Top Addiction Research: 2018 Year in Review

By: Mark S. Gold, MD & Dr. Drew W. Edwards, EdD, MS

1. What Drives the Onset, Progression, and Continuation of Addiction?

Substance use disorder (SUD) is much more than just us – it is a progressive disease. Drugs target the pleasure and motivational circuits in the brain’s reward system and induces profound, and often difficult to reverse, dysregulation of these critical systems. SUDs start with acute and deliberate intoxication. The passing time and regular use is followed by a rebound/negative affect, preoccupation craving and wanting, and anticipatory reward. These stages involve different neurobiological mechanisms conspiring and resulting in exaggerated incentive salience (liking, wanting, needing), increasing anhedonia from the down regulation of the reward biology, the upregulation of the human stress response, iconic and Pavlovian habit formation, and impairment in cognitive skills – most notably usurp focus and attention, memory, and executive function. Drilling deeper, the progressive impact of psychoactive drug use involves changes in dopamine and opioidergic volume in the basal ganglia to produce salience incentive and reward. The dysphoric and stress-like responses observed during drug rebound and forced temporary abstinence involve decreases in the dopamine function within the reward system and concurrent increase of neurotransmitters such as: Corticotrophin – releasing factor (CRF) and the endogenous opioid dynorphin within the neurocircuitry of the extended amygdala. Preoccupation and anticipatory reward involve the disruption of key afferent projections from the prefrontal cortex and insula including glutamate signaling to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in the neurocircuitry associated with the onset, progression and maintenance of addiction that might mediate initial vulnerability, maintenance and relapse associated with addiction. These progressive stages and the diverse mechanisms involved, conspire in the transition from recreational to compulsive drug use in some individuals—but not others. We just don’t know why.

Why Does This Matter?

Addictive disease is a phenotypically heritable disease. In other words, a combination of genetic predisposition and environmental stressors. NIAAA Director George Koob, PhD postulates the individual differences in the neurobiological systems that gird the processing of reward, incentive salience, stress, pain, preoccupation, and habitual behaviors may explain one’s “vulnerability to substance use disorder; the diversity of emotional, motivational, and cognitive profiles of individuals with substance use disorders and heterogeneous responses to cognitive and pharmacological treatments.” Understanding and codifying the neuropsychological conditions and mechanisms that differentiate how addiction manifests in certain ways among certain individuals and not in others is the key to understanding how addiction develops and progresses. Knowing this could lead to the development of new and novel approached to treatment.

Reference:

Farisco, M., Evers, K., & Changeux, J. (2018, November 19). Drug Addiction: From Neuroscience to Ethics. Retrieved from https://doi.org/10.3389/fpsyt.2018.00595 Koob GF,  Schulkin J.  Addiction and stress: An allostatic view. Neurosci Biobehav Rev. 2018 Sep 15. pii: S0149-7634(18)30218-5. doi: 10.1016/j.neubiorev.2018.09.008. [Epub ahead of print]

2. The Importance of Peers, Family, and Social Interaction in Treatment Modeled in Animals

A novel study recently published in Nature Neuroscience reveals what most addiction professionals have always suspected – social interactions have a profound effect on behaviors related to the brain’s response to drug-associated cues leading to addiction or abstinence, successful recovery, or relapse. Social interaction is, after all, why Alcoholics Anonymous and the subsequent 12 step programs evolved.  This great paper suggests social interaction can change the activity of specific neuronal circuits controling drug craving and relapse. Led by Dr. Marco Venniro from the National Institute on Drug Abuse (NIDA), researchers used established animal models of drug addiction to show that when given a choice, rodents repeatedly chose social interaction over self-administration of heroin or methamphetamine. To assess the level of addiction in their rats, the NIDA team utilized complex behavioral paradigms to model the sort of real life choices made by humans who suffer from addictive disease. The model included observation and measurements regarding how hard rodents will work to access an addictive drug, and how long drug seeking would persist despite negative reinforcement, e.g., brief (non-injurious) electric shocks. Although individual subsets emerged in these paradigms, the social reinforcement always won out over the drug. When given that choice, rodents consistently chose social contact over self-administering the drug, even among rodents previously addicted to heroin or meth.

Why Does This Matter?

