Substance Use Disorders, Addiction, Sadness and Depression: Chicken or Egg

Depression is commonly identified among former heroin addicts in methadone maintenance treatment (MMT). Commonly, in opioid use disorders (OUD) programs using methadone maintenance, depression is frequently prescribed as antidepressants[i]. At the same time, rather than think that methadone caused depression, data suggest that methadone treatment reduces depression in patients with OUDs. In the multi-site Prescription Opioid Addiction Treatment Study (POATS), the best predictor of successful opioid use outcome in Suboxone treated patients was a lifetime diagnosis of major depressive disorder[ii].   To make matters even more confusing, self-medication for depression and sadness is a patient and family complaint on the admission evaluation exam. Several studies show antidepressant effects, but none demonstrate a clear improvement in drug abuse. These studies are contrary to “self-medication” but instead suggest depression is either independent or substance-induced.

Nunes and colleagues review the controlled trials of antidepressant treatment in methadone patients[iii]s. are three approved MAT treatments for OUD, methadone, buprenorphine, and naltrexone. Although, in contrast, it is more difficult to initiate patients to injectable naltrexone (XR-NTX)  than Suboxone ( BUP-NX once started, both medications were equally safe and effective. However, the intersection between depression, sadness, suicide, and MAT has been the most compellingly studied in methadone and buprenorphine MAT populations and patients who overdose on opioids. [iv] And those who survive an opioid overdose[v]. Depression, despair, and suicidality may be entirely separate from sad

 “Sadness typically arises,” Dorison et al. wrote, “from experiences of irrevocable loss.”[vi]. To many, it’s just intuitive that our emotions play an essential role in our choices, helping to govern everything from what we want to eat to whether we feel like exercising to the music we want to hear or television we want to watch. Our emotions are like the delicate engines of old cars, misfiring or charmingly humming or roaring us along on a journey. But we don’t like to make this connection about sadness. Sadness is different because it makes us think about ourselves, which makes us want rewards to replace our loss. And that might be why it contributes to addiction.

Researchers have long considered the paradox that substances produce highs, yet those with substance use disorders (SUD) are often sad, depressed, and suicidal. We have tended to think of this in neurobiological terms. Drugs of abuse stimulate brain reward centers, hijack them, and make them less responsive to natural reinforcers. Drug abuse induces a state of well-being and pleasure by releasing pleasure-related molecules. Over-releasing them would down-regulate or make the pleasure system deaf to these stimulations.   Cocaine use previously stood out for this reason—a drug associated with energy led to anhedonia, depression, lethargy, and dopamine depletion in individuals using it.[vii] Alcohol Use Disorders are often accompanied by feelings of helplessness, sadness, depression, and suicidal thoughts. These patients often use alcohol and tobacco, offering little relief from depression and two SUDs to treat.[viii] Cigarette smokers are often depressed, and, more recently, we’ve learned that living in a household exposed to secondhand smoke causes depression.[ix] Individuals using cannabis are also often depressed, and there’s some recent evidence of an association with suicidal thinking in younger individuals using cannabis[x]. (5) Substance use starts high and ends low, in depression and even despair.[xi] The COVID-19 pandemic, through its inundation of pain, deaths, job losses, and isolation,  breeds generalized sadness and puts individuals with SUD at higher risk.

More research confirms our intuition about how emotions influence our behavior, pushing us to danger and safety in powerful and identifiable ways.[xii] As the science has advanced, it’s shown us that we’ll get a better idea of behavioral influence by looking at particular emotions instead of general moods, say, sadness and anger, instead of broadly “positive” or “negative” states. But these findings haven’t focused on emotions influencing behaviors linked to worse health, including ones that can lead to addiction. Dorison et al., a team of Harvard researchers, set out to remedy this by testing the effects of sadness on tobacco use. First, this study found that sadness increases tobacco use, not other negative emotions. Second, Dorison et al. chose tobacco use as a rough proxy for “addictive substance use”—because it’s a legal substance, you can study used in a lab, and it is the leading cause of preventable death. Third, this study looked at sadness because of its associations with reward-seeking and how we try to replace an irrevocable loss by finding something else. It notes, for example, that research suggests we’ll spend more when we’re sad. “Self-focus,” the added attention we pay to ourselves when unhappy, might connect sadness and reward-seeking. This study set up a series of experiments to test the effects of sadness on smoking.

