When Opioids Are the Cure to Depression and Psychache

Avi was 16 years old, a bookish sophomore who played the clarinet in the high school orchestra, when she discovered opioids. Diagnosed with mood and anxiety disorders, she described her teenage self as a “somatic ball of nerves,” and her home life as insecure. “The abuse I was experiencing from my stepdad also escalated that year,” Avi said, which led to her miss school, oscillating between fits of crying and panic, her body in a perpetual fight-or-flight state.

One day, Avi went to study hall where she first met “the other mentally ill girl with dyed hair.” The two moody teens hit it off. After hanging out for a couple of weeks, Avi started venting about her unrelenting psychological anguish. Her friend listened, then said, “This is breaking some sort of rule. But I can’t think of anyone who needs this more than you.” She dug into her purse and presented a couple of pills, which Avi swallowed on the spot. A couple of hours passed and Avi then said to herself, What the heck? What is this? “I had not experienced calm in a year,” Avi said. “Something transformative in a positive way took place there.”

For Avi, opioids—in this case, pharmaceutical pain relievers like Vicodin and Percocet—disrupted the panic spirals and lowered the volume of noisy static in her head in a way that no other psychiatric medicine ever had. Finding a drug that made her feel at ease, Avi embarked on a journey of self-medication, trying different kinds of opioids: pharmaceuticals like oxymorphone (once her favorite, but no longer on the market); street opioids like black-tar heroin and fentanyl analogues; and much weaker ones like kratom, an herbal supplement with opioid-like effects available at head shops or online. These days, Avi prefers kratom because it carries a low risk of overdose, while still providing that warm, secure feeling. Plus, she can buy it in a legal marketplace. But that might not last for long, as the FDA and World Health Organization consider banning kratom, despite it being orders of magnitude safer than substances like alcohol and tobacco. 

In ordinary times, an herbal supplement like kratom would not be attracting regulatory attention. But with drug overdoses killing more than 96,000 Americans in the last year, a new grim milestone, any drug in the opioid family is suspect. Scrambling to flatten the curve of the deadliest overdose crisis in recorded history, policymakers have set their sights on reducing access to opioids. And, by and large, they have. Opioid prescribing has fallen by 60 percent since it peaked in 2011, but overdose deaths continue to soar to new heights. The majority of overdose deaths today occur in the illegal market, and involve a deadly mix of illicit fentanyl, tranquilizers, and stimulants like methamphetamine. 

Opioid use, depression, pain, and suicide, it turns out, are uniquely intertwined. In every human body is an endogenous opioid system: an intricate network of neurons and neurotransmitters tasked with regulating and relieving pain. This system produces natural opioids like endorphin—which in Latin means morphine within—that are released when the brain receives pain signals. Studying the body’s built-in pain reliever, researchers suggest that an impaired opioid system could be causing symptoms of pain and depression, which leads people, like Avi, to self-medicate with opioids.

“People with chronic depression, some are helped when they occasionally take an opioid,” Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford, told me. “You’ll talk to a patient who has got bad depression and they’ll tell you, ‘I had my knee done and I got OxyContin for a few days and my mood was much better.’” But the field of medicine has taken “a Calvinist approach” to the potential of opioids in relieving psychic pain. “Some people benefit from opioids, so what do we do with them?” Schatzberg said. “It’s very, very tricky.” 

A small island of scientific articles and clinical trials suggests that certain opioids, carefully adminstered, can indeed alleviate psychological pain, treat depression, and even prevent suicide. “A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in [major depressive disorder],” according to a 2019 article published in the journal Molecular Psychiatry. Self-medicating depressive symptoms is likely a “substantial contributor” to America’s opioid crisis, according to these researchers. Other studies suggest that certain opioids can soothe “psychache,” a constellation of dreadful symptoms characterized as “aching psychological pain in the psyche.”

Given the tragedy of the overdose crisis, and the role played by pharmaceutical companies and corrupt doctors, the very idea of prescribing opioids to severely depressed and suicidal people will make regulators and the general public balk. This brute fact puts someone like Avi in a double bind. “Being on opioids was the first thing I encountered that allowed me to feel safe,” she said. But to access a class of drugs that help her, Avi is stuck navigating a deadly and dangerous street supply. 