 Certainly, rats lack the cognitive complexity and psychological stressors unique to humans. Rodents do not lie, cheat, hold resentments, or ask for forgiveness. Yet their brain reinforcement systems are sufficiently like humans to be successfully used to study addiction. This model still reinforces for all neuroscientists that early recovery for humans remains a daily choice between social interactions with loved ones, recovering friends, or getting high. We had Medically Assisted Treatments (MAT) in the 1970s such as Naloxone-Narcan, Methadone, and even Clonidine and Naltrexone. Even short term studies showed that MAT program outcomes were poor as retention was negligible. Successful addiction treatment with verified outcomes was reported by researchers at Yale and other programs. Recovery was possible for addicts of every kind. Most managed to attain sobriety via 12-Step Programs or related social/spiritually focused recovery models with and without MATs. These findings reinforce the importance of family treatment and the restoration of relationships torn apart by addiction – only the best centers offer enhanced family treatment.  Outcome data reflect the critical importance of restoring relationship and establishing new ones. Thus, giving credence to the old AA adages: “One day at a time” and “Keep coming back – it works!”

 Reference:

Reiner D, et al. Relapse to opioid seeking in rat models: behavior, pharmacology and circuits October 2018 Neuropsychopharmacology: DOI: 10.1038/s41386-018-0234-2

3. Marijuana: Wishes vs Reality

The ongoing statewide legalization of marijuana has contributed to changes in attitudes, decreased perceptions of harm, and a dramatic increase in the prevalence of users among all ages in the US. The internet has touted marijuana for its medicinal value as a legitimate treatment for a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer’s disease, Parkinson’s disease, post-traumatic stress, inflammatory bowel disease, and even morning sickness. Certainly, if you have a disease or disabling symptoms you too would hope for a marijuana cure or miracle. Typically, the FDA decides to help physicians determine whether a new, proposed medication is safe and effective in treating a particular disease, but in the absence of definitive science and anecdotal reports dominate the public discourse.  As mentioned, the perception of harm regarding marijuana use is at its lowest point in history, when in fact, the actual harm (due to the increased potency and early onset of use by children and teens) has never been higher. It is one thing to say that marijuana is like alcohol and should be legal or decriminalized. It is quite another to say stem cells or marijuana is a proven treatment. This folklore and misinformation regarding the benefits of marijuana is ubiquitous, obscuring objective well-documented science regarding the lack of effectiveness compared to gold standard treatment for a specific disease. With evidence for smoked marijuana coming in well short of such assertions and with the risks of smoking or juuling clearly having short and long-term adverse effects, including addiction. Clearly, marijuana use does not cause overdose deaths like opioids or withdrawal deaths like barbiturates or alcohol, but it has many other well-documented consequences and risks – unfortunately, the list is getting longer. The acute and long-term effects of THC on the brain and behavior are mediated via the vast Endocannabinoid System (ECS), which was not discovered until the early 1990s and still remains poorly understood. However, addiction is addiction. The psychopathology associated with marijuana, especially the high potency products, amid the drumbeat for full legalization, and in the absence of any serious scientific scrutiny is tantamount to political malpractice. Here is the best available evidence revealing how marijuana induced neuroadaptive changes lead to addiction:

• The initial binge/intoxication stage precipitates neuroadaptation in brain regions associated with reward, salience, higher level thinking and emotions
• When marijuana usage stops, a slower but demonstrable withdrawal occurs characterized by negative emotions via changes in the extended amygdala (the fear, fight, or flight center) resulting in restlessness, irritability, mood swings and anxiety
• Anticipatory preoccupation during abstinence result in changes in the prefrontal cortex (PFC), which leads to deficits in motivation, focus, executive function and mediation and inhibition of hedonic drives

Addiction = Neuroadaptations

Due to its unique hydrophobic properties, THC is associated with a whole new set of physical and psychiatric harms. Like all addictive substances, THC is thought to degrade neuronal signaling germane to reward incentive and cognitive processing, which result in marked emotional lability and loss of behavioral control. Cannabis Use Disorder is characterized by emotional dysregulation, which manifests as anhedonia, anxiety, cognitive impairment –most notably the decline of memory retrieval, focus, and executive function. Intoxication can include dissociative symptoms, transient psychosis, and permanent thought disorder. A 10-year study of adolescents who use marijuana two or more times per week were five times more likely to drop out of high school compared to non-users. Chronic use among all age groups is associated with anhedonia, the inability to attain natural emotional rewards and experience pleasure and contentment. The metabolism and storage of metabolites in adipose tissue, the gonads, and the brain cause functional impairment 24-48 hours after the subjective “high” has waned.  Moreover, the increased potency of commercially available marijuana products is driven by free market competition. No dispensary advertises low potency THC products that are extremely safe. Just look at the names of these products, e.g., Blazed, Blissed, Spaceman; and more importantly, in order to increase the THC content, the manufacturers must drastically lower Cannabidiol (CBD) content. CBD is erroneously touted as the new miracle “vitamin” being added to all sorts of food and drinks. It’s true, that a pharmaceutically pure form of CBD had proven safe and effective for two rare forms of childhood epilepsy that did not respond to other medications. Epidolex contains pure CBD and is not psychoactive but is neuroprotective. Epidiolex is a pharmaceutical-grade version of cannabidiol (CBD oil), which many parents have used for years to treat children with rare forms of treatment resistant seizure disorders. Nearly all the scientifically-derived medicinal benefits from cannabis are due to the CBD content. The math is simple – to make high potent THC products, they must remove the neuroprotection that CBD provides. This makes the product much more potent and dangerous. These data are largely unknown by the public or our policy makers. Marijuana Use Disorder aligns with the well-established model of addiction at every level. The challenge is to educate a public that had been inundated with misinformation and manipulated by claims of efficacy for a plethora of diseases and conditions without any FDA scrutiny regarding such claims.