First, Dorison et al. looked at survey data on over 10,000 people, covering 1995-2014. They compared tobacco use to emotions, looking at questions like, “during the past 30 days, how often did you feel so sad nothing could cheer you up?” with respondents answering on a 5-point scale. They had 425 tobacco users divided into three groups: the sad, the disgusted, and the neutral. Then, they tried to stimulate these emotions in each group by having them watch a film clip and write a reflection after. This study is critical because it applies to recent advances in modeling emotional influence over behaviors to addiction-related behaviors and finds that we should guard against the dangers of sadness, in particular, because of its links to reward-seeking as we turn inwards and focus on ourselves. There are healthy ways to process sadness; therapy is a good start. We should practice self-care, eat well, exercise, and follow habits that may decrease the risk of developing a SUD. [xiii]Dorison et al.’s study is also a good reminder of the importance of positive psychology and an optimistic outlook. They also caution, “The present research does not hypothesize that sadness is unique among negative emotions in triggering addictive substance use.” Instead, they say, it’s a more powerful emotion influencing substance use. There’s a nuance to our sadness, chills, and hauntings unique to the details and memories of our particular irrevocable losses. The details are powerful, just the same. They can drive us to darker places still.

Depression is a risk factor for smoking cigarettes. It is also a reason people give for not being able to stop smoking. Smokers themselves report various positive results from smoking, including impact on depression, anxiety, and mental acuity. Smoking has also been shown to have protective effects on Parkinson’s Disease. Very early in her career, Volkow showed that smoking exerted antidepressant effects as an MAO inhibitor. Reduced monoamine oxidase (MAO ) levels have been found in current cigarette smokers, suggesting that cigarette smoke itself exerts an antidepressant effect[xiv]. Some effects of tobacco smoking are due to nicotine, and others are due to other components of tobacco smoke. [xv]

Cocaine users often report depression during a long cocaine run and psychomotoric retarded depression when discontinuing cocaine and during short term abstinence. Methamphetamine withdrawal also is associated with depression. Both psychostimulants cause depression and suicide during an active use disorder and also when trying to detox and become abstinent. Marijuana also causes anhedonia, sadness and depression in regular use. These can be profoundly disabling in teen and young adult users. Depression has a complex relationship to OUDs. It is not clear if depressed patients are self-medicating opioids for depression or an independent disorder or be engendered by psychosocial stress or toxic and withdrawal effects of drugs[xvi]. It is logical to assume that depression may be caused by many risks and factors. Studies of antidepressant medications have produced mixed results, some positive but more negative. But, MATs for opioid use disorders or addiction (e.g., methadone or buprenorphine maintenance or residential treatment) are likely to produce improvement in depression.

Many patients with OUDs come to medical attention after an overdose and their families. Most overdoses are accidental due to the changing nature of the opioid in the sample or supply in the illicit drug supply chain. Still, we do not generally even ask the question of intent. An “intentional” suicide attempt by fatal drug overdose refers to an individual seeking to overdose to end her life. This may sound straightforward enough. But the issue is much more nuanced, related to how we understand and respond to the opioid overdose epidemic. If all overdoses are considered “accidental” until proven otherwise, we may be missing higher rates of suicide and depression and different approaches to prevention, identification, and treatment.

How exactly can coroners and officials who write on death certificates determine whether someone “intentionally” wanted to die by overdose or “unintentionally” killed by overdose without any desire to die? The Directors of the National Institute of Mental Health (NIMH) and National Institute on Drug Abuse (NIDA) recently reviewed the literature linking overdose and suicide[xvii]. For example, up to 30 percent of all accidental overdoses are suicides. Further, they observed that controlling for other conditions, suicidal thoughts are 40-50 percent higher among individuals misusing prescription opioids and that “people with a prescription opioid use disorder were also twice as likely to attempt suicide as individuals who did not misuse prescription opioids.”

