In recent years ketamine has dramatically grown in use from its early days as a Vietnam war battlefield anesthetic, to an evidence-based hospital anesthetic for surgery, and later as a party drug in rave culture. And now in one form as an FDA-approved treatment for major depression and growing off-label treatment for depression, PTSD, chronic pain, anxiety and other conditions,
With this rise in popularity, there is also confusion about its role as a pain reliever compared with opioids such as oxycodone (OxyContin), hydrocodone (Vicodin), heroin, morphine, and now fentanyl. In this article, I clarify the classification of ketamine compared to opioids and describe how this is so.
In summary, ketamine is not an opioid. It is a dissociative anesthetic, a category distinct from opioid drugs. While both ketamine and opioids can relieve pain and cause sedation, they act on entirely different neurochemical systems and have different safety profiles.
A Question Born from Confusion
A common and dangerous question is increasingly asked: “Is ketamine an opioid?” This confusion arises from ketamine’s pain-relieving properties and its potential for misuse, leading some to think it may be an opioid. Understanding the fundamental differences in how each of these drugs work in the brain, their legal classifications, and their respective risk profiles, is a matter of personal and public health.
How Opioids and Ketamine Are Classified
Drug classification is not arbitrary; it is based primarily on a compound’s chemical structure and, most importantly, its mechanism of action in the brain.
Opioids
Opioids are derived from (or synthetically designed to mimic) the opium poppy. They are agonists binding to the mu-, delta-, and kappa-opioid receptors in the central nervous system. Agonists “turn on” receptors to mimic natural substances, whereas antagonists “turn off” or block the receptors.
These receptors are part of the body’s opioid system, responsible for pain relief and euphoria. Opioid drugs mimic the body’s natural endorphins to block pain signals and produce euphoria [1].
Opioids differ in their strength. Fentanyl is 50 to 100 times more potent than morphine. Even small doses of fentanyl can be fatal. And fentanyl can be even more dangerous when it is mixed with other drugs.
Ketamine
Unlike opioids, ketamine is a member of a different chemical family. It works primarily as an antagonist at the NMDA (N-methyl-D-aspartate) receptor. By blocking these receptors in the brain, it interrupts pain signaling and alters perception, sometimes producing a sense of detachment or dissociation.
As a completely different neurological pathway than the one used by opioids, it doesn’t “unlock” the same receptors. However, there is some debate whether mu-opioid receptors, while not the direct target of ketamine, may play a permissive role. More research is needed [2].
Ketamine Under the Microscope: An NMDA Receptor Antagonist
Ketamine’s unique effects stem from its disruption of the NMDA receptor, a key player in learning, memory, and pain perception. When used off-label in Ketamine Assisted Psychotherapy, ketamine has been shown to be effective in treating major depression as well as a wide range of other conditions, such as Post-Traumatic Stress Disorder, substance use disorder, and pain management [3].
The NMDA receptor is a specialized gateway on neurons, central to learning and memory. When the neurotransmitter glutamate binds to it, the channel opens, allowing calcium ions to flow into the cell. This influx triggers long-term strengthening of the synaptic connection between neurons, which is the cellular basis for forming memories.
Ketamine physically blocks the NMDA receptor’s channel, preventing glutamate from activating it. This disrupts communication between the brain’s thalamus and cortex, leading to dissociated anesthesia—a state of pain relief, amnesia, and feeling detached from one’s body and environment [3].
Pain Relief (Analgesia)
Ketamine is particularly effective for “wind-up” pain (central sensitization) and neuropathic pain, caused by nerve damage or dysfunction. This is different from the nociceptive pain opioids typically address. This is the most common type of pain, caused by tissue damage that activates specialized nerve endings called nociceptors.
Rapid Antidepressant Effects
The NMDA blockade is believed to trigger a cascade of events, including increased glutamate release and the formation of new synapses, the connections between neurons, which can rapidly repair neural connections damaged by depression. This is currently the dominant belief by researchers.
However, some believe it is possible that ketamine is acting indirectly to produce its antidepressant effect. It may work through additional receptors, including mu-opioid receptors, adrenaline receptors, and several serotonin and norepinephrine transporters [4].