Why Does This Matter?

Addiction to marijuana has been demonstrated in both animals and humans. Early initiating increases the risk of addiction,  diagnostically differentiated by loss of behavioral control and gross underachievement. Use of the new highly potent strains and edibles are associated with transient psychosis, depression, motor vehicle mortality, suicidality, and premature death. The idea marijuana can be used therapeutically to treat so-called “serious drug addiction” is a peculiar and untested hypothesis, which is counter intuitive considering most opioid overdoses reveal the postmortem presence in the blood and a history of marijuana use disorder. Moreover, there is not a speck of scientific evidence to suggest marijuana is a viable “medically assisted treatment” for opioid addiction or withdrawal. Until recently, it was true cannabis was never listed as the cause of death by overdose. However, recent deaths by toddlers who ingested potent THC candy, presumably purchased by a parent, raises serious public health concerns about the “cost” of legalization.

Reference:

Zehra A, Burns J, Liu CK, Manza P, Wiers CE, Volkow ND, Wang GJ. Cannabis Addiction and the Brain: a Review. J Neuroimmune Pharmacol. 2018 Mar 19. doi: 10.1007/s11481-018-9782-9

4. Binge Drinking: No Longer Just a College Problem

Binge drinking is the most common, costly, and lethal pattern of alcohol use in the United States. The National Institute on Alcohol Abuse and Alcoholism defines binge drinking as a pattern of drinking that brings a person’s blood alcohol concentration (BAC) to 0.08 percent or above; or otherwise defined as consuming five or more drinks per occasion for men, and four or more drinks for women, usually within a two-hour window. Binge drinkers binge in order to get intoxicated quickly, and as a result of this rapid intoxication, these drinkers account for more than half of the 88,000 annual fatalities resulting from alcohol abuse. The severity of binge drinking is measured by the frequency and intensity of intoxication. Recent research by Kanny, et al, (2018) was used to assess these determinants by applying a novel diagnostic algorithm to better understanding the interplay of variants associated with binge drinking. By multiplying annual binge-drinking episodes by binge-drinking intensity (the number of drinks consumed), scientist now has mathematical value that can be used to determine overall risk and mortality at the epidemiological level.  For example, in 2015, 37.4 million (17.1 percent) adults reported an average of 53.1 individual binge-drinking episodes, at an average intensity of seven drinks per binge episode. This was annualized to 467 binge drinks per binge drinker. This annualized value is an important benchmark for evaluating trends and public health prevention efforts. Binge drinking has been a problem on college campuses since the 1960s. However, it is more prevalent among 18 to 34-year-olds. Specifically, 50 percent of the total binge drinks consumed in 2015 were by adults age 35 or older. This data reveals the highest prevalence of binge drinking occurs among those with both low educational levels and low household incomes when compared to those with more education and higher household incomes.

Why Does This Matter?

Binge drinking remains a major, unmet public health problem in the United States. It is a major preventable cause of mortality and years of potential life lost (YPLL), a seldom discussed statistic illuminating the heartbreak of senseless teenage mortality. Better educational efforts for both students and parents, and perhaps stiffer penalties, including assessment for Substance Use Disorder, and mandated treatment should be considered.

Reference:

Kanny D, Naimi TS, Liu Y, Lu H, Brewer RD Annual Total Binge Drinks Consumed by U.S. Adults, 2015. Am J Prev Med. 2018 Apr; 54(4):486-496. doi: 10.1016/j. amepre.2017.12.021.

5. Pain Management: Do Non-Opioid Treatments Work?

Dr. Erin Krebs and colleagues conducted a yearlong investigation comparing opioid vs non-opioid medications based on efficacy, pain-related function, pain intensity, and adverse effects. The study examined the differences using a randomized sample of 240 US veterans with chronic, non-cancer pain. Participants were selected on the basis of chronic back pain or hip or knee osteoarthritic pain of moderate to serve intensity, despite analgesic use. Participants either received an opioid or non- opioid medication, and a “treat- to-target” strategy with the stated objective to improve pain control and function. Treatments were individualized as much as possible based upon objective measure of pain control. The non- opioid group initially received acetaminophen (paracetamol) or a nonsteroidal anti- inflammatory drug. Medications were changed, added, or adjusted within the assigned treatment group according to individual response. Measurements included the Brief Pain Inventory (BPI) interference scale over 12 months, and the BPI severity scale was used to determine outcome.