In the U.S., suicide rates are increasing, overdoses are growing, and life expectancy is decreasing—”deaths of despair,” they are often called. Between 1999 and 2009, opioid-related suicide rates doubled.[xviii] Opioid-related overdose deaths among Americans and adolescents have also surged. And both opioid-related deaths and suicides have increased to epidemic levels in the United States. Doctors Nora D. Volkow and Maria A. Oquendo[xix] have written that declining motivation to live can range “from engagement in increasingly risky behaviors despite a lack of conscious suicidal intent to frank suicidal ideation and intent.” Most of what we used to think of as leading causes of death have decreased. Deaths from cardiovascular disease, cancer, stroke, and lung disease have steadily declined since 2000. But deaths from drugs, alcohol, and suicide have been increasing. Things have changed so fast that more U.S. deaths now result from self-harm than diabetes. Suicide is more than twice as common as homicide in the United States. Yet little attention has been paid to these deaths’ contributions to overdoses, suicide, and addiction.6 In a recent study, nationally recognized research leaders explored the connection between opioid-related overdoses and the spectrum of suicidal motivation. Accidents, which may sometimes be covert suicide, make up the other leading causes of death. Unfortunately, the primary default manner-of-death assignment for injury cases contains misclassified suicides.[xx] Without psychological/psychiatric evidence contributing to the manner of death classification, suicide by drug intoxication in the U.S. is likely profoundly under-reported. Findings harbor adverse implications for surveillance, etiologic understanding, and prevention of suicides and drug deaths[xxi].

A Harvard McLean study found “that a significant number of treatment-seeking patients with OUD have suicidal motivation before nonfatal opioid overdoses.” We know that drug use, alcohol use, and substance use disorders are often accompanied by depression. Experts have debated this chicken and egg for years—which comes first, depression or opioid use? Suicidal motivations may be better understood as a background or underlying continuous issue for patients with SUDs, a “continuum” along which the drive to complete suicide varies over time. Quantitative analyses of suicidal motivation before overdose is a gap in research on the topic. This study measured the extent to which patients with OUD may experience varying suicidal reasons.

This Harvard, McLean Hospital study[xxii] asked participants about their “desire to die” before their most recent opioid overdose and their perception of how likely they were to overdose. Participants filled out questionnaires and rated their suicidal motivation and the likelihood of overdose on scales from 0-10. For suicidal motivation, a rating of 0 meant “no desire to die,” and a ten said, “I wanted to die.” For the likelihood of overdose, 0 meant “no risk of death” and said, “I thought I would die.” This study recruited participants from an inpatient detoxification/stabilization unit. One hundred twenty patients over 18 completed this study’s measures. Their mean age was 34, 85 percent were white, and 41 percent were women. In addition, 60 percent had a psychiatric disorder, 26 percent were receiving mental health treatment, and 32 percent had attempted suicide in the past. This study required patients to undergo substance use disorder treatment and to provide written consent. An astounding 58.5 percent of participants said they had at least some desire to die before their most recent opioid overdose, and only 41.5 percent said they did not want to die, a 0/10. This is quite remarkable when you remember that we had assumed all overdoses were accidental until recent work began to look at the association between depression and overdose. Thirty-six percent said they strongly desired to die, with a score greater than 7/10. In addition, 21 percent reported 10/10, “I wanted to die.” 30.2 percent of participants said they believed it was “not at all likely” they’d overdose, or 0/10. 13.2 percent said that it was “extremely likely,” 10/10. This study also found that 92 percent of participants used heroin or fentanyl. It suggests that the results are consistent with the idea of suicidal motivation as a spectrum, given variations in participant responses about the desire to die. That suicidal motivation before opioid overdose is “common.”

Harvard lead author Dr. Hilary Connery and her Harvard University coauthors write that “the classification of a drug overdose as either ‘unintentional’ or ‘intentional’ may not always reflect accurately upon either the behavioral episode itself or the treatment interventions. Most appropriate for preventing drug-related mortality.” These findings are significant because if suicidal motivation underlies an important number of opioid overdoses, our approach to education, prevention, and treatment of OUD patients needs to change. This McLean Hospital team did critical work here: previous research on heroin use disorders showed low suicidal intention during overdoses but did not gauge the spectrum of suicidal motivation. This study is crucial because there is minimal actual data on depression, suicidality, and overdoses, and this study starts to fill the gap.

