The Bidirectional Relationship Between Major Depression and Opioid Misuse in Adolescents and Adults

Introduction

 Depression has been a growing issue in the U.S. Out of all the psychiatric and behavioral disorders, major depressive disorder (MDD) has been the greatest burden , costing approximately 2.7 million disability-adjusted life-years (DALYs) in 2016, which quantify the number of healthy years lost due to illness or premature death, and $1.5 trillion in 2020. Since then, MDD has only shown drastic increases, affecting 1 in 10 people in the U.S., and 1 in 5 adolescents and young adults (ages 12-25) ^1-3 Based on the nine criteria Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), MDD is characterized by a low mood, lack of interest in pleasurable activities (anhedonia), feelings of guilt or worthlessness, feeling fatigued or having low energy, poor decision-making skills and concentration, weight or appetite changes, hypersomnia or insomnia, suicidal ideations, and/or psychomotor retardation or agitation ^4-5. To be diagnosed with MDD, one must exhibit at least five of the criteria in a period of two weeks, and at least one of them must be “depressed mood”, or “loss of interest in pleasurable activities” ^6-7. Episodes and diagnosis of major depression were found to be greater among females than males by 4%, and were more prevalent among the young adult population aged 18-25 ^8-9.

Opioid abuse is also becoming an increasingly common issue in the U.S., and overdose deaths have accelerated rapidly in the past decade. From 2015-2016, there was a 21.4% increase in drug overdose deaths, 66% of which were from opioid overdoses. From 2013-2017, synthetic opioid overdose deaths increased significantly in 15 states. From 1999 to 2022, 294,000 people have died from prescription opioid overdose. In 2023, 8.9 million people aged 12 or more claimed to have misused prescription opioids ^10-13.

An opioid is a class of natural, semi-synthetic, and synthetic drugs, in the form of prescription medications or illegal drugs ¹⁴. Natural opioids, or opiates, are derived from opium poppy plant seeds. Examples include morphine, codeine, and opium itself. Semi-synthetic opioids are processed in laboratories using natural opioids. These include heroin, hydrocodone, and oxycodone. Finally, synthetic opioids are processed entirely in laboratories. A well-known example is fentanyl. Fentanyl is 100 times more potent than the natural opioid morphine, making it the most deadly substance in the U.S. These drugs can be laced, or covertly mixed, with other drugs, resulting in unintentional overdoses ^15-16. The reason these drugs are considerably more lethal, is because their binding affinity constants are much lower, meaning their tendency to bind to opioid receptors are much stronger, potentially due to their differing chemical structures ¹⁷.

Opioids act as analgesics and are used to relieve moderate to severe pain. Opioids produce their analgesic effects by traveling through the bloodstream and binding to opioid receptors on neurons in specific parts of the brain and the spinal cord. Binding causes potassium conductance, where potassium ions flow out of a postsynaptic cell, promoting a repolarizing state across the cell membrane. Since this counteracts depolarization, the driving force of action potentials, nerve signals become inhibited. Opioids also bind to receptors on the terminal of the previous nerve cell which is supposed to send the pain signals. When this occurs the flow of calcium is inhibited, which prevents the cell from releasing neurotransmitters in response to pain. Therefore, nerve signals coming from nociception are ceased. This prevents our brain from processing it, thus resulting in an inability to feel pain. Our body produces hormones called endorphins, which are opioid peptides that act as natural painkillers. Endorphins are what normally bind to the opioid receptors on our nerves, and when this happens the neurotransmitter dopamine is released, which causes a feeling of pleasure during regular activities such as games, or satisfying hunger. However, when one ingests opioids, these new molecules compete with endorphins to bind to the same receptors, acting as agonists. This stimulates a larger number of receptors, which increases the intensity dopamine release, resulting in an immense and unusual euphoric rush ^18-22. Due to this mechanism, opioids are extremely addictive. Opioids are depressants due to their sedative effects, including slowed down respirations, heart rate, and blood pressure, which can result in hypoxia, and worse, a cardiac arrest ^{18, 23-24}. Breathing becomes sluggish because over-activation of opioid receptors in the brainstem and pons area disrupts the natural respiratory rhythm ^25-26. Withdrawal symptoms involve chills, diarrhea, muscle cramps, and severe anxiety. Opioid misuse is characterized as using the drug outside of a physician’s prescription, or in unusually large amounts not consistent with prescribed dosage.