Results

The two groups did not significantly differ on pain- related function over 12 months (overall P = .58); the mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95 percent CI, -0.5 to 0.7]). Pain intensity was significantly better in the non-opioid group over 12 months. BPI severity was 4.0 for the opioid group and 3.5 for the non-opioid group (difference, 0.5 [95 percent CI, 0.0 to 1.0]). Adverse medication- related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); the mean medication-related symptoms were 1.8 in the opioid group and 0.9 in the non-opioid group (difference, 0.9 [95 percent CI, 0.3 to 1.5]). Treatment with opioids was not superior to treatment with non-opioid medications for improving pain-related function over 12 months among US Veterans with chronic non-cancer pain.  However, some in the non-opioid group did receive Tramadol, which is a scheduled, mood-altering, addictive analgesic.  Overall, the results do not support initiation of opioid therapy for moderate to severe chronic back, hip or osteoarthritic knee pain. However, the study did not specifically investigate neurogenic pain or regional pain syndrome, a major cause of chronic, intractable pain and disability.

Why Does This Matter?

A good study published in JAMA (Chang, et al, 2017) concluded there was no clinical or statistical difference in pain reduction for acute extremity injury between opioid and non-opioid pain medication; however, acute pain is vastly different than chronic pain. Therefore, all patients presenting with pain syndromes require a full medical work up in addition to education on the down regulation of nociceptors as a result of exogenous opioids, hyperalgesia, and thus increased sensitivity to pain and tolerance to pain medication. Non-steroidal medications such as ibuprofen and acetaminophen are effective in acute pain and in some patients with chronic pain.  Moreover, it is established that less than 10 percent of chronic pain patients treated with opioids, under the management of a skilled pain doctor, will abuse or become addicted versus develop a physical dependence. Legitimate, non-addicted pain patients seek relief so they can participate in and enjoy their life at some level. Whereas addicted individuals seek relief from pain, plus the “high” and a life now organized around getting high, while jeopardizing their values, family, friends, career, etc. This is a vitally important distinction physicians must make when determining a course of action in treating pain. It’s never easy to determine how much pain someone is in. Psychosocial factors play a larger role than previously thought. For some patients with untreatable conditions, such as neuro-inflammatory pain and regional pain syndromes, opioids may be the only thing providing relief, self-efficacy, and a quality of life. All medical treatment should be individualized and collaborative. Assessing for SUDs and psychopathology is essential as depression and chronic pain nearly always co-occur and exasperate the sequelae in a bi-directional manner. Lastly, checking pharmacy histories provides objective data to assist physicians in determining a pattern of drug abuse or good compliance. We are in desperate need of opioid alternatives with stronger analgesia and less harmful effects. Until then, we do no harm and relieve suffering as best we can.

Reference:

Krebs, EE. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA.2018Mar 6; 319(9):872-882. doi: 10.1001/jama.2018.0899.

6. Treatment for Impaired Medical Professionals: A Model for Success

Impairment among medical professionals continues to be an under-recognized, under-identified, and under-treated problem with serious implications for public health. Substance use disorder, depression, anxiety, and stress disorders are associated with high rates of professional burnout and suicide. The development and growth of state physician health programs resulted in countless careers and lives saved. The five- year success rate is unparalleled in addiction treatment in part because this model embraced a chronic disease management model much like those available for persons with asthma, diabetes, coronary artery disease, and hypertension – all of which provide continuous care, medical monitoring, and social support.

Why Does This Matter?

 The prevalence of substance use disorders among physicians is not unlike that observed in the general population, although burn out and self-medication during medical training is unique to the medical profession and is associated with increased suicide among medical students and residents. As a result of the unique nature and risks associated with medical care, impaired medical professionals present a public health and safety problem. Accordingly, physician intervention and health programs provide an integrated system of identification, assessment, evidence-based, patient centered treatment, and long-term care and monitoring – the results of this model are outstanding with the five-year abstinence and return-to-work rates at approximately 80 percent. In contrast, modalities available to the general population are commonly crisis-driven, episodic, of sub-therapeutic duration, and without continuous care or monitoring. Finding a way to duplicate this physician health model for all those seeking treatment for SUD has proven to be more challenging than expected. Education of policy makers is desperately needed if we are to impact the current epidemic of addiction and rising mortality.