Where is the psychiatrist, psychologist, and mental health expert evaluating patients rescued with naloxone or who entered programs for medication-assisted treatment? Often, patients do not have a psychiatric consultation in the hospital or emergency department or an evaluation for co-morbid depression, anxiety disorders, or trauma. Better screening standards and techniques, and more effective and targeted versions, could help health care providers more accurately assess the range of challenges patients face and better recognize the kinds of treatment options that may be required in different situations. For example, screening standards targeting suicidal motivation in OUD patients could save lives and improve outcomes. But the idea would be to evaluate patients earlier and not wait until they are actively suicidal.

It’s difficult to tease out the contributions of trauma or depression and anhedonia to an overdose and even harder to know what it all means for public health policy and responses to the opioid overdose epidemic. It seems evident that individuals with OUD who die of fentanyl overdoses are often not deliberately even seeking fentanyl, let alone death. But it is essential to look at actual data. Drugs of abuse cause structural changes to the same brain systems that we rely upon to estimate risk. This study points out that SUDs compromise self-assessment of dangers, leaving some patients in jeopardy after they did not realize the life and death risk they were exposed to. Better prevention and education initiatives could help here, not just by trying to stop suicide but by assisting patients in realizing the genuine risks of their attitudes and behaviors. Rather than assuming that all overdoses are “accidental,” it is time to evaluate and treat patients with co-existing diseases who have suicidal thoughts, passive or active suicidality, anhedonia, or sadness.

References

[1] Updated: From the APF Sep 12, 2020 blog

[2] Peles E, Schreiber S, Naumovsky Y, Adelson M. Depression in methadone maintenance treatment patients: rate and risk factors. J Affect Disord. 2007 Apr;99(1-3):213-20. doi: 10.1016/j.jad.2006.09.017. Epub 2006 Oct 19. PMID: 17055063.

[3] Peckham AD, Griffin ML, McHugh RK, Weiss RD. Depression history as a predictor of outcomes during buprenorphine-naloxone treatment of prescription opioid use disorder. Drug Alcohol Depend. 2020 Jun 12;213:108122. doi: 10.1016/j.drugalcdep.2020.108122. Epub ahead of print. PMID: 32563846; PMCID: PMC7736247.

[4] Nunes E, Quitkin F, Brady R, Post-Koenig T. Antidepressant treatment in methadone maintenance patients. J Addict Dis. 1994;13(3):13-24. doi: 10.1300/j069v13n03_02. PMID: 7734456.

[5] Oquendo MA, Volkow ND. Suicide: A Silent Contributor to Opioid-Overdose Deaths. N Engl J Med. 2018 Apr 26;378(17):1567-1569. doi: 10.1056/NEJMp1801417. PMID: 29694805.

[6] Connery, H.S., Taghian, N., Kim, J., Griffin, M., Rockett, I.R.H., Weiss, R.D., Kathryn McHugh, R. (2019). Suicidal motivations reported by opioid overdose survivors: A cross-sectional study of adults with opioid use disorder. Drug and Alcohol Dependence

[7] Dorison, C. A., Wang, K., Rees, V. W., Kawachi, I., Ericson, K. M. M., & Lerner, J. S. (2019b). Sadness, but not all negative emotions, heightens addictive substance use. Proceedings of the National Academy of Sciences, 117(2), 943–949. https://doi.org/10.1073/pnas.1909888116

[8] Dackis, C. A., & Gold, M. S. (1985). New concepts in cocaine addiction: The dopamine depletion hypothesis. Neuroscience & Biobehavioral Reviews, 9(3), 469–477. https://doi.org/10.1016/0149-7634(85)90022-3

[9] Epstein, J.F., Induni, M., Wilson, T. (2009). Patterns of clinically significant symptoms of depression among heavy users of alcohol and cigarettes. Blah blah, 6(1), A09

[10] Milic, M., Gazibara, T., Pekmezovic, T., Kisic Tepavcevic, D., Maric, G., Popovic, A., … Levine, H. (2020). Tobacco smoking and health-related quality of life among university students: Mediating effect of depression. PLOS ONE, 15(1), e0227042. https://doi.org/10.1371/journal.pone.0227042