DSM-5 defines opioid use disorder (OUD) as having six or more of the following symptoms: opioids are taken over longer time intervals and greater amounts than recommended, attempts to discontinue use failed, high effort is put to gain access, cravings occur, frequency of use interferes with daily work, use continues despite social and interpersonal damage, activities are discontinued, usage is continued in dangerous situations or despite awareness of a medical issue which opioids can worsen, tolerance is high, and withdrawal symptoms are present ^27-29. In a study by Mark Sullivan, it was shown that depressed patients tended to opt for therapies involving opioids ³⁰. Studies have also shown that patients diagnosed with depression are generally more likely to be given opioid prescriptions, at times high-dose ones ^31-33. This can make them especially prone to misuse ^34-36. A third of MDD patients tend to be diagnosed with an opioid abuse disorder ^37-38. This is the most used drug associated with depression. Around 60,000 hospitalizations due to OUD between 2016-2019 have shown diagnoses of MDD as well, and between 2011 and 2015, for every 1% increase of depressed diagnoses, there was a 26% increase in opioid related deaths ^39-40. Mental health and substance abuse are highly intertwined issues in society today. Studying how depression is connected to the use of such a deadly class of drugs can provide clarity on the mechanisms behind MDD and OUD and how it can impact individuals’ decision-making. This can prompt efficient methods to address these disorders, and raise awareness on susceptible populations. Currently, there are limited studies discussing the cyclical relationship between depression and opioid abuse. As a result, examining this relationship in both ways will be beneficial since it can provide more insight not only into whether people tend to abuse opioids more due to being depressed, but also how that usage can have a compounding impact, thus leading to the main research question: How does MDD influence analgesic opioid misuse, and what effects does depression have on affected candidates that drives them to misuse? Are candidates with MDD more inclined to resort to opioid misuse compared to those who are not depressed, and can opioid use further impact existent depression, and if so how? The methods associated with this study are discussed in more detail in the next section.

Methods

This is a systematic review on strictly clinical trials from PubMed using the MeSH (Medical Subject Headings) terms: Major Depressive Disorder, Analgesic Opioids, NOT Bipolar Disorder. Initially, only the first two MeSH terms were used, and this yielded 105 papers originally, but after the final term it became 95. “Not bipolar disorder” was specified due to the fact that when the first two terms were searched on their own, many papers discussed the relationship between opioids and bipolar disorder. This strayed from the relationship between opioids and depression, so the term had to be excluded. The PRISMA diagram in Figure 1 indicates the article screening criteria.

Figure 1: PRISMA Diagram explaining article screening criteria

An abstract screening was done among the 95 papers received from the final MeSH terms. Papers were included if they discussed depression, mentioned some sort of correlation or causation between opioid use and depression, were studied strictly on humans, sampled from the U.S., and included adolescents and young adults (ages 12-25). Papers were excluded if they discussed any other forms of physical unrelated depression, focused on other irrelevant variables and related them to depression or opioid use, didn’t connect the main two variables, were studied on animals other than humans (such as rats or mice), were studied outside the U.S., or didn’t include young adults at all as part of their sample. It is essential that the mental health disorder depression is studied (based on DSM 5 criteria), and not any other type of disorder. Since we are connecting this to the opioid addiction epidemic in the U.S., humans have to be the focus of the study. While a wide variety of age groups is encouraged to be included (12-90), young adults under 25 have to be included since this age group is particularly known to misuse opioids.

Finally, there needs to be a relationship studied between opioid misuse and MDD, since the goal of this study is to determine how MDD influences opioid use, and vice versa (both ways). Therefore, it is crucial to eliminate any papers which stray from this relationship and instead compare either of these to an irrelevant variable, or include a strong confounding variable which may manipulate the relationship between our two variables of focus (such as physical pain).

Finally, 15 papers were singled out following the abstract screening for which a full-length review was done. At the end, a total of 7 papers were utilized for this study. The others were eliminated due to the presence of strong confounding variables that could potentially blur the sole relationship between depression and opioid abuse. In certain trials or survey studies involving opioid treatments or inquiring about opioid habits, respectively, it was discovered that many candidates were previously chronic pain patients who were already prescribed opioids for this reason (n=3), or had family histories of OUD or MDD, or prior mental health conditions or other substance use disorders which highly influenced the results (n=2). Additionally, there were cases the relationship between MDD and OUD were studied following major procedures, such as cesarean sections, joint arthroplasties, or treatments for spinal cord injury (n=3). These physical issues, which involve the confounding variable of pain, could make it unclear whether depression influenced opioid use, or the discomfort from other medical conditions or operations.

 For each paper, major trends were analyzed regarding the progression of opioid misuse following major depression symptoms or diagnoses, and vice versa. Thus, data analysis was performed by comparing proportion sizes in a sample, reporting percentage point differences between the experimental and control groups (depressed vs. non-depressed, or misuse vs. no misuse), or using likelihood coefficients as predictors of future behavior.