Reference:

Srivastava, A B. Impaired Physicians: Obliterating the Stigma. Residents Journal of the American Journal of Psychiatry 4-6 pp. March 2018.

7. The Love Drug is Back

Multidisciplinary Association for Psychedelic Studies (MAPS) is a 501(c)(3) non-profit research and educational organization that develops medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana. They estimate that proposed phase three studies of 3, 4-Methylenedioxymethamphetamine (MDMA) will be completed by 2020, and also suggest a new drug application will be submitted to the FDA shortly thereafter. MDMA may have some therapeutic potential, but a fast-track to FDA approval should give everyone pause and concern. It seems as though it is somehow predetermined that MDMA will be moved forward by expedited review through FDA special protocol rules. These rules are, in fact, less rigorous and will increase the likelihood of approval after phase three trial results (there are usually four), and MDMA may be approved for prescription by 2021.

Why the hurry?

 In the 1990s, hyperthermia and adverse cardiac events, in addition to the findings from Johns Hopkins showing serotonergic blunting and what appears to be permanent brain damage in some users resulted in countless deaths due to MDMA. Although this interesting article notes healthy young volunteers had not experienced any adverse effects using low controlled dosing of MDMA, the risk to older persons and those with psychiatric disease, including PTSD and SUDs, has not been studied. The author suggests that MDMA would only be used during prolonged intensive therapy sessions for couples or for those with PTSD, yet it is not clear whether these populations will be included in the next trials.

Why Does This Matter?

 It is noteworthy that MDMA, psilocybin, and other psychedelic drugs are being studied and tested for psychiatric diseases, which are very difficult to treat. This paper is important for laying out the case. The author cites anecdotal case data and theories, but the paper lacks well powered, double-blind, randomly assigned, and placebo-controlled study of the effects of MDMA among different cohorts for a specific condition. However, it is logical that case studies are first steps and future studies will be designed in this way to obtain FDA clearance. We also do not understand why some users of MDMA experienced adverse effects at doses comparable to those who do not. Phenotype studies are needed to address this important question because the cost of not understanding adverse effects is simply too high. Regrettably when the news of fast tracking MDMA broke, many rushed to the erroneous conclusion that MDMA was already proven safe and effective. MDMA is not “penicillin for the soul” as many have touted. It is a poorly understood, unpredictable, dangerous and addictive drug. The FDA has always taken the position that a new drug is dangerous until proven safe. In the case of MDMA, there is ample evidence of its abuse and harm, even for occasional or first-time users. Amid the current epidemic of addictive disease and rigorous scientific scrutiny, the current FDA standards for safety and efficacy is the only way to assure dose dependent efficacy and public safety.

Reference:

Bedi G. 3,4-Methylenedioxymethamphetamine as a Psychiatric Treatment. JAMA Psychiatry. 2018 Mar 21. doi: 10.1001/jamapsychiatry.2018.0063. [Epub ahead of print]

8. The Impact of Marijuana Use on Neural Connectivity and Life Trajectories Among Adolescents

Data from the Monitoring the Future study conducted by the University of Michigan revealed marijuana use and abuse among adolescents increased consistently over the past decade – 44.5 percent of 12th-graders report lifetime usage and 6.0 percent report daily use within the last 30 days. Vaping, often another way to use marijuana, is also increasing at alarming rates. At the same time, the percent of adolescents who consider cannabis use as “harmful” has declined. It is clearly established marijuana use is associated with rising mental health problems, including depression, anxiety disorders, acute psychosis, schizophrenia and suicidality, yet the precise mechanisms remain unclear. In this well-designed and well-powered study by Lichenstein, et al, 158 young men were recruited from the Pittsburgh Mother and Child Project (PMCP). Data regarding substance use and numerous variants, including current and previous alcohol use, were collected and analyzed; functional magnetic resonance imaging (fMRI) were attained from study participants at age 20. The stated endpoints of the investigation were to measure the influence of cannabis use on functional connectivity of the nucleus accumbens (NAc) with the prefrontal cortex and to assess psychosocial functioning two years later. Adolescent cannabis use trajectory, frequency of recent cannabis use, and the participant’s age of initiation were considered important developmental factors. These data and subsequent analysis suggest different trajectories of adolescent cannabis use are associated with distinct patterns of neural reward circuit function in early adulthood. Brain network-level, rather than regional, alterations may be more informative in predicting future negative outcomes in cannabis users. Moreover, individual factors guiding these changes in neural network function can facilitate prevention and early intervention more effectively.

Why Does This Matter?

