The Advanced Guide to Opioids As Antidepressants

Why do so many depressed individuals respond poorly to antidepressants?

About one-third of patients fail to respond to prescription antidepressants and are labeled "treatment resistant." There's a clear need for novel drugs to help people who don't respond to conventional drugs like SSRIs.

Opioids merit further investigation as "unconventional antidepressants."

The NMDA Ketamine antagonist has recently garnered attention as a treatment resistant depression.

Unconventional antidepressants like ketamine share one common thread: their primary mechanism doesn't hinge on altering monoamines like serotonin or norepinephrine.

From Opioids to Monoamines: A Brief History

A century ago opioids were a standard treatment for depression. This was before their addictive potential was fully appreciated.

In the 1950s, tricyclic antidepressants entered the scene. They were effective and non-addictive, although their side effect burden was high. Tricyclic antidepressants soon became standard treatments for depression.

The first prescription for the SSRI Prozac was written around 1986. SSRIs supplanted tricyclics as standard of care because of their more tolerable side effects and low cardiotoxicity.

SSRIs and tricyclics are monoaminergic treatments - they boost serotonin and norepinephrine.

In the 80's and 90's, the prevailing view was that depletion of monoamines causes of depression. This view has been exposed as overly simplistic; the brain is not a hydraulic system with different amounts of chemicals.

What's Wrong With Conventional Antidepressants?

By conventional antidepressants, I'm talking about drugs like SSRIs, SNRIs, tricyclics, MAOIs, and Remeron.

Conventional antidepressants are effective for only about 40% of patients and have serious drawbacks. This is just the tip of the iceberg:

  • Antidepressants fail to treat all the symptoms of depression. Even after patients' mood improves with SSRIs and SNRIs, they often report residual anhedonia and cognitive difficulties.
  • Antidepressants can induce insomnia, irritability, hypomania and "rock the boat" in some patients.
  • Some researchers argue that prolonged antidepressant use can result in a "chronification" of what would have been transient mood instability.

Opioids Make A Comeback

Since the 1950s, opioids have been widely studied for their implications in pain and addiction. Their pharmacology is well understood. But their mood-brightening effects are understudied (except by the recreational user).

µ, δ, and k opioid receptors (also indicated as MORs, DORs and KORs, respectively) play key roles in many physiological processes. These processes include:

  • pain
  • immune system
  • respiration
  • stress and reward processing

µ-opioid receptors are implicated in reward processing and mood regulation.

δ-opioid receptor activation appears to improve depressive mood.

k-opioids mediate stress-related dysphoria and anxiety. k-opioid receptors are distributed in the anterior cingulate cortex and in the prefrontal cortex. These brain regions regulate the stress response.

A growing body of evidence suggests a link between opioid dysregulation and depression. Also, patients formerly labeled as "treatment resistant" tend to respond positively to µ receptor therapies.

Do Physical and Mental Pain Overlap?

If opioids can influence both physical and mental pain, does this imply an overlap in neural circuitry? This question is a point of contention in the scientific literature.

One angle to clarify this connection is social pain. Social and physical pain activate partly overlapping brain areas. Moreover, chronic social stress adds fuel to the fire of depression.

Studies on µ- and k-opioid receptors point to an optimal opioid tone for mood stability and social success. Higher or lower shifts from this baseline opioid tone can induce mood instability. For example, high social hedonic capacity is also associated with heightened rejection sensitivity, as is seen in borderline personality disorder.

Maternal Care Has A Lifelong Impact On The Opioid System

The influence that maternal care exerts on the opioid system is a remarkable example.

According to Bowlby's theory, the development of strong social skills depends on the relationship with the primary caregiver.

Animal studies have taught us a little about how maternal separation influences µ-opioid receptor expression. Activation of µ-opioid receptors apparently weakens maternal separation anxiety. Also, variations in the gene encoding the µ-opioid receptor correlate with the quality of parental attachment in infants.

Opioid-mediated regulation of social behaviors has a life-long impact on affective regulation. Thus, opioid-based treatments have important implications also for the prevention of depression.

The idea of an optimal intermediate tone may also clarify the correlation between chronic opioid use and depression. When treated with opioids for physical pain, patients with a history of depression are more prone to relapse. Whereas, in patients without past depression, analgesic opioid use seem related to pain severity.

Depression-Addiction Comorbidity

Depression and addiction go hand-in-hand. It's unclear which direction the causality runs (perhaps both ways)? In the near-term, substance use provides relief from depression. But long-term, there's no doubt that substance dependence contributes to depression.

Some researchers have tried to sidestep opioid's addictiveness with opioids that are less habit-forming. For example, tramadol, buprenorphine and methadone have been tested in depressed patients with promising results.

Is it possible to dissociate the antidepressant effects of opioids from their habit-forming nature?

To date, it is not clear whether the addictive and antidepressant properties of opioids are separable. Some researchers have proposed combining opioid agonists with antagonists. Sounds crazy, right?