Results

A total of seven papers were extracted for this systematic review. Since we are going to be examining how depression and opioid abuse influence each other, there were some papers that studied how depression impacts the likelihood of opioid misuse, some that studied how opioid misuse impacts the likelihood of depression, and some that delved into both sides of the relationship. In Table 1 below, the results and details about each study are reported.

Table 1 Studies Examining the influence of Depression on Opioid Abuse, and vice versa *CI = confidence interval, p = p-value

A National Survey on Drug Use and Health (NSDUH) by Cruden G, et al. (2021) analyzed the likelihood of participants self-medicating with opioids as a result of mental health struggles, including major depressive episodes (MDE) experienced in the last year ⁴¹. They also examined how unmet mental health treatment needs in the last year can affect misuse more.

Clustered survey sampling analysis revealed that those who faced at least one MDE in the past year were predicted to misuse prescription opioids or heroin significantly more than those who didn’t experience any, by 2.43 percentage points. Those with MDE’s also were predicted to misuse more if they had unmet treatment needs in the past year, compared to those whose struggles were addressed, by 5.12 percentage points.

A study by Scherrer, et al. (2014) examined the reverse relationship of whether prescription opioid use leads to depression ⁴². This study was performed on a group that had been medically prescribed opioids, with no recent history of opioid use or depression. Patients were split into three groups: level 1 included exposure for 1-89 days, level 2 was 90-180 days, and level 3 was greater than 180 days. It was found that depression prevalence among participants significantly increased as opioid use duration increased, and as higher doses were being taken.

The odds ratio of the patients exhibiting depressive symptoms increased as the exposure level progressed, by 57% over the span of 1-180 days (Figure 2). Overall, it was concluded that opioid use can cause an onset of depression.

Figure 2: The progression of depressive symptoms as a result of prolonged opioid exposure Scherrer, et al. (2014)

Grattan A, et al. (2012) sought to study if depression among opioid therapy candidates affected their tendency to misuse ⁴³. Patients were sampled equally from each morphine equivalent dose group: 1-49 mg, 50-99 mg, and 100 mg or more. It was shown that patients who showed mild, moderate or severe levels of depression were significantly more likely to misuse opioids and take doses much higher than the prescribed amount. Severely depressed people were 3.1 times more likely than non-depressed people to misuse, moderately depressed individuals were 2.9 times more likely, and the mildly depressed ones were 1.9 times more likely. These results are represented in Figure 3.

Figure 3: Shown above is the correlation of depression intensity to misuse tendency; ratio was used instead of numbers to provide a comparison not just between different levels of depressed misusers, but also to compare each category to misusers who had no depression at all (this way, we don’t have to display the same bar representing non-depressed individuals three times); e.g. first bar shows 3.1 times more severely depressed misusers than non-depressed misusers

An NSDUH study by Sanmartin, et. al (2019) ⁴⁴ determined if there was an increasing rate of OUD and MDE among reproductive aged parenting women. Out of all parenting women with MDE, in the past 12 months approximately 25% resorted to opioid misuse with or without OUD. The risk of women with MDE misusing opioids was twice as much as those without MDE. Logistic regression analyses of these results showed that having MDE in the past 12 months among reproductive aged parental women was linked to a significantly high risk of misusing prescription opioids. The majority of these women reported friends, family, and physicians as main sources of obtaining the drugs, but a smaller amount also reported stealing or illegal sources.

A 2-year National Epidemiological Survey on Alcohol and Related Conditions (NESARC) by Li, et al. (2020) determined if a baseline MDD diagnosis impacted a new onset of NMOU, and vice versa ⁴⁵. The first year surveyed any baseline presence of the two, and the second year was a follow up of the baseline, to examine any changes associated with it. After statistical analysis of the results, it was found that a baseline diagnosis of MDD in participants was linked to 1.68 times the odds of a new onset of NMOU during the follow up period, significantly more compared to participants with no MDD diagnosis. Baseline symptoms of MDD were linked to 1.25 times the odds of new onset of NMOU, significantly more compared to participants with no MDD symptoms. Baseline NMOU among participants was linked to 1.42 times odds of incident major depressive symptoms over the follow up period, significantly more compared to those without NMOU. However, baseline NMOU was surprisingly linked to 0.79 times the odds of a new MDD diagnosis among participants, significantly less than those without NMOU, which is an outlier compared to all the other results. Also, those who had a new onset of NMOU were majority young, male, and unmarried while those with an onset of MDD were majority young, female, unmarried, and from a low-income household.