Adolescent marijuana use is not the same as use by adults or 60-year-olds. Cannabis Use Disorders have become the number one cited cause of rehab admissions for this younger cohort.  Escalating marijuana use presents a higher risk for impaired motivation, including elevated depressive symptoms, anhedonia (the inability to feel pleasure), and poor educational attainment. It follows that alterations, perhaps the degradation of the reward circuitry, represent the mechanism by which cannabis users fail to attain their potential, resulting in both developmental and dose-dependent impairment in their higher-level functioning.

Reference:

Lichenstein S., et al.  The Influence of Cannabis Use on Neural Connectivity Between the Nucleus Accumbens and the Prefrontal Cortex: Consequent Life Trajectories Among Adolescents Addiction. 2017 Nov; 112(11): 1961–1970. Published online 2017 Jul 25. doi: 10.1111/add.13882

9. Dying Young and Addicted: Suicide and Substance Use Disorder

Suicide is now the second leading cause of death for children, adolescents, and young adults age 15-to-24 years old in the United States. Data from the World Health Organization indicate that suicide is the leading cause of premature death in teens and young adults worldwide, with a global incidence rate of 16 per 100,000 people. This adds up to more than a million people committing suicide each year. Traumatic injury from accidents and “accidental drug overdose” are also common causes of death for adolescents and young adults. In reality, many are in fact suicide. Moreover, depression and Substance Use Disorder (SUD) is increasing dramatically and directly associated with countless “accidental overdose” and suicides. Suicide Facts:

• Suicide is now the secondleading cause of death for 10-to -24-year-olds.
• The mortality rate from suicide among teens and young adults is higher than the mortality rate from cancer, heart disease, pneumonia, influenza, AIDs, stroke, and lung disease
• In the US, 3,470 high school age kids (grades 9-12) attempt suicide every day. These numbers do not include the aforementioned 10-to-14-year old age group.
• Suicide now (2017) accounts for 14 percent of all deaths among 15 –to-19 year-olds, and 8 percent of deaths among children aged 10-to-14-years-old

The majority of persons who attempt or commit suicide have a serious mental illness, namely depression, especially among 20-to-40 year olds. In addition, Substance Use Disorder (SUD), especially opioid misuse and addiction, is directly associated with a 200 percent increase since 2000, and more than 33,000 deaths in 2015 alone. Which begs the question, why is depression and overdose from drugs, especially opioids, seemingly so prevalent? The answers are complicated and not well understood. In general, suicide attempts among children, teens, and young adults are often an impulsive response to an acute stressor, or a chronic, seemingly unchanging stressor, such as addiction, in which they see no way forward. These young people experience intense sadness, confusion, hopelessness, grief and anger, and most do not have the internal coping skills to manage these feelings or the extern assets to seek help or to change their circumstances. Depression is a multifaceted brain disease, of which the exact cause is unknown. Certainly, painful circumstances in one’s daily life such as loss and grief, social rejection, and bullying are all external stressors children and teens identify with when describing their depression. Neurobiological processes, hopelessness, and genetic vulnerability are also confirmed risk factors for depression. The American Academy of Child and Adolescent Psychiatry identified the most common risk factors for suicidality:

• Depression
• Family history of suicide attempts
• Exposure to violence
• Divorce
• Impulsivity, aggressive, or disruptive behavior
• Access to firearms
• Bullying, acute loss, or rejection
• Feelings of hopelessness or helplessness

Substance Use Disorder and Suicidality

Depression is the number-one risk factor for suicide, but alcohol and drug abuse are a close second. The best available evidence established drug and alcohol abuse during adolescence is a major risk factor for depression. Specifically, persons with substance use disorders are approximately six times more likely to commit suicide than the general population. We also know men with an opioid use disorder were twice as likely to commit suicide compared to men the same age without opioid use disorder. Believe it or not, it’s even worse for women. Opioid abusing women are eight times more likely to commit suicide compared to others in the same age group. In general, opioid misuse is associated with a 40-60 percent increased risk for suicidal thought, and a 75 percent increased likelihood of a suicide attempts.