Writing in a 1988 article in International Clinical Psychopharmacology, Matthias M. Weber and Hindrek M. Emrich, both German psychiatrists and medical historians, contend that the Greek epic may very well represent “one of the oldest written descriptions of the mood improving effects of opium in a pathological psychiatric situation: alleviation of depression.” After all, the vivid colors and silky petals of Papaver somniferum, the genus of tall plant that births the dark heart of opium poppies, predates ancient Greece. In 3400 BC, the Sumerians referred to poppies as the “joy plant.” In the dust of Neolithic civilizations, archeologists have found poppy seeds and evidence of opium use. From global trade and bitter wars to epic poetry and Romantic literature, few plants have left such an enduring stamp on human affairs.  

Neglected, forgotten, or written off as primitive prescribing, opium casts a long shadow on the birth of psychopharmacology. According to Weber and Emrich, opium was long viewed as one of the most effective medications to manage what would today be called major depressive disorder, known throughout history as “melancholia.” A family dynasty of German psychiatrists called the Englekens popularized one of the earliest known methods of systematic opium administration for severely depressed patients: the Opiumkur (or opium cure). Patients were started on small doses of opium that would gradually increase over time; Weber and Emrich estimated daily opium doses were equivalent to a low dose of 20 to 30 milligrams of morphine. Once patients showed signs of improvement, their dose would plateau and then be gradually tapered down. The cautious dosing and long-term monitoring were implemented to mitigate the potential for dependence and withdrawal.

In contrast to barbaric psychiatric treatments of the era—restraint devices, crude electrocution, lobotomies, and freezing ice baths—opium treatments were considered much more humane. Most importantly, the Opimkur actually produced rapid improvements in otherwise desperate patients, so much that the Englekens publicly advocated, in papers and lectures, for the use of “acute medical opium therapy in psychiatry.” But the Englekens’ methods also had critics and sparked a fierce medical discourse across Europe, one familiar to us now, over how to balance opium’s therapeutic properties against the risks of dependence and addiction. 

By the late 19th and early 20th century, the problem of opioid addiction and overdose became much more visible after inventions like the hypodermic needle collided with the availability of more potent opioids like morphine. As doctors saw their patients succumb to morphine addiction, then known as “morphinism,” opiates became associated with so-called criminals, fiends, and moral defectives. Then, after World War II, came a spate of revolutionary discoveries in psychiatric medicine, including lithium, as well as the first generation of antidepressant drugs, which lacked the potential for addiction. 

By the 1950s, the new antidepressants overtook opium therapy as the go-to medication to treat depression. Opium’s long reign in treating melancholy has since faded away from memory. But doctors, clinicians, and neuroscientists are increasingly looking to the brain’s enigmatic opioid system as a possible pathway to help depressed and suicidal people who do not find relief from first-line treatments. 

Major depressive disorder affects around 17 million adults in America, and an estimated two-thirds of them do not get better from the first medication they try, if they receive treatment at all. Depression is typically considered “treatment resistant” after two consecutive antidepressants fail to provide relief. First-line treatments for depression include a combination of Cognitive Behavioral Therapy (CBT) and antidepressant drugs, like Prozac and Zoloft that mainly target neurotransmitters called serotonin or norepinephrine. One study estimated that 33 percent of depressed patients do not respond to four medication attempts. Tilley was one of them.

“When people are considered to be treatment resistant, how often is it that the treatment is failing the person?” Tilley wondered. “I always felt like I was failing my therapist in a way that was frustrating, and I’d have these moments of breakthrough, then I would go right back into severe depression and PTSD.” 

Suicide is highly prevalent among treatment-resistant cases, and consistently ranks in the top ten leading causes of death in America. In 2020, 44,834 people died by suicide; though that figure is considered to undercount the true tally. Adding another tangled layer of complexity, two-thirds of people with a substance use disorder also have a co-occurring mental health diagnosis; experts and researchers are increasingly calling for a more integrated approach to addiction and depression as intertwined phenomena. 