A one-month NSDUH study by Schepis, et al. (2019) ⁴⁶ surveyed opioid use disorder among adolescents in the past month, investigated different sources they approach to obtain prescriptions, and evaluated associated past-year mental health troubles with MDD. It was found that adolescents who misused prescription opioids, especially obtaining it from multiple sources, including physician, friends, or illegally, were linked to a significantly higher chance of having a past-year MDD diagnosis. MDD prevalence among those who misused prescription opioids from multiple sources was high, at 30.7%, with an adjusted odds ratio of 1.91, meaning adolescents who obtained opioids for misuse from different sources were almost 2 times as likely to have an MDD diagnosis recently. Similarly, Wu LT et al. ⁴⁷ studied the prevalence of non-prescribed prescription pain reliever (mostly includes opioids) abuse and dependence among adolescent users, general symptoms reported by users, and associated mental health risk factors including MDD. In the past 12 months, 1-5 days of use was characterized as experimental use, 6-11 days was infrequent use, 12-51 was about monthly use, and 52 and higher was about weekly use. The higher the use went on this scale, the closer it got to dependence and abuse. An adjusted odds ratio of 1.77 was found for the likelihood of adolescents who had major depressive episodes in the past year, to show significantly high dependence on non-prescribed pain-relieving opioids compared to those without any episodes. Overall, having MDE increased adolescents’ odds of abusing or depending on opioids for non-prescription use, and the more frequent the use, the stronger this link was.

In the larger scale, each of the seven papers support the main idea that candidates with major depressive disorder are more inclined to resort to opioid misuse or abuse and spiral into addiction compared to those who are not depressed, and vice versa that opioid abuse can also worsen or trigger a new onset of depression. These results are interpreted and explained in more detail in the next section.

Discussion

 Overall, all seven of these studies showed that depression and opioid misuse are strongly linked, among adolescent, young adult, and older adult populations aged 12-90 in the U.S. More specifically, they showed depression can induce opioid misuse, and that opioid misuse can trigger an onset of, or intensify existent depression. We will now look into what factors cause this.

Why Depression can trigger opioid misuse

The endogenous opioid system in our body, which produces healthy feelings of pleasure, plays a role in this relationship. These include endorphins, enkephalins, and dynorphins which normally bind with complexes called μ (Mu), δ (Delta), and κ (Kappa) receptors. When one has MDD, endogenous opioid activity is low, so having a depressed mood and being reclusive becomes a natural survival instinct to protect from any external “danger” that might worsen the depression, such as lack of acceptance or an inability to fit in. When these candidates use opioids, the newly introduced drugs can compete with our natural endogenous opioids to bind to the same receptors ³⁰. As a result, the opioid drugs serve as a replacement for lack of natural endogenous opioid response among depressed individuals. MDD patients get easily addicted this way.

Why Opioid misuse can trigger depression

Misusing opioids increases the brain’s reward pathway threshold due to a buildup of tolerance for the drug. Therefore, regular endorphin release from daily activities no longer satisfies the patient and they keep expecting more, which can result in an inability to find happiness and thus an incidence of depression. This two-way relationship between depression and opioid misuse can spiral into a vicious cycle. Another way depressive symptom can worsen is that more use of opioids makes withdrawal increasingly painful each time. In a state of abuse, κ receptor activity (which increases the reward threshold) skyrockets, so more of the drug is needed to maintain this ⁴².

More reasons for the association, and demographic factors

MDD patients who misused opioids often mentioned reasons such as insomnia, or stress⁴³. Opioids can treat mental distress and pain, which are symptoms of depression. Perception of pain and stress in depression is higher than normal. Frequently reported reasons for misuse among survey participants was to address depression-associated physical pain, feel euphoria, alleviate stress, or cope with negative feelings ⁴¹. Biological differences also affect the tendency to abuse opioids or display depressive symptoms. In the NESARC study ⁴⁵, young men were more likely to develop NMOU from depression, and young women were more likely to develop depression from NMOU. This coincides with the consistently higher depression rates among females, and a greater level of impulse in males causing them to jump quicker to drug use than females. A potential reason MDD can cause one to misuse opioids so easily could be the self-medication pathway. This is the idea that those with suffering mental health use substances non-medically as cope or temporary fixes. Impaired brain activity (especially in the prefrontal cortex, which controls planning) in those with depression can cause a demand for instant reward without considering consequences ⁴⁸. In the NSDUH study on reproductive aged women ⁴⁴, motivations to use opioids included physical pain, emotional distress, insomnia, and lack of support while raising young children amongst poverty. The youth is another key population affected. As we can recall from the NSDUH survey on adolescents ⁴⁶, those who obtained opioids for misuse from multiple sources were more likely to have a recent MDD diagnosis. This indicates a strong desperation to obtain opioids by any means, thus signifying how heavily these candidates are affected by the depressive symptoms, for which they seek relief rapidly. Recent needs for mental health treatments were also high, showing how misuse further affected depressive symptoms. In the other 12-month NSDUH study on adolescents ⁴⁷, it was found that the majority of depressed youngsters were more likely to use opioids to relieve themselves of despair rather than to feel a “high”. Removing the stressor was more important than adding a stimulus. Girls tended to be more dependent on opioids to cope with depression, versus boys who were more likely to use it to feel an intoxication, again indicating the more drastic effect depression has on females. Overall, young males showed a higher likelihood of seeking multiple source use compared to older adults. This is most probably due to more impulse and an inability to foresee consequences. The lack of prefrontal cortex development of the youth contributes to this ⁴⁹. Boys are more likely to chase the intoxication since females mature earlier than males during the teen ages ⁵⁰.

