Substance dependence

• 1. Introduction

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  Substance dependence is a biopsychological state in which a person's ability to function comes to rest on the repeated re-consumption of a psychoactive substance. The body adapts. Stop taking the drug, and an unpleasant withdrawal state arrives, which pushes the person back toward another dose. That loop is the heart of dependence, and it is not quite the same thing as addiction. Addiction, by contrast, is defined as compulsive, out-of-control drug use that continues despite negative consequences. The distinction matters enough that in 2013 the manual psychiatrists rely on collapsed two separate diagnoses into one. So what exactly happens inside the brain when this adaptive state takes hold? Why do some drugs trap users far more readily than others? And why does treatment look so different depending on which country you happen to live in?

• 2. Dependence Versus Addiction

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  ΔFosB is a gene transcription factor now understood to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence. That single clause draws the line the field has worked to clarify. An addictive drug is one that is both rewarding and reinforcing, while dependence is the adaptive state that produces withdrawal on its own terms.

  The International Classification of Diseases files substance dependence under mental and behavioural disorders. The Diagnostic and Statistical Manual took a sharper turn in its fifth edition, released in 2013, when substance abuse and substance dependence were both eliminated and folded into the single diagnosis of substance use disorders. The reasoning was blunt. As the manual put it, the tolerance and withdrawal that previously defined dependence are actually very normal responses to prescribed medications that affect the central nervous system and do not necessarily indicate the presence of an addiction. A patient taking a prescribed drug as directed could meet the old definition without ever being addicted at all.

• 3. The Pull Of Withdrawal

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  Withdrawal is the body's reaction to abstaining from a substance on which a person has developed a dependence syndrome. Once that syndrome exists, stopping produces an unpleasant state, and that state drives continued use through negative reinforcement. The drug becomes a way to escape or avoid re-entering the very discomfort the absence of the drug created.

  The symptoms split into categories. Physical-somatic symptoms mark physical dependence, while emotional-motivational symptoms mark psychological dependence, and many people experience both at once. When the substance is withheld, chemical and hormonal imbalances may arise, and psychological stress may follow as well.

  Infants are not spared. Neonatal abstinence syndrome, known as NAS, is substance withdrawal experienced by newborns, and its effects can be severe and life-threatening. Addiction to drugs such as alcohol in expectant mothers does not only cause NAS. It can also produce an array of other issues that continue to affect the infant throughout their lifetime.

• 4. Why Some Drugs Trap Harder

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  The dependence potential of a drug varies from substance to substance and from individual to individual. Dose, frequency, the pharmacokinetics of the particular substance, the route of administration, and time are all critical factors in whether dependence develops.

  An article in The Lancet compared the harm and dependence liability of 20 drugs, scoring each from zero to three on physical dependence, psychological dependence, and pleasure to produce a mean dependence score. Heroin and morphine topped the list at a mean of 3.00, with perfect threes across all three measures. Cocaine followed at 2.39, then tobacco at 2.21, barbiturates at 2.01, and alcohol at 1.93. Benzodiazepines scored 1.83, amphetamine 1.67, ketamine 1.54, cannabis 1.51, and ecstasy lowest among them at 1.13.

  Capture rates tell a different story. They measure the percentage of users who reported becoming dependent at some point, and the ranking does not match the dependence scores. Tobacco captured the most users at 31.9 percent, ahead of heroin at 23.1 percent, cocaine at 16.7 percent, and alcohol at 15.4 percent. Cannabis and caffeine sat at the bottom, each at 9 percent. A drug can be highly pleasurable yet capture relatively few users, while a less intense drug like tobacco quietly ensnares nearly a third of those who try it.

• 5. The Brain's Machinery

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  Corticotropin-releasing factor and a gene transcription factor called cAMP response element binding protein, or CREB, sit at the center of psychological dependence. The nucleus accumbens, abbreviated NAcc, is one brain structure tied to this psychological component. There, immediately after a high, cyclic adenosine monophosphate activates CREB, which triggers changes in gene expression affecting proteins such as dynorphin. Dynorphin peptides reduce dopamine release into the NAcc by temporarily inhibiting the reward pathway. Sustained CREB activation therefore forces a larger dose to reach the same effect. It also leaves the user feeling depressed, dissatisfied, and unable to find pleasure in once-enjoyable activities, which often pulls them back for another dose.

  Koob and Kreek hypothesized that stress systems play their own role. They proposed that drug use engages corticotropin-releasing factor, the hypothalamic-pituitary-adrenal axis, and other stress systems in the extended amygdala, shaping the dysregulated emotional state of psychological dependence. As drug use escalated, they found, the presence of CRF in human cerebrospinal fluid rose alongside it. In rat models, CRF inhibitors and CRF receptor antagonists each decreased self-administration of the drug under study. The same review found dysregulation of other neuropeptides affecting the HPA axis, including enkephalin, an endogenous opioid peptide that regulates pain and acts on μ-opioid receptors influential in the reward system.