As depression rates rise, pharmaceutical companies have substantially cut back research and development for new psychiatric drugs. Decades of research in neuroscience failed to bring novel psychiatric treatments to the market, leading biotech firms to abandon their hunt for the next generation of drugs that treat mental illness. “This exodus creates a dangerous gap in the public health ecosystem,” Dr. Steven Hyman, director of the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, wrote in a 2019 Science commentary titled “Revolution Stalled.” Hyman observes that numerous antidepressants have been developed since the mid-century spate of discoveries in psychiatric medicine, “but none has improved on the efficacy of imipramine or the first MAOIs [monoamine oxidase inhibitors].”

Most of today’s antidepressants are based on the monoamine hypothesis, which supposes that deficiencies in neurotransmitters like serotonin cause depression. Tweaking the uptake and flow of these neurotransmitters, in theory, can reverse the illness. The newer generation of antidepressants are far safer than the old ones, and some people with opioid addictions are indeed helped by drugs targeting serotonin. But what if serotonin is the wrong target for a subset of people whose depression has been deemed treatment resistant? 

One part of our body’s internal opioid system plays a role in pain relief, euphoria, and, notably, social bonding, while another part is known to cause feelings of dysphoria, like stress and anxiety. “What might it look like if someone had an imbalance between these two opioid systems—if perhaps they had too much of one or a paucity of the other or a defective receptor,” Dr. Anna Fels, a psychiatrist at Cornell, wondered in an op-ed titled “Are Opioids the Next Antidepressant?” in the New York Times. “This could theoretically occur as a result of environment—trauma, for example, or chronic stress—or from a genetic problem or some combination.” 

Since Avi and Tilley’s use of opioids is criminalized, and could be viewed by some doctors as “drug seeking,” they are iced out of mainstream medicine. Methadone and buprenorphine are the two opioids that Tilley and Avi would have the easiest time accessing. But acquiring a steady supply of methadone through America’s bureaucratic (and sometimes punitive) clinic system is no picnic. Both methadone and buprenorphine are FDA-approved to treat opioid addiction, not depression. After all, the most effective treatments for opioid addiction are opioids (other treatments, like naltrexone or group therapy and counseling alone, have not been found to reduce the risk of fatal overdose). 

This concept is hardly new. People with Attention-Deficit Hyperactivity Disorder (ADHD), whose symptoms include excessive talking, the inability to focus or sit still, are prescribed stimulants. Stimulants may cause the rest of us to talk incessantly and fidget, but people with ADHD have the opposite reaction from stimulants: they are calmed down, enabled to focus. Similarly, opioids cause most people to feel drowsy, sedated, and itchy, but people like Avi and Tilley describe an opposite effect. “I could get up, clean the house, and take a shower,” Tilley said about her opioid use. “I remember thinking to myself, this is what’s been missing in my system.” 

“If a doctor had literally prescribed me an opiate, I don’t think I ever would have used heroin,” Tilley said. “Almost 23 years later, how have we still not come across a way to prescribe a safe supply of opiates to people?” 

Despite taking a slew of antidepressants and mood stabilizers, the veteran’s suicidal ideation and depression wouldn’t budge and he spent his days lying in bed. That went on for two weeks until he was started on buprenorphine; suddenly, his entire mood and demeanor radically shifted. “We came back the next morning and he was teaching yoga to other patients,” Dr. Lynch said. “He became a new person from the one that we’d known so many times before. It works that quickly.” Most antidepressant treatments can take weeks to fully take effect, so a drug that can rapidly relieve suicidal thinking can be a literal lifesaver. 

Dr. Lynch and his colleagues were so taken aback by the veteran’s breakthrough that, in 2019, they decided to write a case report in the American Journal of Psychiatry titled, “Depression: What’s Buprenorphine Got to Do With It?” For the veteran, buprenorphine acted as a one-two punch, simultaneously treating physical and psychological pain. In 2020, Dr. Lynch co-authored another case report detailing a suicidal 39-year-old man with a long history of injection heroin use (he once set himself on fire at a gas station). When he started buprenorphine, his physical and mental pain lifted. 

Figuring out exactly why buprenorphine produces such rapid results in these patients is a complicated scientific endeavor. “We know that people with substance-use disorders are more likely to also have a co-occurring mental illness and vice-versa,” Dr. Lynch said. “So it becomes a chicken and the egg thing: Are people depressed and then they’re self-medicating with substances like opioids? Or has using those drugs changed the way their brain works and then caused them to be depressed or anxious after?”  

