Introduction to Addiction Sean Koon, MD California Academy of Family Physicians And California Society of Addiction Medicine April 14, 2005

Goals Explain the medical model of addiction Explain what makes some chemicals addictive (and others not) ? Explain what makes some people become addicted (and others not) ? What keeps them from stopping when “enough is enough”? When they do stop, why do some people relapse “after they’ve been doing so well” ?

Medical Model of Addiction Expression of addiction (phenotype) is based on a genetic predisposition (genotype) that is influenced by environmental factors Well-studied biological mechanism Treatment compliance is similar to other chronic medical conditions (diabetes, hypertension, asthma) Follows a relapsing and remitting course Most effectively managed as a chronic disease Both medical and behavioral interventions are used

Similarities with Other Chronic Diseases (Type II Diabetes, HTN, Asthma) Genetic impact is similar The contributions of environment and personal choice are comparable Medication adherence and relapse rates are similar. Long term maintenance treatments proven most effective. ( McLellan, JAMA 2000)

Genetics: Pedigree Monozygotic twins have higher concordance of addiction than dizygotic twins (the more genes you share, the more similar your addiction propensity) Men whose parents were alcoholics have an increased likelihood of alcoholism even when adopted and raised by non-alcoholic parents from birth

Genetics: The Genome The minor (A1) allele of the TaqIA D2 dopamine receptor gene has been linked to severe alcoholism and polysubstance dependence A single nucleotide polymorphism in the gene encoding fatty acid amide hydrolase has been associated with increased recreational and problem use of drugs or alcohol

Genetics: The Genome A Leu7Pro polymorphism of the neuropeptide Y gene has been correlated with increased alcohol consumption Single nucleotide polymorphisms of the gene encoding the mu-opioid receptor correlates with an increased likelihood of heroin abuse Genes that affect metabolism of drugs/alcohol/nicotine affect propensity for dependence

Pathophysiology Why and how do people get addicted to drugs ? Why are some chemicals addictive and others not ?

Pathophysiology Within our bodies we have very precise mechanisms for maintaining homeostasis (e.g. pituitary hormones, thyroid, insulin/glucagon, etc.) These mechanisms titrate necessary chemicals within the body to obtain this balance

Pathophysiology If something is needed from outside of the body, systems of craving and satiation are necessary The urgency of the need is promoted by the intensity of the craving At this moment are you more thirsty or hungry (or neither?)

How it Works: The Reward Pathway Many parts of the brain work together to maintain this homeostasis The “mesolimbic” pathway uses reward (often a sense of well-being or pleasure) to promote life sustaining and life fulfilling behaviors (eating, drinking, sex, nurturing, etc.) Addiction occurs by dysregulation of this natural function

MESOLIMBIC REWARD SYSTEM

So, if we all have this reward pathway, why don’t all substance users develop addiction ? Why are some chemicals addictive and others not ?

The Reward Pathway Drugs of addiction are identifiable by their ability to stimulate dopamine secretion in this pathway Addicts are identifiable by their unique response to addictive chemicals by hypersecretion of dopamine in this brain pathway

Dopamine release in the Nucleus Accumbens

Cocaine Preventing Dopamine Re-Uptake in the Nucleus Accumbens

Opiate Action on the Nucleus Accumbens Promotes Dopamine Release

Cannabis Action on the Nucleus Accumbens Promotes Dopamine Release

How and when does a person “get addicted” ?

The “Switch” The progression from social drinking to abuse to dependence ranges from 3-15 years in duration in susceptible persons Average age of the “switch” is mid- thirties, but can vary “continued repetition of voluntary drug taking begins to change into involuntary drug taking,...at which (point) the behavior is driven by compulsion to use the drug.” (Leshner, 2000)

The “Switch” Frequent drug use in a person with biological predisposition alters the hedonic set-point and creates a starvation or craving response. The drug loses its pleasurable effects but becomes pathologically “wanted” Cravings may continue or even increase despite satiation or drug use

Chronic Use: Hedonic Homeostatic Dysregulation Hedonic Scale Normal Affective Response to Drugs/Alcohol Altered Dysregulated Set-Point following chronic drug use (Koob, Science, 1997) Hedonic Set Point is Altered with Chronic Drug Use Initially use to get high… Now use to “get normal” “ Cravings ” “Feel good” “Feel bad” Slide from Pating,D.

So, why don’t they just stop when they start to suffer consequences ?

