Credit: Getty Images
Is Ketamine an Opioid?
Despite growing clinical use for treatment-resistant depression, ketamine is often misunderstood. One of the most common misconceptions is that ketamine is an opioid. This belief gained traction following a 2018 study titled "Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism", published in the American Journal of Psychiatry. The study found that the opioid receptor antagonist naltrexone blocked ketamine’s antidepressant effects, leading some to conclude that ketamine acts like an opioid.
However, a growing body of evidence—including new commentary from researchers at Johns Hopkins University—suggests otherwise: Ketamine isn’t an opioid and treats depression in a unique way. Understanding ketamine’s actual mechanism of action is critical to advancing its use, particularly in a medical environment wary of opioid misuse.
This viewpoint is strongly advocated by Dr. Adam Kaplin, a contributor to Psychology Today and a previous assistant professor of psychiatry and behavioral sciences at Johns Hopkins, who has been working to correct the record and highlight ketamine’s true pharmacological pathway.
The Origins of the Confusion: Naltrexone and Opioid Receptors
In 2018, researchers at Stanford University and Palo Alto University found that the opioid receptor antagonist naltrexone blocked ketamine’s antidepressant effects. This led some to conclude that ketamine must be acting as an opioid. Naltrexone, often used to reverse opioid overdoses, binds to opioid receptors, preventing substances like heroin or morphine from activating them.
However, Dr. Adam Kaplin says this interpretation oversimplifies the biology. According to Kaplin, ketamine primarily acts on NMDA receptors, not opioid receptors. The interference observed in the 2018 study is likely a result of receptor cross-talk and downstream signaling effects—not direct opioid receptor activation by ketamine.
The NMDA Receptor and mTOR Activation
Ketamine works by blocking NMDA (N-methyl-D-aspartate) receptors, which are typically activated by the excitatory neurotransmitter glutamate. Under normal conditions, glutamate binds to these receptors and initiates a cascade that suppresses the activity of the mTOR (mechanistic target of rapamycin) pathway. This suppression is associated with reduced synaptic plasticity and slower formation of new neural connections.
- When glutamate activates NMDA receptors → mTOR turns off → decreased neuroplasticity.
- When ketamine blocks NMDA receptors → mTOR turns on → enhanced neuroplasticity and synaptogenesis.
This activation of mTOR is thought to drive ketamine’s hallmark rapid antidepressant effects, which are often observed within hours or days, significantly faster than the multi-week onset period typically associated with SSRIs or SNRIs. Importantly, mTOR regulates protein synthesis critical for forming new synapses, which may help reverse the structural brain changes linked to chronic depression.
Ketamine’s impact on this signaling pathway represents a paradigm shift in our understanding of antidepressant mechanisms, emphasizing the importance of neuroplasticity over traditional monoaminergic approaches.
The Role of cAMP and Opioid Interference
Dr. Kaplin offers a more nuanced explanation for the 2018 findings. While ketamine activates mTOR by inhibiting NMDA receptors, naltrexone disrupts this process indirectly through complex intracellular signaling.
Here's how it works:
- Opioid receptors exhibit low-level, tonic activity that helps suppress the production of cyclic AMP (cAMP).
- When naltrexone blocks these opioid receptors, it leads to an artificial spike in cAMP levels.
- Elevated cAMP levels can inhibit the mTOR signaling cascade, essentially overriding ketamine’s activation of this crucial neuroplasticity pathway.
Therefore, the antidepressant-blocking effects observed with naltrexone may not indicate that ketamine is acting as an opioid. Instead, it highlights the indirect biochemical interference mediated through cAMP's ability to modulate mTOR activity.
This distinction is vital. The presence of crosstalk between receptor systems is well-documented in neuropharmacology, and such interactions should not be confused with direct pharmacodynamic equivalence. In other words, just because naltrexone blunts ketamine's effects does not mean ketamine behaves like an opioid.
Why This Distinction Matters
Before diving into the broader implications, it’s essential to understand how misconceptions about ketamine’s classification can ripple across clinical, regulatory, and societal domains. Misidentifying ketamine as an opioid doesn't just cloud scientific discourse—it affects real-world treatment decisions and patient outcomes.
Lab Management Certificate
The Lab Management certificate is more than training—it’s a professional advantage.
Gain critical skills and IACET-approved CEUs that make a measurable difference.
Labeling ketamine as an opioid carries significant consequences:
- Stigma: In the midst of an opioid epidemic, associating ketamine with opioids may deter patients and clinicians from considering it.
- Access: Regulatory and clinical hesitancy may limit the availability of ketamine treatment for those with urgent mental health needs.
- Research: Misclassification can hinder funding and research progress into alternative antidepressant mechanisms.
"This interference and cross-talk does not mean that ketamine is an opioid," says Kaplin. "To wrongly label it as such could eventually keep patients from essential antidepressant medications that could make a huge difference in their quality of life."
Clinical Oversight and Future Directions
The FDA has approved esketamine, a nasal spray form of ketamine, for treatment-resistant depression. To minimize risk and monitor for potential side effects such as dissociation or increases in blood pressure, its administration is required to take place under the supervision of qualified healthcare professionals in certified treatment centers.
Ketamine’s unique properties continue to set it apart from conventional antidepressants:
- Rapid onset of action, often producing mood improvements within hours.
- Efficacy in treatment-resistant depression, where other medications have failed.
- Novel mechanism targeting glutamatergic pathways rather than traditional serotonin or dopamine systems.
Recognizing this potential, Kaplin and his colleagues at Johns Hopkins are in the process of launching a dedicated ketamine clinic, aimed at both expanding access to this novel treatment and facilitating rigorous clinical research into its long-term efficacy, safety, and optimal therapeutic protocols.
FAQs
Q1: Is ketamine an opioid?
No, ketamine is not an opioid. It primarily acts on NMDA receptors and has a unique mechanism of action involving the mTOR pathway.
Q2: Why does naltrexone affect ketamine’s antidepressant effects?
Naltrexone increases cAMP levels that interfere with mTOR activation, thereby reducing ketamine’s efficacy—without ketamine acting as an opioid itself.
Q3: Is ketamine safe for depression?
When administered in a clinical setting at low doses, ketamine is considered safe and has shown rapid, effective relief for treatment-resistant depression.
Q4: Will calling ketamine an opioid affect patients?
Yes. Mislabeling ketamine as an opioid may contribute to stigma and reduce access to effective, potentially life-saving treatment.
Conclusion
Ketamine is not an opioid. Misconceptions surrounding its mechanism of action could jeopardize its potential to transform depression treatment. As new studies clarify how ketamine works—via NMDA receptor inhibition and mTOR activation—it becomes increasingly clear that it represents a novel, fast-acting, and highly promising therapy. Dispelling myths and educating the public and health professionals alike will be critical for its continued success. If ketamine’s misunderstood reputation can finally be put to rest, it may not only reshape how we treat depression—but how we think about innovation in mental health care altogether.