One study reported that buprenorphine (an opioid agonist) plus samidorphan (an opioid antagonist) improved mood in patients with treatment resistant depression. This approach sounds insane, but it may merit further investigation.

What about other pharmacotherapies?

Alternatives also come from clinical and pre-clinical studies on glutamatergic, cholinergic and GABA-ergic modulators.

Among these, the glutamatergic ketamine seems very promising. Promising studies on ketamine's role in mood regulation are increasing. Results highlight robust and rapid effects also in on treatment-resistant depression. These observations open the way for other, more selective and effective, glutamatergic modulators.

When talking about novel pharmacotherapies, we have to bear in mind that most data very often come from animal models. Translation to humans is not always straightforward. For depression, in particular, most animal studies focus on behaviors rather than emotions. Whereas human studies tend to do the opposite. Clinical trials for some novel compounds are already in place. But more are needed to test costs and benefits if we want to achieve more effective and long-lasting treatments for depression.


Garay, R. P., Zarate, C. A., Charpeaud, T., Citrome, L., Correll, C. U., Hameg, A., & Llorca, P.-M. (2017). Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Review of Neurotherapeutics, 1–17.

Iglewicz, A., Morrison, K., Nelesen, R. A., Zhan, T., Iglewicz, B., Fairman, N., … Irwin, S. A. (2015). Ketamine for the Treatment of Depression in Patients Receiving Hospice Care: A Retrospective Medical Record Review of Thirty-One Cases. Psychosomatics, 56(4), 329–337.

Scherrer, J. F., Salas, J., Sullivan, M. D., Schneider, F. D., Bucholz, K. K., Burroughs, T., … Lustman, P. J. (2016). The influence of prescription opioid use duration and dose on development of treatment resistant depression. Preventive Medicine, 91, 110–116.

Goesling, J., Henry, M. J., Moser, S. E., Rastogi, M., Hassett, A. L., Clauw, D. J., & Brummett, C. M. (2015). Symptoms of Depression Are Associated With Opioid Use Regardless of Pain Severity and Physical Functioning Among Treatment-Seeking Patients With Chronic Pain. The Journal of Pain, 16(9), 844–851.

Scherrer, J. F., Salas, J., Copeland, L. A., Stock, E. M., Schneider, F. D., Sullivan, M., … Lustman, P. J. (2016). Increased Risk of Depression Recurrence After Initiation of Prescription Opioids in Noncancer Pain Patients. The Journal of Pain, 17(4), 473–482.

Hamon, M., & Blier, P. (2013, August). Monoamine neurocircuitry in depression and strategies for new treatments. Progress in Neuro-Psychopharmacology and Biological Psychiatry.

Dale, E., Bang-Andersen, B., & S??nchez, C. (2015, May). Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochemical Pharmacology.

Tenore, P. L. (2008). Psychotherapeutic benefits of opioid agonist therapy. Journal of Addictive Diseases, 27(3), 49–65.

Lutz, P. E., & Kieffer, B. L. (2013, March). Opioid receptors: Distinct roles in mood disorders. Trends in Neurosciences.

Ehrich, E., Turncliff, R., Du, Y., Leigh-Pemberton, R., Fernandez, E., Jones, R., & Fava, M. (2014). Evaluation of Opioid Modulation in Major Depressive Disorder. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 40(6), 1–8.

D. Rosenblat, J., S. McIntyre, R., S. Alves, G., N. Fountoulakis, K., & F. Carvalho, A. (2015). Beyond Monoamines-Novel Targets for Treatment-Resistant Depression: A Comprehensive Review. Current Neuropharmacology, 13(5), 636–655.

Papakostas, G., & Ionescu, D. (2015). Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Molecular Psychiatry, 20(10), 1142–1150.

Lutz, P. E., & Kieffer, B. L. (2013, March). Opioid receptors: Distinct roles in mood disorders. Trends in Neurosciences.

David Kaye, A., Beakley, B. D., Kaye, A. M., & Kaye, A. D. (2015). Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician, 18, 395–400. Retrieved from

Miotto, K., Cho, A. K., Khalil, M. A., Blanco, K., Sasaki, J. D., & Rawson, R. (2016). Trends in Tramadol. Anesthesia & Analgesia, XXX(Xxx), 1.

Lutz, P.-E., & Kieffer, B. L. (2013). Opioid receptors: distinct roles in mood disorders. Trends in Neurosciences, 36(3), 195–206.

Conway, C. R., George, M. S., Sackeim, H. A., AJ, R., K, T., D, A., … DL, D. (2016). Toward an Evidence-Based, Operational Definition of Treatment-Resistant Depression. JAMA Psychiatry, 163(11), 1905–1917.

Ehrich, E., Turncliff, R., Du, Y., Leigh-Pemberton, R., Fernandez, E., Jones, R., & Fava, M. (2014). Evaluation of Opioid Modulation in Major Depressive Disorder. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 40(6), 1–8.

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Xavier Kent

I'm interested in nutrition, nootropics, and javascript. I'm a firm believer in getting really good at one thing.


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