Evidence for buprenorphine’s distinctive ability to treat suicide and depression goes back decades. A 2015 study conducted at the University of Haifa in Israel gave ultra-low doses of buprenorphine to severely suicidal patients in a randomized, placebo-controlled trial. The trial demonstrated that buprenorphine had a positive effect on depression and led to a significant drop in suicidal thinking compared to the placebo group. Despite crisis levels of depression and suicide in America, the study didn’t make much of a splash beyond an insulated community of researchers.

Buprenorphine has a unique action on two different opioid receptors in the brain. Most opioids activate what’s called the “mu-opioid” receptor, which can produce feelings of pain relief and euphoria, but also induce respiratory depression, which causes fatal overdoses. By contrast, buprenorphine only partially activates mu-receptors, which makes the drug overall less risky  compared to more potent opioids like heroin or fentanyl. As for why it may help treat depression or prevent suicide, buprenorphine also antagonizes—or blocks—a different opioid receptor called kappa, or the “k-opioid” receptor. When kappa is activated, it can produce those dysphoric feelings, like anxiety, sadness, and the loss of motivation. When kappa is blocked, research finds those depressive feelings fade away. Researchers theorize that buprenorphine’s activation of mu-receptors and blockage of k-receptors could be what’s producing such rapid antidepressant and antisuicide effects. 

In Scientific American, Anne Skomorowsky explained how the concept of “separation distress” influenced the Israeli scientists to look at an opioid like buprenorphine in the first place. Our brain’s naturally-produced opioids are released when we are around loved ones, but our internal opioid levels drop off when we’re alone. Neuroscience journalist Maia Szalavitz calls this “The Social Life of Opioids.” Think of a baby wailing when their mother stops holding them; or, if you’ve ever felt lonely, it can sometimes hurt, physically. The Israeli researchers figured by targeting the opioid system in severely suicidal patients, they could ease mental pain and psychache. A mild opioid activating the endogenous opioid system could be plugging some sort of deficit, like applying lubricant on a squeaky door hinge. Suddenly, going about life feels smoother. 

Building off of the results from the Israeli study, Dr. Schatzberg is currently running an innovative clinical trial at Stanford focused on suicide prevention. First, severely suicidal patients will receive an infusion of ketamine, then they will be randomized into two groups where one group receives a placebo and the other receives ultra-low doses of buprenorphine. In recent years, ketamine has been shown to also produce rapid improvements in people struggling with depression and suicidal ideation. But ketamine’s benefits can also feel fleeting and short-lived, so this study is testing whether buprenorphine can help extend the effects of ketamine. Though ketamine isn’t typically thought of as an opioid, research shows that its antidepressant and antisuicide effects actually hinge on the drug’s activation of the internal opioid system. 

The results from Dr. Schatzberg’s trial are still a long way off, but if they replicate previous findings, they could help expand the horizons of opioids as an antidepressant. So far, efforts to get an opioid on the market for depression in America have failed. In 2018, the American pharmaceutical company Alkermes submitted the first of its kind drug proposal to the FDA, an opioid for major depressive disorder, but it failed FDA approval due to major methodological and statistical issues cited by the advisory committee. An opioid for treatment-resistant depression may still be years away from FDA approval. 

Unfortunately, uber-potent fentanyl analogues have begun to infiltrate the street supply of black-tar heroin in the Pacific Northwest, which is causing an uptick in overdose deaths across the region. “I started to have issues when fentanyl started showing up,” Avi said. “That’s when I started having overdoses.” She found kratom when she started searching for a solution to keep her out of the chaotic heroin and fentanyl supply. “Kratom is one of my biggest harm-reduction measures,” she said, adding that it does not produce the same high as other opioids, but still gives her a sense of feeling safe, grounded, and at ease. 

“At some point, I may feel like daily or near daily opioid use is no longer serving me,” Avi said. “But as of right now, I really feel that having kratom, and sometimes other opioids, just stabilizes my brain chemistry.”

If you or someone you know is considering suicide, help is available. Call 1-800-273-8255 to speak with someone now or text START to 741741 to message with the Crisis Text Line.

Zachary Siegel is a journalist living in Chicago. His coverage of health, science, and addiction can be found in The New York Times Magazine, The Nation, The New Republic, and elsewhere. Follow him on Twitter.