Neurobiology

Both SUD and depression are rooted within the activity of specific neurotransmitters – dopamine, serotonin, and norepinephrine, as well as specific hormones such as thyroid and oxytocin, to name a few. Dysfunction in neurotransmission involving these neurotransmitters are implicated in neuropsychiatric disorders including SUDs, depression, anxiety, and psychosis. Collectively known as the reward center, abusing drugs impacts the volume and activity of the aforementioned neurotransmitters. Drugs have chemical structures that seize the brain’s reward biology by mimicking and binding to selective protein receptors. When this occurs, the brain is high jacked, which produces acute reward and euphoria normally reserved for reinforcing important survival activity. Drug abuse also degrades essential neuronal signaling between important centers in the brain and the body. Therefore, addiction and mental illness commonly co-occur and must be addressed and treated concurrently and aggressively. Suicidal ideation, plan, and intent are considered a medical emergency. On demand psychiatric triage for these emergencies and same day appointments after acute care has been the most efficacious model. Evaluating suicidality, lethality, and the risk for future attempts is a critical component of individualized, patient-centered care within the addiction treatment paradigm. Information regarding concurrent psychiatric, medical, or substance abuse diagnoses and a thorough understanding of the precipitating or inciting event is critically important when assessing coping skills, resilience, treatment, and future risk. Both depression and SUDs are serious and life threatening disorders of the brain, but they are also highly treatable – early recognition is critical. On the prevention side, it’s equally important to teach parents and school personnel about both disorders, including how to identify risk factors and how to intervene when symptoms occur.

Why Does This Matter?

Substance Use Disorders (SUDs) not only increase the likelihood that a person will take their own life, but also provide the means for committing suicide. Approximately one-third of suicides are committed under the influence of drugs or alcohol. Most recently, illicit opioids, such as heroin and home-made fentanyl, are associated with both accidental overdose and suicide. With that said, it’s difficult to determine if an OD was intentional or not. Anyone who overdosed or had a Naloxone reversal should have a complete psychiatric evaluation and suicide assessment.

Reference:

The American Academy of Child and Adolescent Psychiatry. Facts For Families Guide Number 10:  2018 by the American Academy of Child and Adolescent Psychiatry. Retrieved December 26, 2018, from https://www.aacap.org/AACAP/Families_and_Youth/Facts_for_Families/FFF-Guide/Teen-Suicide-010.aspx

10. Advancing the Neuroscience of Long-Term Recovery

Recently two titans in addiction research, Warren Bickel, the director of the Virginia Tech Carilion Research Institute (VTCRI) Addiction Recovery Research Center, and Keith Humphreys, the Esther Ting Memorial Professor in psychiatry and behavioral science at Stanford University, sounded a clarion call for increased neuroscientific research on recovery from this chronic, relapsing, debilitating, and often lethal brain disorder. In an article published in JAMA Psychiatry (2018), a journal curated by the American Medical Association (AMA), the rationale for this call is established. More than 25 million Americans smoke cigarettes, and nearly 23 million people are currently suffering from Substance Use Disorder (SUD) Mortality and morbidity directly attributed to drug use – that is only the beginning of this horror story. It’s not just the addicts themselves who are sick and dying, but secondary mortality and morbidity in terms of infectious diseases, accidents under the influence, and substance-induced violence or domestic abuse also destroys lives. Yet, in spite of having the most pro-drug society in US history, more than 25 million Americans are currently in recovery, many of them enjoying sustained sobriety and progressively increasing quality of life for years. SUD is a multifaceted, phenotypically derived neurobiological disease involving a continuous and dynamic interaction between the patient, their family and friends, and social environment. Every person with this disease is an individual with a unique genetic makeup, varying vulnerabilities, risk factors and precursors – morbidity demands a tailored, patient-centered, and continuous recovery plan process based on the individual’s unique disease sequelae. Neuroadaptation redefines reward salience, degrades inhibitory control, and represents the constant pathophysiological basis of the disease. It takes time for the neuronal circuitry to heal, yet craving and impulsivity continue through the healing process. Boredom and a flattened emotional response to natural rewards are common sequelae in the recovering person. The article lists four distinct benefits of elucidating the functional anatomy of SUD and neuroadaptations that remain after detoxification:

• Helping clinicians incorporate a chronic disease recovery model

The 28-day inpatient or residential approach is not based upon any empirically derived data. Illness severity, motivation and desire to get well, and level of social support are the best indicators of treatment need in terms of duration, intensity, and individualized continuing care.  As it is now, some patients relapse on the very day of discharge, while some continue on to become lifetime abstainers with everyone else somewhere in between. This is where translational neuroscience research can provide important insight regarding the determinants and treatment modalities, outcome, and measurement relating brain health to quality of life and longevity.

• Educating doctors and mental health professionals, patients, and families

Understand one’s unique role in the recovery process and to setting expectations is critical. Addiction is a chronic, complex disease like cancer. Yet, doctors are unable to empirically estimate probabilities or provide accurate predictive scenarios for addicted patients and their families. But unlike cancer, SUD is more dynamic and responsive to a wider range of intervention, of which motivation and treatment adherence can change on a dime and make all the difference in determining outcome.  The use of neuroscientific data on a patient’s degree of gradual recovery provides a valuable feedback loop also serving to motivate and encourage. This also helps set the expectation of families and friends, simultaneously preparing them for continuing collaboration and education in the recovering process, including how to identify the predictors of relapse and how to handle a crisis or medical emergency, such as overdose and the safe use of a Narcan administration device.