Dissociative State
A distinct aspect of ketamine use is the dissociative state it brings about. This dissociative state creates a dreamlike sense of being a detached observer. You may feel separated from your physical body, as if floating above it, while your surroundings seem unreal or distant. This disrupts the normal integration of sensory perception, identity, and memory.
In a medically supervised ketamine treatment for depression or pain, the intense dissociative state typically lasts between 40 to 60 minutes after the infusion starts. The most profound effects peak and then subside, though patients may feel residual relaxation or grogginess for a couple of hours.
Opioids Explained: Agonists at the Mu-Opioid Receptor
As mu-opioid agonists, opioids bind to and activate these and other opioid receptors on cells located in many areas of the brain, spinal cord, and other organs in the body, especially those involved in feelings of pain and pleasure.
This blocks pain signals sent from the brain to the body and releases large amounts of dopamine throughout the body. This release can strongly reinforce the act of taking the drug, making the user want to repeat the experience.
Opioid misuse can depress the central nervous system and slow breathing, which can cause hypoxia, a condition that results when too little oxygen reaches the brain. Hypoxia can have short- and long-term psychological and neurological effects, including coma, permanent brain damage, or death [5].
Untangling the Knot: Why the Confusion Exists
In the US, given their greater potential for dependence and abuse, many opioids are Schedule II drugs. Ketamine is classified by the FDA as a Schedule III controlled substance, reflecting its medical utility for the treatment of major depressive disorder, with some potential for misuse. However, this decision was not made without controversy.
Despite their different mechanisms, several factors have contributed to the mistaken belief that ketamine is an opioid.
1. Overlap in clinical use for pain management
- Both are powerful analgesics used in emergency and surgical settings.
- The layperson’s perspective: “A strong drug that kills pain = an opioid.
2. The 2018 Study and Subsequent Retraction
- A high-profile paper was published in Nature that suggested ketamine works on opioid receptors. This study received significant media attention. The study was retracted in 2019 due to a lack of evidence and faulty data. However, the initial headline had already spread.
- Subsequent, more rigorous studies have confirmed that ketamine’s antidepressant effect is not blocked by opioid antagonists like naloxone, proving its primary action is non-opioid. Research is still ongoing.
3. Potential for Misuse
- Opioids and ketamine can both be misused. Opioid misuse and its devastating effects is well known. Ketamine can be misused recreationally for its hallucinogenic effects, while under proper medical supervision, the risk of dependence is considerably lower.
Key Implications: Safety, Addiction, and Overdose
Clearing up misconceptions about ketamine compared with opioids is an important public health challenge, primarily in these areas:
The Opioid Overdose Crisis
- Opioid overdose is characterized by respiratory depression which can lead to death. The lifesaving antidote naloxone (Narcan), works by removing opioids from the mu-opioid receptors.
Ketamine Overdose
- An overdose primarily causes severe dissociation, unconsciousness, and dangerously slowed breathing or apnea due to central nervous system depression, but through a different mechanism.
- However, Naloxone is ineffective in reversing a ketamine overdose, proving the biological difference with opioids.
Addiction Potential
- Ketamine can lead to psychological dependence but much less so than opioids with their powerful physical dependence and painful withdrawal.
The Public Health Consequences
Ketamine, while not an opioid, can complement traditional pain and mood disorder treatments to offer unique advantages as an adjunct medicine [6].
Alternative therapies for pain management and challenging mental health conditions, offered by ketamine therapy, have opened new possibilities in personalized medicine.
During a public health crisis centered on opioids, and as ketamine therapy becomes more mainstream, accurate public understanding can prevent dangerous misconceptions. The future of psychedelic and novel medicine centered on the evidence-based promise of ketamine depends on this kind of clarity.
Help Is Available at Hideaway Recovery
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Sources
[1] NIDA. 2024, November 22. Opioids.
[2] Malinow et al. Reply to Hashimoto: Ketamine is not an opioid but requires opioid system for antidepressant actions. PNAS. 117 (21) 11202-11203.
[3] Drozdz, S. et al (2022). Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature. Journal of pain research, 15, 1691–1706.
[4] Ionescu, D. et al(2018). Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Harvard review of psychiatry, 26(6), 320–339.
[5] NIDA. 2021, June 1. Prescription Opioids DrugFacts.
[6] Verdun A. nd. Is Ketamine an Opioid?: Clarifying Misconceptions and Exploring Its Medical Usefulness.