[11] Gobbi, G., Atkin, T., Zytynski, T., Wang, S., Askari, S., Boruff, J., … Mayo, N. (2019). Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood. JAMA Psychiatry, 76(4), 426. https://doi.org/10.1001/jamapsychiatry.2018.4500

[12] Grant, B. F. (1995). Comorbidity between DSM-IV drug use disorders and major depression: Results of a national survey of adults. Journal of Substance Abuse, 7(4), 481–497. https://doi.org/10.1016/0899-3289(95)90017-9 ;

Jacob, L., Smith, L., Jackson, S. E., Haro, J. M., Shin, J. I., & Koyanagi, A. (2020). Secondhand Smoking and Depressive Symptoms Among In-School Adolescents. American Journal of Preventive Medicine. https://doi.org/10.1016/j.amepre.2019.12.008

[13] Lerner, J. S., Li, Y., Valdesolo, P., & Kassam, K. S. (2015). Emotion and Decision Making. Annual Review of Psychology, 66(1), 799–823. https://doi.org/10.1146/annurev-psych-010213-115043

[14] Robison, L. S., Alessi, L., & Thanos, P. K. (2018). Chronic forced exercise inhibits stress-induced reinstatement of cocaine conditioned place preference. Behavioural Brain Research, 353, 176–184. https://doi.org/10.1016/j.bbr.2018.07.009

[15] Fowler JS, Logan J, Wang GJ, Volkow ND. Monoamine oxidase and cigarette smoking. Neurotoxicology. 2003 Jan;24(1):75-82. doi: 10.1016/s0161-813x(02)00109-2. PMID: 12564384.

[16] Hong SW, Teesdale-Spittle P, Page R, Ellenbroek B, Truman P. Biologically Active Compounds Present in Tobacco Smoke: Potential Interactions Between Smoking and Mental Health. Front Neurosci. 2022 Apr 26;16:885489. doi: 10.3389/fnins.2022.885489. PMID: 35557609; PMCID: PMC9087043.

[17] Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004 Nov 15;56(10):793-802. doi: 10.1016/j.biopsych.2004.06.037. PMID: 15556125.

[18] Gordon, J., Volkow, N. (2019) Suicide Deaths Are a Major Component of the Opioid Crisis that Must Be Addressed. Retrieved from https://www.nimh.nih.gov/about/director/messages/2019/suicide-deaths-are-a-major-component-of-the-opioid-crisis-that-must-be-addressed.shtml

[19] Braden, J.B., Edlund, M.J., Sullivan, M.D. (2017) Suicide Deaths With Opioid Poisoning in the United States: 1999-2014. American Journal of Public Health

[20] Oquendo, M.A., Volkow, N.D. (2018) Suicide: A Silent Contributor to Opioid-Overdose Deaths. The New England Journal of Medicine

[21] Rockett IRH, Caine ED, Connery HS, D’Onofrio G, Gunnell DJ, Miller TR, Nolte KB, Kaplan MS, Kapusta ND, Lilly CL, Nelson LS, Putnam SL, Stack S, Värnik P, Webster LR, Jia H. Discerning suicide in drug intoxication deaths: Paucity and primacy of suicide notes and psychiatric history. PLoS One. 2018 Jan 10;13(1):e0190200. doi: 10.1371/journal.pone.0190200. PMID: 29320540; PMCID: PMC5761891.

[22] Connery HS, Weiss RD, Griffin ML, Trinh CD, Kim J, Rockett IRH, McHugh RK. Suicidal motivations among opioid overdose survivors: Replication and extension. Drug Alcohol Depend. 2022 Jun 1;235:109437. doi: 10.1016/j.drugalcdep.2022.109437. Epub 2022 Apr 2. PMID: 35427980; PMCID: PMC9106902.

[23] Connery HS, Weiss RD, Griffin ML, Trinh CD, Kim J, Rockett IRH, McHugh RK. Suicidal motivations among opioid overdose survivors: Replication and extension. Drug Alcohol Depend. 2022 Jun 1;235:109437. doi: 10.1016/j.drugalcdep.2022.109437. Epub 2022 Apr 2. PMID: 35427980; PMCID: PMC9106902.