Objectives Participants will: • Recognize the difference between Substance abuse and Dependency • Learn basic principles of the neurobiology of addiction • Recognize the relationship between perceptions of harmfulness of substances and their use • Recognize warning signs of addiction in colleagues
Addiction Concepts: Dr Andrew P Mallon
Acknowledgements • The better quality anatomical slides are from the NIDA Teaching Packet of Slides available for educational use at the NIDA web site (www. nida. gov) • The speaker is offering a summary of emerging concepts which he finds useful in his understanding the interplay between addictions and psychiatric disorders • The audience is strongly encouraged to review the original works cited in this presentation
Short version • Drugs and alcohol are freely available • Our culture as a whole encourages experimentation • The less afraid people are about using a substance, the more likely they are to try it • People start an addiction career by choosing to use drugs or alcohol (voluntary component) • Persistent use of substance changes the structure and function of the brain in areas that control the ability to change behavior – Including substance use, which takes a life of its own (loss of control) • Some people are more likely to develop these brain changes • Chronic stress, drug abuse and several psychiatric syndromes may change normal neurogenesis • Although physicians are affected by addiction as frequently as other mortals, they can recover twice as often
What is addiction • Abuse (one or more of the following): – A maladaptive pattern of substance use resulting in a failure to fulfill major role obligations at work, school, home – Use in situations in which it is physically hazardous – Recurrent substance related problems – Continued use despite persistent problems caused or made worse by the use of drugs
Dependency (Addiction) Three or More: – Tolerance • Need to use increasing quantities of the substance to achieve desired effect. o • The effects of the substance are less prominent with repeated use – Withdrawal symptoms: • When use of the substance ceases withdrawal symptoms characteristic to the drug occur • The same substance or a substitute is used to prevent withdrawal • The substance is used for longer than intended • There are recurrent wishes to limit or reduce its use • A lot of time is spent in activities designed to obtain the substance • Important social activities are interrupted as a result of the use of the substance • Use continues despite serious physical or emotional consequences
ECA Community Study Lifetime Prevalence, mental health and addictive disorders Ref: Burke et al: Age of Onset of selected mental Disorders in five community populations-Arch Gen. Psychiat 511 -518 • • • Alcoholism (dependency & abuse) Phobias Drug Abuse/Dependence Major Depression Antisocial Personality Obsessive Compulsive Disorder Panic Disorder Schizophrenia Mania - 13. 7% - 12. 6% - 6. 1% - 5. 1% - 2. 5% - 1. 0% - 0. 4%
High Comorbidity • 22. 5% lifetime diagnosis of non-SA disorder • 29% of those with mental illness had a drug/alcohol problem • 16. 4% had lifetime Dx of substance use DO • 55% of those with drug abuse/dependency had mental illness Dx • 37% with alcohol abuse/dependency had mental illness Dx
Why Do People Take Drugs In The First Place?
I FEEL GOOD (sensation seeking) I FEEL BETTER (self medication)
Drugs have to be available No drug exposure, no abuse
Animal Models • Animals of many species seek intoxicants in the wild • In the laboratory, animals exposed to drugs quickly learn to develop drug-seeking behaviors • Drugs that are addictive to humans are also voluntarily self-administered by lab animals » Ref: Gardner E. Addiction and Animal Models of Self Administration. Am J Addictions 9: 285 -313 2000
Drug-Seeking in Monkeys “the animals took the researcher's hand, dragged him to the cupboard where the morphine, syringes, and needles were stored, and voluntarily assumed the proper position to receive injections” Ref: Spraag SDS - Morphine Addiction in Chimpanzees Comp Psychol Monographs 1940; 15(7): 1 -32
PERCEIVED RISK • Use of drugs increases as people believe that drugs are harmless