Outliers in results

One exception in the results of the NESARC study ⁴⁵ was when it showed NMOU led to a greater incidence of certain depressive symptoms, but was linked to lower risk for a full MDD diagnosis. Although opioid dependence can aggravate negative symptoms of depression due to withdrawal, a full diagnosis doesn’t occur due to the temporary stability the drug provides for the individual during that time, and since the follow up period is a short window of one year. Years down the road, however, dependence can catch up, leading to diagnosis.

Recommended treatment

Close monitoring of depression among those receiving opioid treatment is necessary. There should be a significant reduction or termination of opioid treatment if any depressive symptoms are detected, since depression can induce misuse, which will further worsen MDD ³⁰. As shown in one of the NSDUH studies ⁴¹ unmet needs for professional treatment of depression can drive one to resort to opioids as cope. A lack of a social support system can also play a role. Better mental health care access to counteract social isolation (including therapy, counseling, support groups, etc.) is vital. Early detection of MDD and taking appropriate measures immediately is also crucial, which will prevent the spiral into opioid misuse ⁴⁵. Special treatment also has to be catered toward particular populations which are especially at risk of opioid abuse induced by depression, such as the reproductive aged women in the NSDUH study ⁴⁴. Mental health treatment, prescription drug monitoring programs, and integrated healthcare for parenting women is necessary to lower OUD risk, and further resource allocation for women from vulnerable socio-economic backgrounds is also needed. The same goes for the younger crowd of adolescents who need thorough mental health youth evaluations, since MDD diagnosis puts them at risk for opioid misuse as well.

Conclusion

This study examined the relationship between depression and opioid misuse, and discovered how they can cause the onset of one another. Overall, the evidence shows that not only are MDD and opioid misuse positively correlated, but can also causally affect each other's progression. Demographically, it was evident that the majority of those ending up with depression, and resorting to using opioids as cope were females. On the other hand, those who misused opioids in greater amounts and were more likely used it to feel euphoria, were males. Compared to adults, adolescents were more likely to obtain opioids through multiple sources. Also, in general the younger crowd showed more of a motivation to misuse opioids for immediate coping, or as a recreational escape compared to the older populations. MDD and opioid misuse having this lasting effect on each other indicates that together, they can spiral into a dangerous cycle affecting both the mental and physical health of individuals’ in the long run. Thus, immediately addressing the mental health concerns of individuals, especially women, who show symptoms of depression is essential. This way, addiction can be prevented in the early stages. It is equally as important to push for proper rehabilitation and treatment programs to address addiction, and monitor mental health to ensure depression is mitigated as well.

Limitations and Future Directions

Some confounding variables in the analyzed surveys and trials may have clouded the relationship between depression and opioid misuse. For example, in the NESARC study ⁴⁵, certain candidates had family history of MDD, which could have affected the incidence of depression that rose from NMOU. In the study on reproductive aged parenting women ⁴⁴, the burden of parenting, unemployment of the mothers, and lack of education could have played a role in misusing opioids, on top of the mental struggles of depression. For future studies, creating as uniform a sample as possible could ensure no other stressors specific to a population are playing a role in drug abuse.

 Numerous new topics could be explored as a follow up to this study. Delving deeper into the structure of mental health evaluations, support groups, and drug monitoring programs could provide more insight into how these interventions actually address MDD and drug-using behaviors. Specific treatments such as cognitive behavioral therapy (CBT) could be explored as well. Going through all potential options can help come up with a solution to which works best. Since this study also showed how depression tends to affect females more than males, the psychology of depressed females can be further studied to compare their perception of MDD symptoms to males. We could also study the psychobiology of males driving them to attempt risky behaviors. Lastly, studying the relationship between depression and other drugs, such as stimulants, can also be useful. The same applies for studying different mental health disorders like anxiety, schizophrenia, or bipolar disorder. This study, compounded by all these further studies can shed more light into how rampant substance abuse and associated mental health conditions are in society.

References

1.     Friedrich MJ. Depression is the leading cause of disability around the world. JAMA.2017;317(15):1517. https://doi.org/10.1001/ jama.2017.3826.

