been unable to do on its own. Ketamine also has rapid antidepressant effects that can reduce the co-occurring depression that frequently accompanies prolonged grief.

Is ketamine for grief FDA-approved?

No. Ketamine is FDA-approved as an anesthetic, and its use for prolonged grief disorder is considered off-label. There are no large-scale randomized controlled trials specifically studying ketamine for grief. The evidence comes from case reports, small clinical observations, and the broader research on ketamine's effects on depression, PTSD, and emotional processing. We are transparent about this because informed decision-making matters.

Can I do ketamine therapy while seeing a grief therapist?

Yes, and we encourage it. Ketamine appears to open a window of increased neuroplasticity in the days following an infusion. Working with a therapist during this period may help you process emotions and build new cognitive patterns more effectively than either approach alone. If you are already seeing a grief counselor or therapist, we are happy to coordinate with them.

Will ketamine make me forget my loved one or stop caring?

No. Ketamine does not erase memories or remove the bond you have with the person you lost. What patients describe is not caring less but rather being able to hold the memory without being consumed by it. The goal of treatment is not to eliminate grief but to help the brain move from a stuck, overwhelming state to one where you can carry the loss and still engage with the life around you.

Ketamine for Prolonged Grief: When Loss Gets Stuck

We want to say something clearly before we go any further: grief is not a disorder. Losing someone you love is supposed to hurt. The ache, the waves of sadness, the disorientation of waking up in a world that has fundamentally changed—these are not symptoms to be treated away. They are the cost of having loved someone deeply, and they deserve respect.

What we are writing about here is something different. For a subset of people, the acute phase of grief does not gradually loosen its grip the way it does for most. Instead, it persists at full intensity for months or years, interfering with the ability to work, maintain relationships, or experience anything beyond the loss. The DSM-5-TR recognized this as prolonged grief disorder (PGD) in 2022, describing a condition that affects an estimated 7–10% of bereaved adults and is distinct from both normal grief and major depression.

If you are reading this because you lost someone and the pain has not lifted despite time, therapy, and your best efforts, we want you to know that what you are experiencing has a neurobiological basis. And there may be options you haven’t considered.

What Happens in the Brain During Prolonged Grief

Normal grief involves a gradual process of adaptation. The brain, painful as it is, slowly reorganizes its expectations and emotional responses to accommodate the reality that the person is gone. Neuroimaging studies show this process depends on interactions between the prefrontal cortex (which handles reasoning and perspective-taking) and the limbic system (which processes emotion and memory). Over time, the prefrontal cortex exerts increasing regulation over the raw emotional responses generated by the amygdala and related structures.

In prolonged grief, this adaptation stalls. A 2020 study in Psychological Medicine found that individuals with PGD show altered connectivity between the prefrontal cortex and the nucleus accumbens, a structure involved in reward processing and attachment bonds. The brain, in effect, continues to expect the deceased person to return. The attachment circuitry has not updated. And because that circuitry involves some of the same reward pathways implicated in dopamine-driven motivation, the result can look a lot like anhedonia: a collapse of interest in the present because the brain is still oriented toward a relationship that no longer exists in the physical world.

There are also significant overlaps between PGD and PTSD. Both involve intrusive thoughts, avoidance behaviors, and a kind of temporal disorientation where the person feels stuck in the past. We discuss the neuroscience of ketamine for PTSD in a separate article, but much of the same circuitry is involved.

Neuroplasticity and Why It Matters Here

One of the most consistent findings in prolonged grief, depression, and PTSD is a deficit in neuroplasticity. The brain’s ability to form new connections and reorganize existing ones is reduced, which is part of why people feel stuck. The neural patterns encoding the loss become rigid. The prefrontal cortex loses some of its capacity to generate new perspectives and modulate emotional responses.

This is where ketamine’s mechanism becomes relevant. As we describe in our article on how ketamine works, ketamine is an NMDA receptor antagonist that triggers a cascade of downstream effects, including a rapid increase in brain-derived neurotrophic factor (BDNF) and synaptogenesis in the medial prefrontal cortex. In plain language: ketamine appears to restore the brain’s ability to form new connections and reorganize its response patterns, particularly in the regions most involved in emotional regulation and cognitive flexibility.