Use of MJ compared to perceived harmfulness availability Perceived harm use WOD ’ 75 ’ 81 ’ 85 ’ 91 NIDA: Monitoring the Future Study (1999) ’ 99
Marihuana in the 1920’s
Marihuana in the 1990’s
Coca des Incas
Cocaine was sold over-the counter
Delicious! Refreshing! Invigorating! The New and Popular Soda Fountain Drink, containing properties of the wonderful coca plant and the famous cola nuts. For sale by Willis Venable and Nunnally & Rawson. “
As American as Apple Pie
Alcohol use within the past 2 weeks • 15% 8 th graders • 24% 10 th graders • 34% 12 th graders NIDA: Monitoring the Future Study (1999)
Meet Adult Criteria for Alcohol Use Disorder • 9% adolescent girls • Up to 20% adolescent boys CSAT TIP 32: Treatment of Adolescents with Substance Use Disorders Online: http: //text. nlm. nih. gov/ftrs/tocview
Pop Music Culture has Glorified Alcohol and Drug Use for Several generations Lyrics of popular songs, for example: The many “Dust” songs of the 30’s “Scotch and Soda” “Cocaine” (Eric Clapton) “A Little High With a Little Help from my Friends” (Beatles) “No Limit Soldier”(Puffy Coombs) And lots more…. . Encourage young users to expose themselves to drugs as a normal part of growing up
Heroin – increased non injection use – 1. 6% 8 th graders • double the rate since 1991 NIDA: Monitoring the Future Study (1999)
Heroin Use in Past 12 months NIDA: Monitoring the Future Study (1999)
Perceived risk of sniffing heroin NIDA: Monitoring the Future Study (1999)
Disapproval of Sniffing Heroin NIDA: Monitoring the Future Study (1999)
Smoke Cigarettes Daily • 20% high school seniors NIDA: Monitoring the Future Study (1999)
Vulnerability Why do some people become addicted while others do not?
Complex genetic factors play a role In animals and people
Relevance of Animal Models • Drugs that are voluntarily self administered by animals are the same as the ones that humans abuse • Almost without exception, self administered drugs increase brain reward functions in the mesolimbic reward system Useful reading: Gardner E - What we have learned about addiction from animal models of drug self-administration Am J Addict 2000; 9: 285 -313
Lewis Rats not to be confused with the Martin Rat (of the Rat Pack) • High vulnerability for self-administration of alcohol and cocaine • Learn alcohol/cocaine self administration more readily • Work harder for IV cocaine or opioid selfadministration • Cue-condition for cocaine or opiates more rapidly • Resemble type II alcoholics Ref: Lepore M Studies on the neurobiological interrelationship between vulnerability to depression and vulnerability to drug abuse in animal models. Behav Pharmacol 1995; 6(suppl 1): 82 -84
Lewis Rats • Dopamine surges in response to a variety of addictive drugs (opiates, THC, nicotine, cocaine) are much more pronounced in Lewis rats Ref: Lepore M Studies on the neurobiological interrelationship between vulnerability to depression and vulnerability to drug abuse in animal models. Behav Pharmacol 1995; 6(suppl 1): 82 -84
DA Receptor Levels and Response to MPH In People low receptor levels MPH pleasant high receptor levels MPH unpleasant 2. 5 unpleasant response Ref: Volkow, ND, Wang, G-J, Fowler, JS, Logan, J, Gatley, SJ, Gifford, A, Hitzemann, R, Ding, YS, Pappas, N. Brain dopamine D 2 receptor levels predict reinforcing responses to psychostimulants in humans. Am J Psychiatry, September 1999. 0 pleasant response
Relative Appetitiveness • Cocaine>morphine>benzodiazepines • Cocaine is so desirable, that if given continuous access, animals will spend essentially all of their waking hours self-administering the drug • The parallel to the extreme appetitiveness of crack cocaine at the human level is striking • Ref: Johanson CE Self administration of psychomotor stimulant drugs: the effects of unlimited access Pharmacol Biochem Behav. 1976; 4: 45 -51
A Major Reason People Take a Drug is They Like What it Does to Their Brains
cannabis
Dopamine binding to receptors and uptake pumps in the nucleus accumbens
Cocaine binding to uptake pumps; inhibition of dopamine uptake
Increased c. AMP produced in post-synaptic cell
All addictive substances are associated with increased Dopamine activity in the Nucleus Accumbens