2.     The US Burden of Disease Collaborators. The State of US Health, 1990–2016: burden of diseases, injuries, and risk factors among US States. JAMA. 2018;319(14):1444–72. https://doi.org/10.1001/jama.2018.0158.

3.     Goodwin RD, Dierker LC, Wu M, Galea S, Hoven CW, Weinberger AH. Trends in U.S. Depression Prevalence From 2015 to 2020: The Widening Treatment Gap. Am J Prev Med. 2022 Nov;63(5):726-733. doi: 10.1016/j.amepre.2022.05.014. Epub 2022 Sep 19. PMID: 36272761; PMCID: PMC9483000.

4.     Malhi GS, Mann JJ. Depression. Lancet. 2018 Nov 24;392(10161):2299-2312. doi: 10.1016/S0140-6736(18)31948-2. Epub 2018 Nov 2. PMID: 30396512.

5.     Thompson RJ, Mata J, Jaeggi SM, Buschkuehl M, Jonides J, Gotlib IH. Maladaptive coping, adaptive coping, and depressive symptoms: variations across age and depressive state. Behav Res Ther. 2010 Jun;48(6):459-66. doi: 10.1016/j.brat.2010.01.007. Epub 2010 Feb 10. PMID: 20211463; PMCID: PMC2872051.

6.     Jaser SS, Langrock AM, Keller G, Merchant MJ, Benson MA, Reeslund K, Champion JE, Compas BE. Coping with the stress of parental depression II: adolescent and parent reports of coping and adjustment. J Clin Child Adolesc Psychol. 2005 Mar;34(1):193-205. doi: 10.1207/s15374424jccp3401_18. PMID: 15677293.

7.     Pacek, L. R., Weinberger, A. H., Zhu, J., and Goodwin, R. D. (2020) Rapid increase in the prevalence of cannabis use among people with depression in the United States, 2005–17: the role of differentially changing risk perceptions. Addiction, 115: 935–943. https://doi.org/10.1111/add.14883.

8.     Parker G, Parker G, Malhi Gin, et al. Self-Harming in Depressed Patients: Pattern Analysis. Australian & New Zealand Journal of Psychiatry. 2005;39(10):899-906. doi:10.1080/j.1440-1614.2005.01662.x

9.   Substance Abuse and Mental Health Services Administration. (2022). Key substance use and mental health indicators in the United States: Results from the 2021 National Survey on Drug Use and Health (HHS Publication No. PEP22-07-01-005, NSDUH Series H-57). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/report/2021-nsduh-annual-national-report

10. Seth P, Scholl L, Rudd RA, Bacon S. Overdose Deaths Involving Opioids, Cocaine, and Psychostimulants - United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2018 Mar 30;67(12):349-358. doi: 10.15585/mmwr.mm6712a1. PMID: 29596405; PMCID: PMC5877356.

11. O'Donnell JK, Gladden RM, Seth P. Trends in Deaths Involving Heroin and Synthetic Opioids Excluding Methadone, and Law Enforcement Drug Product Reports, by Census Region - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017 Sep 1;66(34):897-903. doi: 10.15585/mmwr.mm6634a2. PMID: 28859052; PMCID: PMC5657786.

12. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics. Available at http://wonder.cdc.gov.

13. Key Substance Use and Mental Health Indicators in the United States: Results from the 2023 National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration.

14. Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012 Feb;6(1):11-6. doi: 10.1177/2049463712438493. PMID: 26516461; PMCID: PMC4590096.

15. Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019 Nov;106:49-57. doi: 10.1016/j.neubiorev.2018.12.005. Epub 2018 Dec 5. PMID: 30528374; PMCID: PMC7233332.

16. Pergolizzi J Jr, Raffa R, LeQuang JAK, Breve F, Varrassi G. Old Drugs and New Challenges: A Narrative Review of Nitazenes. Cureus. 2023 Jun 21;15(6):e40736. doi: 10.7759/cureus.40736. PMID: 37485167; PMCID: PMC10361140.

17. Donna A. Volpe, Grainne A. McMahon Tobin, R. Daniel Mellon, Aspandiar G. Katki, Robert J. Parker, Thomas Colatsky, Timothy J. Kropp, S. Leigh Verbois, Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs, Regulatory Toxicology and Pharmacology, Volume 59, Issue 3, 2011, Pages 385-390, ISSN 0273-2300, https://doi.org/10.1016/j.yrtph.2010.12.007.

18. Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008 Jun;100(6):747-58. doi: 10.1093/bja/aen094. Epub 2008 May 1. PMID: 18456641.

19. Stein C. Opioid Receptors. Annu Rev Med. 2016;67:433-51. doi: 10.1146/annurev-med-062613-093100. Epub 2015 Aug 26. PMID: 26332001.