Hedonic Homeostatic Dysregulation The reward pathway is intimately connected, via neural pathways, to our judgment and emotional areas (via projections to the prefrontal cortex and limbic system respectively) Judgment can be aligned or distorted to favor the restoration of homeostasis The brain begins to treat the chemical as necessary for homeostasis and thus survival

Hedonic Homeostatic Dysregulation The patients are logically aware they do not “need” the drug, but survival drives tend to take precedence over logic and judgment Continued substance use slowly takes “survival precedence” over life goals, self esteem, relationships, stability, safety, and health

So how is it that drugs with completely opposite effects can be equally addictive? Each Substance of Abuse Has Both Primary and Secondary Actions

Action Sites of Marijuana

Action Sites of Cocaine

Action Sites of Opiates

Substance Abuse and Moods Addictive substances can mimic mood disorders directly and indirectly –All addictive substances can cause anxiety and depression indirectly via the secondary effect of life chaos –They also mimic many psychiatric disorders directly

Substance Abuse and Moods Depression: –alcohol, sedatives, MJ –withdrawal from stimulants, ecstacy Anxiety: Stimulants, MJ (panic) –withdrawal from alcohol or sedatives Paranoia: MJ, stimulants (intoxication or w/d) Psychosis: –stimulants, hallucinogens –alcohol or sedative withdrawal Bipolar d/o: stimulants Insomnia: alcohol (midnight awakening), stimulants, occasionally (short acting) sedative withdrawal

Mood Disorders Chicken and the Egg: “Do I drink or use because I’m depressed/anxious/bipolar or is it vice-versa ?” History will help delineate when this occurred –Was there evidence of a mood disorder pre- experimentation? –Were there problems with mood during periods of abstinence? –Do they get better or worse when you detox them?

Relapse How can people relapse after they’ve quit for such long periods of time?

Craving and Relapse During repeated drug use patients become biologically hypersensitized to: –The Drug of Choice –Other addictive drugs –Stimuli associated with drug use –Stress induced craving This hypersensitization is long-lasting due to adaptive and structural changes in the reward pathway

Craving and Relapse Functional Changes Long lasting changes in the functional activity of the mesocorticolimbic dopamine system, in glutamate and dopamine transmission in the nucleus accumbens Long lasting adaptive changes in gene expression and protein activation, especially “Fos” proteins (these occur through activation of the cAMP cascade via D1 dopamine receptors in the VTA)

Craving and Relapse Structural Changes Changes in caliber of dopamine dendrites and cell bodies in the VTA (opioids) Increase in density/number of dendritic branches in Nucleus accumbens (stimulants) Decrease in neurofilament proteins

Craving and Relapse By these and likely other mechanisms, the patient remains hypersensitized to the rewarding effects of the drug AND exhibit the PRIMING and CONDITIONING effects

Craving and Relapse Priming: An introduction of even a tiny amount of the drug can cause intense cravings and imminent relapse Conditioning: During substance use, patients also become hypersensitized to environment cues associated with use (associated smells, sights, location, sounds, stressors, people, etc.) These cues (or “triggers”) can cause dopamine release AS IF A SMALL AMOUNT OF THE DRUG WERE TAKEN Due to the stable biological changes, both priming and conditioning effects can persist for years

The “Formula” for Addiction Genetic or biological predisposition A specialized response to addictive chemicals Risk factors (mood disorders, life trauma, environmental factors, drug availability) Practice (“experimentation”) The “Switch”: hypersensitization and hedonic dysregulation

The Crisis of Addiction When addicts initially choose to use, they are often unaware of their genetic propensity Their initial experimentation is often acceptable and typical for their subculture or society at large (or even recommended as in the case of rx meds) Continued use can cause severe consequences to self, others, and community, though these consequences often only occur after addiction has taken hold Once addiction is fully developed, the use of drugs and the behaviors that follow can become out of control At the same time, chemically dependent persons remain completely responsible for their continued use of drugs AND the resultant behaviors

Timeline of Untreated Addiction The “Switch” Experimentation Maintenance LOSS Predisposing factors: Genetics Co-morbid conditions Environment Multiple crises with brief periods of abstinence

Chemical Dependency as a Chronic Condition Abuse Early Abstinence Sobriety Stable Maintenance Complex outcomes in CD treatment: relapse is common, success is measured by retention in recovery, decreased morbidity, life improvement

Primary Care Workshop California Academy of Family Physicians and California Society of Addiction Medicine April 14, 2005