• Informing public policy on addiction

There are too many public policy decisions regarding the addiction crisis devoid of any pertinent scientific input, e.g., access to Narcan for at-home emergency use.  As it stands, most treatment is driven by reimbursement models based on acute care for a chronic disease. Neuroscience research could provide clinical direction and treatment guidelines that would provide care of optimal intensity and duration based upon each patient’s disease. Severity, level of support, and other empirically derived indicators are considered as is routinely done for chronic conditions such as hypertension, asthma, and even cancer. A neuroscience model of addiction recovery could provide substantial input in making these and many other public policy decisions in a more objective manner.

• Strengthening knowledge about the brain, its acquired dysfunctions, and healing process

Sufficient evidence indicates generic neuroadaptation processes of learning and memory are mediated by addiction. Learning about neuroadaptation and reward biology has a direct impact on long-term recovery and measuring behavioral changes and quality of life.

“Understanding long-term recovery is important for science and for society. For science, unraveling the nature and treatment for medical disorders requires us to understand both the cause of disease, the course it takes, and the recovery—but in the addiction field, we have focused almost entirely on the first two. For society, while many people understandably despair over the horrors of the opioid epidemic, the reality of recovery gives us hope that happy and healthy lives are possible for those currently suffering.” –Dr. Keith Humphrey

Why Does This Matter?

Sustained, long-term recovery is possible as proven by so many successfully treated or recovering people, yet so much remains unknown. Bickel and Humphreys continue addressing these important questions in hopes of garnering more neuroscience research focused on long-term recovery from addiction. We could not agree more.

References:

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2681171 https://www.ncbi.nlm.nih.gov/pubmed/29847627 https://medicalxpress.com/news/2018-09-addiction-experts-neuroscience-long-term-recovery.html

11. Pavlovian Response Among those with SUDs Increases Craving and Relapse

The ability to form associations between innocuous stimulus and a rewarding event or outcome is a fundamental aspect of the conditioned behavior seen in addicted persons. But the reasons why a conditioned stimulus can result in such disastrous consequences has not been elucidated by science – until now. This seemingly simple Pavlovian conditioning involves complex neural processing that has developed as a result of our reward biology and environmental stimuli, which increases over time as normal maturation includes the uses of environmental cues and icons representing natural rewards. This learned process evolves and assists in the attainment of food, water, and shelter via sensory information. Emerging evidence from both animal and human research suggests reward processing is mediated in part by the nucleus accumbens (NAc). The NAc is required for a number of reward-related behaviors and provides reward salience, availability, time estimates, value, and context. In addition, these nuclei are critical for the acquisition and expression of anticipatory reward-driven behavior. In other words, the Pavlovian stimulus-reward conditioning, where learned cues and icons predict reward, produce robust changes in neural activity, most notably so in the NAc, via release of dopamine. This Pavlovian anticipatory reward system is implicated in human drug addiction, including the ability of drug-paired cues to direct and control behavior. The authors of this important research measured local field potential (LFP) recordings from the NAc in both rodents and human subjects during a period of reward anticipation. They found robust delta wave oscillations elicited during the time between anticipation of reward and behavioral change. The investigators found that through the use of responsive neurostimulation (RNS), which increased the oscillations from 1- to 4-Hz during drug reward anticipation, a reduction in consumption behavior via sensitization to highly palatable food occurred. Because similar oscillations are present in the human NAc during reward anticipation, it is hoped the translational potential of these findings may result in the development of a novel treatment for a major unmet need in the field of addictive disease.

Why Does This Matter?

Drug taking begets more drug taking via stimulation of the reward biology and neuronal degradation of inhibitory control. Brain stimulation approaches have shown encouraging results for many neuropsychiatric conditions and may be effective in mediation of neuroadaptive changes associated with SUDs, specifically cue-driven craving and relapse. Addictive disease affects more than 40 million Americans (23 million addicts plus their families). The relapse rate during the first few months post-treatment is high and related to conditioned stimulus evoking drug craving. Medically Assisted Treatment has benefited some individuals tremendously, but not for others. A new and novel approach, as described in this current research, suggests mediating both biological and environmentally triggered anticipatory cues is a viable pursuit and desperately needed. Non-pharmacological interventions such as targeted brain stimulation could potentially be a game changer for millions of suffering addicts and their families.

Reference:

Wu, H. Et al. Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proc Natl Acad Sci U S A. 2017 Dec 18. pii: 201712214. doi: 10.1073/pnas.1712214114. [Epub ahead of print]