20. Corder G, Castro DC, Bruchas MR, Scherrer G. Endogenous and Exogenous Opioids in Pain. Annu Rev Neurosci. 2018 Jul 8;41:453-473. doi: 10.1146/annurev-neuro-080317-061522. Epub 2018 May 31. PMID: 29852083; PMCID: PMC6428583.

21. Serguei Marshansky, Pierre Mayer, Dorrie Rizzo, Marc Baltzan, Ronald Denis, Gilles J. Lavigne, Sleep, chronic pain, and opioid risk for apnea, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 87, Part B, 2018, Pages 234-244, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2017.07.014.

22. Kosten TR, George TP. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect. 2002 Jul;1(1):13-20. doi: 10.1151/spp021113. PMID: 18567959; PMCID: PMC2851054.

23. U.S. Food and Drug Administration. Label: oxycodone (package insert). U.S. Department of Health and Human Services; 2019.

24. Krantz MJ, Palmer RB, Haigney MCP. Cardiovascular Complications of Opioid Use: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021 Jan 19;77(2):205-223. doi: 10.1016/j.jacc.2020.11.002. PMID: 33446314.

25. Ballantyne JC, Koob GF. Allostasis theory in opioid tolerance. Pain. 2021 Sep 1;162(9):2315-2319. doi: 10.1097/j.pain.0000000000002280. PMID: 33769368.

26. Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A. Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18(37):5994-6004. doi: 10.2174/138161212803582469. PMID: 22747535.

27. U.S. Food and Drug Administration. Label: morphine sulfate (package insert). U.S. Department of Health and Human Services; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022207s011lbl.pdf.

28. Karagiannis TT, Cleary JP Jr, Gok B, Henderson AJ, Martin NG, Yajima M, Nelson EC, Cheng CS. Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program. Nat Commun. 2020 May 26;11(1):2611. doi: 10.1038/s41467-020-16159-y. PMID: 32457298; PMCID: PMC7250875.

29. Bluthenthal RN, Simpson K, Ceasar RC, Zhao J, Wenger L, Kral AH. Opioid withdrawal symptoms, frequency, and pain characteristics as correlates of health risk among people who inject drugs. Drug Alcohol Depend. 2020 Jun 1;211:107932. doi: 10.1016/j.drugalcdep.2020.107932. Epub 2020 Mar 18. PMID: 32199668; PMCID: PMC7259345.

30. Sullivan MD. Depression Effects on Long-term Prescription Opioid Use, Abuse, and Addiction. Clin J Pain. 2018 Sep;34(9):878-884. doi: 10.1097/AJP.0000000000000603. PMID: 29505419.

31. Davis L, Uezato A, Newell JM, Frazier E. Major depression and comorbid substance use disorders. Curr Opin Psychiatry. 2008 Jan;21(1):14-8. doi: 10.1097/YCO.0b013e3282f32408. PMID: 18281835.

32. McHugh RK, Weiss RD. Alcohol Use Disorder and Depressive Disorders. Alcohol Res. 2019 Jan 1;40(1):arcr.v40.1.01. doi: 10.35946/arcr.v40.1.01. PMID: 31649834; PMCID: PMC6799954.

33. Edlund MJ, Martin BC, Devries A, Fan MY, Braden JB, Sullivan MD: Trends in use of opioids for chronic noncancer pain among individuals with mental health and substance use disorders: the TROUP study. Clin J Pain 26: 1-8, 2010

34. Markou A, Kosten TR, Koob GF. Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology. 1998 Mar;18(3):135-74. doi: 10.1016/S0893-133X(97)00113-9. PMID: 9471114.

35. Hermes G, Hyman SM, Fogelman N, Kosten TR, Sinha R. Lofexidine in Combination With Oral Naltrexone for Opioid Use Disorder Relapse Prevention: A Pilot Randomized, Double-Blind, Placebo-Controlled Study. Am J Addict. 2019 Nov;28(6):480-488. doi: 10.1111/ajad.12942. Epub 2019 Aug 26. PMID: 31448846.

36. Woody GE, Luborsky L, McLellan AT, O'Brien CP, Beck AT, Blaine J, Herman I, Hole A. Psychotherapy for opiate addicts. Does it help? Arch Gen Psychiatry. 1983 Jun;40(6):639-45. doi: 10.1001/archpsyc.1983.04390010049006. PMID: 6847332.

37. Glenn E. Hunt, Gin S. Malhi, Harry Man Xiong Lai, Michelle Cleary, Prevalence of comorbid substance use in major depressive disorder in community and clinical settings, 1990–2019: Systematic review and meta-analysis, Journal of Affective Disorders, Volume 266, 2020, Pages 288-304, ISSN 0165-0327, https://doi.org/10.1016/j.jad.2020.01.141.

