The day I first watched ketamine lift a human being out of despair, I was standing in a quiet room at the National Institute of Mental Health. The fluorescent lights hummed, the monitor ticked, and a young adult who had been drowning for months came up for air. Hours, not weeks. That speed rewired me as much as it rewired their brain. In the early 2000s, most of us were still waiting on serotonin to do its slow work. Ketamine forced a new question. What if depression could yield at the pace of a crisis, not the pace of a calendar.

I did not meet ketamine in an infusion suite. I met it in conversation with researchers and patients who had run out of road. Those early NIMH protocols taught me two enduring lessons. First, hope needs a timeline. Second, molecules are only half the story. A person changes when biology and meaning move together. I took that frame with me into practice and I have used ketamine in carefully selected patients for more than twenty years, alongside psychotherapy, sleep repair, movement, nutrition, and community. Ketamine opens the door. People still have to walk through.

Here is the plain-language version of what the drug does. Ketamine temporarily blocks N-methyl-D-aspartate (NMDA) receptors. That changes glutamate traffic, which triggers a downstream cascade, including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation and a surge in brain-derived neurotrophic factor (BDNF). New synapses sprout. Circuits that have been stuck start to move. In my teaching video, I describe it this way: Depression prunes possibility. Ketamine briefly flips the soil, and in that window plasticity returns. The work then is to plant. The drug is not the garden. The drug is the invitation to grow.

Two decades later the field caught up to what many patients had already shown us. In 2019, the FDA approved esketamine, the intranasal S-enantiomer of ketamine, for adults with treatment-resistant depression when paired with an oral antidepressant. Early this year the label expanded. Esketamine can now be used as a standalone treatment for adults with treatment-resistant depression, still inside the REMS (Risk Evaluation and Mitigation Strategies) framework and still under observation in clinic. That change matters for people who cannot tolerate or do not benefit from daily antidepressants. It does not turn esketamine into a quick fix. It does give clinicians another way to meet the moment.

Racemic ketamine given intravenously remains off-label for depression, but the clinical signal has been consistently strong across controlled studies, with high-velocity relief that can appear within hours and then taper over days to weeks. Meta-analyses and major reviews show meaningful benefits, especially in patients who have failed conventional medications. The core message is consistent. Ketamine is fast, potent, and not for everyone. It works best when embedded in a treatment plan that anticipates maintenance, relapse prevention, and careful selection of candidates.

The practical reality is more nuanced than headlines. Esketamine requires a certified clinic, two hours of post-dose monitoring, and structured follow up. Those requirements are not red tape. They are the safety rails that keep patients from drifting into dissociation or driving home before they are ready. The FDA label is explicit about blood pressure monitoring, dissociation, and abuse potential. In other words, we can harness this medicine’s speed without glamorizing it. Respect the power, and you get the upside. Ignore the guardrails, and you inherit the risk.

What about new delivery forms and access. The pipeline is busy. A preservative-free intravenous ketamine, NRX-100, recently received Fast Track designation for suicidal ideation in depression, which could help open insurance coverage pathways that generic IV ketamine never enjoyed. On the pain side, the FDA approved an IM ketamine product, KETARx, for surgical pain, reminding the public that ketamine’s first home was anesthesiology. None of that changes the fact that using IM or IV ketamine for depression remains off-label. It does suggest that cleaner formulations and clearer labels are coming, and that insurance payers will have fewer excuses to look away.

Patients ask me about ketamine for home use. Researchers are exploring telehealth-supported protocols and extended-release tablets. These are promising for people who live far from certified clinics, and early studies show feasibility and symptom reduction. They are not standard of care. The FDA has been clear about safety concerns with compounded at-home products. My stance is steady. If a person is stable, well-screened, and closely followed, we can discuss future options. Until then, clinic-based care is the right side of the risk curve.

For physicians, the operational questions matter. Who is a good candidate. How do we write the note. What is the plan when the pharmacy backorders a critical drug. My playbook is simple. Choose patients who have failed evidence-based treatments and who can commit to monitoring. Screen for psychosis, unstable cardiovascular disease, and substance misuse risk. Pair every infusion or esketamine session with therapy and skills practice. Document target symptoms, functional goals, and safety checks. From day one, discuss what happens if access changes. We owe our patients speed and stability, not speed alone.

For the public, the message is different. Relief in hours can feel like a miracle. It is not magic. Ketamine creates a neurobiologic opening. Use that opening to reconnect with people and purpose. In those first forty-eight hours, patients often tell me the world looks wider. That is the window to schedule therapy, walk, sleep, call a friend, call a parent, go to the lake, pray, breathe. Biology and meaning again. The molecule and the life it is trying to serve.

I still carry faces from the early NIMH days. The first patient who laughed in clinic after months of stone. The mother who told me she finally recognized her son’s eyes. The veteran who said the noise turned down enough to hear his own thoughts. I have also sat with people for whom ketamine did not work, or worked and then faded, or stirred up anxiety they could not tolerate. Integrity is telling both stories. The power and the limits. The light and the responsibility it brings.

We also need to stay honest about tradeoffs. Intravenous racemic ketamine usually delivers a larger clinical effect than intranasal esketamine in the literature. Esketamine offers on-label access with structured oversight. Both can be integrated into effective treatment plans. Either one without psychotherapy and lifestyle repair is a missed opportunity. The field is shifting toward personalization, not one path for all comers. That is good medicine.

The science press often frames ketamine as a revolution. I think of it as a second chance. For many, the first chance was years of good care that helped some but not enough. Ketamine gives people another opening, and it gives clinicians a reason to move fast when lives are small and days are long. Twenty years after I first watched hope arrive in hours, I still feel the same quiet gratitude when a patient looks up and says, “I feel like myself again.”

If you are a clinician, build your protocol now. Get certified. Train your team. Create a plan for maintenance. If you are a patient, ask your doctor if ketamine is right for you. Bring your questions. Bring your goals. Bring someone who loves you. Relief is real. The work that follows is how you keep it.

Muhamad Aly Rifai is a nationally recognized psychiatrist, internist, and addiction medicine specialist based in the Greater Lehigh Valley, Pennsylvania. He is the founder, CEO, and chief medical officer of Blue Mountain Psychiatry, a leading multidisciplinary practice known for innovative approaches to mental health, addiction treatment, and integrated care. Dr. Rifai currently holds the prestigious Lehigh Valley Endowed Chair of Addiction Medicine, reflecting his leadership in advancing evidence-based treatments for substance use disorders.

Board-certified in psychiatry, internal medicine, addiction medicine, and consultation-liaison (psychosomatic) psychiatry, Dr. Rifai is a fellow of the American College of Physicians (FACP), the American Psychiatric Association (FAPA), and the Academy of Consultation-Liaison Psychiatry (FACLP). He is also a former president of the Lehigh Valley Psychiatric Society, where he championed access to community-based psychiatric care and physician advocacy.

A thought leader in telepsychiatry, ketamine treatment, and the intersection of medicine and mental health, Dr. Rifai frequently writes and speaks on physician justice, federal health care policy, and the ethical use of digital psychiatry.

You can learn more about Dr. Rifai through his Wikipedia page, connect with him on LinkedIn, X (formerly Twitter), Facebook, or subscribe to his YouTube channel. His podcast, The Virtual Psychiatrist, offers deeper insights into topics at the intersection of mental health and medicine. Explore all of Dr. Rifai’s platforms and resources via his Linktree.