A 2022 review in Molecular Psychiatry confirmed that this neuroplastic response is central to ketamine’s antidepressant effects, and that the changes are measurable within hours of a single infusion. A 2025 publication in Brain (Oxford Academic) expanded on this, showing that ketamine shifts how people process emotional information, reducing the cognitive biases that keep patients locked in negative thought patterns.

For someone with prolonged grief, the clinical implication is this: if the brain has become rigid in its grief response, unable to form the new associations and perspectives needed to adapt, ketamine may help restore the flexibility that adaptation requires. This is not about forgetting. It is about allowing the brain to do what it has been unable to do.

What the Clinical Evidence Shows So Far

We want to be direct: there are no large randomized controlled trials studying ketamine specifically for prolonged grief disorder. The evidence at this stage comes from case reports, clinical observations, and extrapolation from the broader literature on ketamine for depression and PTSD.

A 2016 case report published in the Journal of Palliative Medicine described rapid resolution of grief symptoms in a patient treated with IV ketamine, with the authors noting that the improvement occurred faster than expected and involved a qualitative shift in how the patient related to the loss. The patient did not stop grieving. What changed was the intensity and rigidity of the grief, and their ability to function alongside it.

We have observed similar patterns in our own practice. Patients who come to us with depression or PTSD that is rooted in a significant loss sometimes report that the grief itself shifts during or after a series of ketamine infusions. They describe being able to think about the person they lost without the thought consuming them. They notice they can hold the sadness and still feel other things alongside it. One patient put it this way: “The grief is still there, but it moved from sitting on my chest to sitting beside me.”

These are clinical observations, not controlled data. We include them because they are consistent with what the neuroscience predicts, but we also want you to understand the difference between a well-studied indication and an area where the evidence is still building.

The Neuroplastic Window and Grief Processing

One of the concepts we discuss frequently at Music City Ketamine is the neuroplastic window—the period of enhanced brain plasticity that follows a ketamine infusion. This window, which appears to last several days to a couple of weeks, represents a time when the brain is more receptive to forming new connections and integrating new experiences.

For grief work specifically, this window may be particularly valuable when paired with therapy. Grief-focused psychotherapy, particularly approaches like complicated grief treatment (CGT), works by gradually helping patients confront the reality of the loss and rebuild a sense of meaning and engagement. If ketamine opens a period of increased neural flexibility, therapeutic work during that window may have a greater chance of producing lasting change.

We are not saying that ketamine replaces therapy. We are saying that for patients whose grief has been resistant to therapy alone, ketamine may create the neurobiological conditions that allow therapy to work more effectively. Marla and our team often talk with patients about how to structure the days following an infusion to take advantage of this period.

PGD and Co-Occurring Depression

Prolonged grief frequently occurs alongside major depression, and the two conditions can reinforce each other. The depressive symptoms (fatigue, hopelessness, concentration problems) make it harder to engage in grief work. The unresolved grief feeds the depression. Conventional antidepressants may partially address the depressive symptoms but rarely touch the core grief.

Ketamine’s rapid antidepressant effects can be relevant here. A reduction in depressive symptoms within hours or days of an infusion may give the patient the functional capacity to engage in the grief-processing work that the depression had been blocking. This is not a cure for grief. It is a potential way to interrupt the cycle that keeps someone trapped between two conditions, neither of which can improve while the other persists.

What We Can and Cannot Promise

At Music City Ketamine, we believe strongly in being honest about the limits of the evidence. We can tell you that ketamine has well-documented effects on neuroplasticity, that it has a strong evidence base for treatment-resistant depression and PTSD, and that the neurobiological mechanisms are plausible for prolonged grief. We can tell you that we have observed clinical improvements in patients whose grief was a significant part of their presentation.

We cannot tell you that ketamine is a proven treatment for prolonged grief disorder, because the research is not there yet. We cannot promise that an infusion series will resolve your grief. And we would be suspicious of any clinic that did.

What we can offer is a careful clinical conversation. If you are living with grief that has not responded to time and conventional treatment, we are willing to discuss whether ketamine might be worth considering as part of a broader approach. Marla reviews every patient individually, and we do not recommend treatment unless we believe the clinical rationale supports it.