38. Tumenta T, Ugwendum DF, Chobufo MD, Mungu EB, Kogan I, Olupona T. Prevalence and Trends of Opioid Use in Patients With Depression in the United States. Cureus. 2021 May 28;13(5):e15309. doi: 10.7759/cureus.15309. PMID: 34221762; PMCID: PMC8238014.

39. Adeolu Funso Oladunjoye, Crystal Obi-Azuike, Funmilola Babalola, Gibson Anugwom, Henry Onyeaka, Kammarauche Aneni, Eduardo D. Espiridion, Major Depressive Disorder prolongs hospital stay among hospitalizations with Opioid Use Disorder, Psychiatry Research Communications, Volume 3, Issue 2, 2023, 100118, ISSN 2772-5987, https://doi.org/10.1016/j.psycom.2023.100118.

40. Foley M, Schwab-Reese LM. Associations of state-level rates of depression and fatal opioid overdose in the United States, 2011-2015. Soc Psychiatry Psychiatr Epidemiol. 2019 Jan;54(1):131-134. doi: 10.1007/s00127-018-1594-y. Epub 2018 Sep 1. PMID: 30173316.

41. Cruden G, Karmali R. Opioid misuse as a coping behavior for unmet mental health needs among U.S. adults. Drug Alcohol Depend. 2021 Aug 1;225:108805. doi: 10.1016/j.drugalcdep.2021.108805. Epub 2021 Jun 18. PMID: 34174774.

42.  Scherrer JF, Svrakic DM, Freedland KE, Chrusciel T, Balasubramanian S, Bucholz KK, Lawler EV, Lustman PJ. Prescription opioid analgesics increase the risk of depression. J Gen Intern Med. 2014 Mar;29(3):491-9. doi: 10.1007/s11606-013-2648-1. Epub 2013 Oct 29. PMID: 24165926; PMCID: PMC3930792.

43. Grattan A, Sullivan MD, Saunders KW, Campbell CI, Von Korff MR. Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse. Ann Fam Med. 2012 Jul-Aug;10(4):304-11. doi: 10.1370/afm.1371. PMID: 22778118; PMCID: PMC3392289.

44. Sanmartin MX, Ali MM, Chen J, Dwyer DS. Prescription opioid misuse, sources of opioids and reasons for opioid misuse among reproductive aged parenting women with major depressive episode. Addict Behav. 2019 Nov;98:106057. doi: 10.1016/j.addbeh.2019.106057. Epub 2019 Jul 16. PMID: 31376658.

45.  Li X, Fu Q, Scherrer JF, Humphrey D, Leigh I. A temporal relationship between nonmedical opioid Use and major depression in the U.S.: A Prospective study from the National Epidemiological Survey on Alcohol and Related Conditions. J Affect Disord. 2020 Aug 1;273:298-303. doi: 10.1016/j.jad.2020.04.047. Epub 2020 May 11. PMID: 32421616.

46. Schepis TS, Wilens TE, McCabe SE. Prescription Drug Misuse: Sources of Controlled Medications in Adolescents. J Am Acad Child Adolesc Psychiatry. 2019 Jul;58(7):670-680.e4. doi: 10.1016/j.jaac.2018.09.438. Epub 2018 Oct 30. PMID: 30768405; PMCID: PMC6491250.

47. Wu LT, Ringwalt CL, Mannelli P, Patkar AA. Prescription pain reliever abuse and dependence among adolescents: a nationally representative study. J Am Acad Child Adolesc Psychiatry. 2008 Sep;47(9):1020-9. doi: 10.1097/CHI.0b013e31817eed4d. PMID: 18664996; PMCID: PMC2636856.

48. Fellows LK, Farah MJ. Different underlying impairments in decision-making following ventromedial and dorsolateral frontal lobe damage in humans. Cereb Cortex. 2005 Jan;15(1):58-63. doi: 10.1093/cercor/bhh108. Epub 2004 Jun 24. PMID: 15217900.

49. Arain M, Haque M, Johal L, Mathur P, Nel W, Rais A, Sandhu R, Sharma S. Maturation of the adolescent brain. Neuropsychiatr Dis Treat. 2013;9:449-61. doi: 10.2147/NDT.S39776. Epub 2013 Apr 3. PMID: 23579318; PMCID: PMC3621648.

50.  Laureys F, Middelbos L, Rommers N, De Waelle S, Coppens E, Mostaert M, Deconinck FJA, Lenoir M. The Effects of Age, Biological Maturation and Sex on the Development of Executive Functions in Adolescents. Front Physiol. 2021 Sep 10;12:703312. doi: 10.3389/fphys.2021.703312. PMID: 34566676; PMCID: PMC8461056.