Effects of Drugs on Nucleus Accumbens Dopamine Levels Amphetamine Cocaine DA DA 0 Nicotine 3 h 5 h 0 5 h Morphine 5 h Timothy P. Condon, Ph. D. Addiction as a Brain Disease: New Implications for Research and Practice Connecticut Statewide Addiction Medicine/Psychiatry Grand Rounds September 20, 2001 Source: Di Chiara and Imperato
Natural Rewards Elevate Dopamine Levels Timothy P. Condon, Ph. D. Addiction as a Brain Disease: New Implications for Research and Practice Connecticut Statewide Addiction Medicine/Psychiatry Grand Rounds September 20, 2001 Nac DA Feeding Empty Box 0 Intromissions 60 m 120 m FOOD Ref: Di Chiara et al. 180 m SEX Ref: Fiorino and Phillips
• when you make a mistake a lawyer can always find a colleague who knew you were going to screw up
Prolonged Drug Use Changes The Brain In Fundamental and Long-Lasting Ways
Normal Cocaine Abuser (10 Days) Cocaine Abuser (100 Days) NIDA slide teaching packet. Photo courtesy of Nora Volkow, Ph. D. Volkow ND, Hitzemann R, Wang C-I, Fowler IS, Wolf AP, Dewey SL. Long -term frontal brain metabolic changes in cocaine abusers. Synapse 11: 184 -190, 1992; Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer D, Dewey 5, Wolf AP. Decreased dopamine D 2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14: 169 -177, 1993
Initial Protein Targets for some drugs of abuse Receptor agonists • Opiates • Cannabinoids • Nicotine Transporter Ligands • Cocaine • Amphetamine • Methylphenidate Ion Channel Ligands • PCP • Alcohol
Molecular Biology of Addiction Beyond Initial Cellular Targets: Transcription Factor CREB (c. AMP response element-binding protein) and its target BNDF • Brain-derived neurotrophic factor is a member of the nerve growth factor family, which also includes the prototype nerve growth factor as well as neurotrophin-3 and neurotrophin-4. • These growth factors are involved in the differentiation and growth of many types of neurons in the developing brain as well as the maintenance and survival of neurons in the mature brain. • Ref: Lo DC. Neurotrophic factors and synaptic plasticity. Neuron. 1995; 15: 979 -981.
This is your brain Thanks to BDNF Think of it like fertilizing and pruning your rose bushes
Intracellular Targets Ion Channels Gs Adenyl cyclase Receptor Ca++ c. AMP / Second Messengers PKA / protein kinases Ca dependent kinases Change in Gene Expression Adaptations in neural function CREB Target Genes BDNF Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
Molecular Biology of Addiction: Addiction is a form of drug-induced neural plasticity • Upregulation of c. AMP pathway – Occurs in response to chronic administration of drugs – Resulting activation of transcription factor CREB – Both mediate aspects of tolerance and dependency • Induction of another transcription factor, d Fos. B – Exerts opposite effects – May contribute to sensitized responses to drug exposure Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
Basis for Plasticity: Summary • Drugs enter the brain and bind to an initial protein target • Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug • Acute effects of the drug do not explain addiction by themselves Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
• Addiction produces a change in brain structure and function (adaptation to the drug) • molecular and cellular changes in particular neurons alter functional neural circuits • This leads to changes in behavior consistent with addicted states • Addiction is therefore a form of drug induced neural plasticity Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
The switch from acute to chronic addiction Drug => D Synaptic => D signaling => D neuronal => Persistent behavioral transmission pathways activity abnormalities Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
The switch from acute to chronic addiction Acute effects Drug => chronic molecular and cellular adaptation D Synaptic => D signaling => D neuronal => Persistent behavioral transmission pathways activity abnormalities CREB DFos. B Adenyl Cyclase type 8 Tyrosine Hydroxylase Dynorphin Many others Glu. R 2 Cyclin dependent kinase-5 Many others Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001
This is your brain After drugs Think about it as what happens when you fail to fertilize, water, and prune your garden
Altered neurogenesis: A common pathway for addiction and other complex neurobehavioral syndromes?