  Physical dependence runs on a partly different circuit. Upregulation of the signal transduction pathway in the locus coeruleus has been implicated in opioid-induced physical dependence. The temporal course of withdrawal correlates with locus coeruleus firing, and administering α2 agonists there decreases that firing and norepinephrine release during withdrawal. Upregulation of NMDA receptors appears to be involved, supported by the way NMDA receptor antagonists blunt withdrawal. Physical dependence on opioids has been observed to raise extracellular glutamate and increase NMDA receptor subunits NR1 and NR2A, phosphorylated CaMKII, and c-fos.

• 6. Categories Of Diagnosis

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  Substance dependence as defined in the DSM-IV could be diagnosed with physiological dependence, with evidence of tolerance or withdrawal, or without physiological dependence at all. The manual broke the diagnosis down by substance and assigned each a code. Alcohol dependence carried code 303.90 and opioid dependence 304.00. Sedative, hypnotic, or anxiolytic dependence, which included benzodiazepine and barbiturate dependence, fell under 304.10. Cocaine dependence was 304.20, cannabis dependence 304.30, and amphetamine or amphetamine-like dependence 304.40. Hallucinogen dependence sat at 304.50 and inhalant dependence at 304.60. Polysubstance dependence was coded 304.80, while phencyclidine or phencyclidine-like dependence and other or unknown substance dependence shared 304.90. Nicotine dependence stood apart at 305.10. The granularity of those codes shows how finely the diagnosis once distinguished between substances, the very distinctions the 2013 revision would later sweep into a single category.

• 7. Paths To Recovery

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  Addiction is described as a complex but treatable condition, characterized by compulsive drug craving, seeking, and use that persists even when the user knows the consequences are severe. For some people it becomes chronic, with periodic relapses even after long stretches of abstinence, which is why it may require continued treatment to lengthen the intervals between relapses and soften their intensity. The ultimate goal is to enable a person to manage their substance misuse, which for some means abstinence. The immediate goals, often called harm reduction, are to reduce substance abuse, improve the patient's ability to function, and minimize medical and social complications.

  Residential treatment falls broadly into two camps: 12-step programs and therapeutic communities. The 12-step approach is a nonclinical, support-group and spiritual model, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, and Pills Anonymous. Therapeutic communities lean on cognitive-behavioral therapy, which examines the relationship between thoughts, feelings, and behaviors and treats addiction as a behavior rather than a disease, and therefore as something curable or unlearnable. Medications support both. Benzodiazepines are used for alcohol detoxification to prevent delirium tremens, while clonidine and loperamide assist opioid detoxification, and baclofen reduces cravings and is especially effective in stimulant users and alcoholics.

  Opioid replacement therapy stands as the gold standard for treating opioid dependence in developed countries. By substituting an opioid that can be administered legally, reduces or eliminates cravings, and does not produce a high, such as methadone or buprenorphine, it replaces drugs like illicitly-obtained heroin, dilaudid, or oxycodone. The stakes are stark. Among first-time opioid users or those attempting abstinence-based recovery with clonidine and loperamide, 90 percent relapse to active addiction within eight months or become multiple relapse patients.

  The field is not free of belief. In a survey of treatment providers from the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems, and the Society of Psychologists in Addictive Behaviors, scores on a Spiritual Belief Scale explained 41 percent of the variance in how providers responded on an Addiction Belief Scale measuring adherence to the disease model versus the free-will model.

• 8. Geography Disparity And Law

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  The United States and Eastern Europe hold the countries with the highest substance abuse disorder occurrence, at 5 to 6 percent, while Africa, Asia, and the Middle East hold the lowest, at 1 to 2 percent. Across the globe, those with higher prevalence tended to be in their twenties, unemployed, and men. Within the U.S., 2021 figures for people aged 12 and older showed American Indian and Alaskan Native populations among the highest substance use disorder rates at 27.6 percent and Asian populations among the lowest at 8.0 percent, with mixed race at 25.9 percent, Black at 17.2 percent, White at 17.0 percent, and Hispanic at 15.7 percent.

  Health disparities, defined by the National Institute of Health as preventable inequities caused by barriers that overwhelmingly affect minority demographics, run through these numbers. Native American, Pacific Islander, Black, and Latinx populations are much less likely to have health insurance than White populations, which limits access to treatment. Black patients with opioid use disorder were significantly less likely to receive a treatment prescription and follow-ups. The justice system deepens the gap, since White individuals are more likely to receive treatment instead of imprisonment, and a jail term makes it harder to find employment and resume a role in society.

  Women face a distinct burden. They become addicted faster and have more difficulty quitting than men, shaped by differences in sociocultural norms, biology, and psychology. They also face unique risk factors, including increased chances of abuse, anxiety and depression, and stress from managing households and children, and Native American and Black women are more likely to experience abuse.

  Law shapes the experience at every turn. Most countries place drugs under licensing systems, making unlicensed production, supply, or possession a criminal offence. That illegality, combined with the addict's need, lets sellers command a premium, sometimes hundreds of times the production cost, which can push addicts toward crime to support their habit. In recent years U.S. states have begun shifting from criminalizing drug abuse toward treating it as a health condition. Twenty-eight states currently allow needle exchanges, an idea first introduced in Amsterdam in 1983. A bill to operate safe injection sites in the City and County of San Francisco, AB-186, was vetoed on the 30th of September 2018 by California Governor Jerry Brown, and no such sites yet exist in the United States.