Paradigm change: Adult Neurogenesis • Paradigm change: neurogenesis occurs in post-mitotic cells • Hippocampal neurogenesis in rodents, primates, and humans can be stimulated by manipulations such as environmental enrichment – Gould E, Learning enhances adult neurogenesis in the hippocampal formation Nat Neurosci 1999; 2: 894 -897
STRESS Hypothalamus CRF Behavioral Effects of Chronic Stress Hormones (CRF) DECREASED • Eating • Sleeping • Reproductive activity Anterior Pituitary INHIBITORY SIGNAL CORTISOL INCREASED • Restless activity in familiar environments • Avoidance behaviors Bloodstream Physiological changes Supporting flight or fight responses
Gluco-Corticoids or Stress inhibit Neurogenesis in rats • Age-associated neurogenesis in rats is eliminated by removing the elevated GC levels typical of aging • Cameron H; Restoring production of hippocampal neurons in old age. Nat Neurosci 1999: 2: 894 -897
In humans, with the abatement of the stressor of GC exposure, there is regrowth of dendritic processes Recommended reading: Sapolsky R Glucocorticoids and hippocampus in neuropsychiatric disorders Arch Gen Psychiat Vol 57 10/2000
NMDA receptor activation by Glu inhibits neurogenesis • GCs increase glutamate concentration in Hippocampus • Cameron H; Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci. 1995; 15: 4687 -4692
• chronic stress of several types (i. e. , restraint or psychosocial) or glucocorticoid treatments are reported to cause atrophy, or even death, of vulnerable neurons in the hippocampus • Sapolsky RM, Krey LC, Mc. Ewen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985; 5: 1222 -1227.
Stress Glucocorticoids BDNF Neuronal Death Atrophy Think about it as the combined effects of drought, a heat wave, and neglecting to prune and fertilize on your garden
Impaired Neurogenesis in Depression • the ability of the hippocampus to inhibit the hypothalamic-pituitary-adrenal axis is reduced in certain patients with depression, consistent with a deficit of hippocampal function in these individuals • Young EA, Haskett RF, Murphy-Weinberg V, Watson SJ, Akil H. Loss of glucocorticoid fast feedback in depression. Arch Gen Psychiatry. 1991; 48: 693 -699. Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
• there is a small decrease in hippocampal volume as determined by magnetic resonance imaging in patients with depression or post-traumatic stress disorder • Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, Mc. Carthy G, Charney DS, Innis RB. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995; 152: 973 -981. Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
• there may be a decrease in the size of certain brain structures in depression – ventricular enlargement and increased sulcal prominence • Elkis H, Friedman L, Wise A, Meltzer HY. Meta-analysis of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Arch Gen Psychiatry. 1995; 52: 735 -746. Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
• Depression, particularly stress-associated cases, may result from the atrophy or death of vulnerable pyramidal neurons in the CA 3 region of the hippocampus. • a consequence, at least in part, of decreased levels of BDNF available to these neurons? • Elevated levels of glucocorticoids are also known to play a notable role in stress-induced damage of CA 3 neurons Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
• BDNF is reported to enhance the growth of serotonin and NE neurons, as well as to protect these neurons from neurotoxic damage Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
CREB Cakes • expression and function of the transcription factor c. AMP response element-binding protein (CREB) is increased by different types of antidepressant treatments, suggesting that CREB is a common postreceptor target for antidepressants Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
Neuronal plasticity and survival and the treatment of depression. • BDNF is reported to have antidepressant effects in 2 behavioral models of depression, the forced swim and learned helplessness paradigms • long-term antidepressant administration, and ECT increase the expression of BDNF in the hippocampus Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997 Condorelli DF, Dell'Albani P, Mudo G, Timmusk T, Belluardo N. Expression of neurotrophins and their receptors in primary astroglial cultures: induction by c. AMP-elevating agents. J Neurochem. 1994; 63: 509 -516.
• BDNF is reported to enhance the growth of serotonin and NE neurons, as well as to protect these neurons from neurotoxic damage Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
• Antidepressant treatments and ECT could reverse this atrophy by increasing BDNF expression and function • Normalization of glucocorticoid levels by antidepressant treatments in some individuals could be an additional mechanism for the prevention of further neuronal damage Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997
This is your brain after repeated episodes of depression, mania, chronic stress, chronic addiction
Drug-triggered relapse • In animals, the most potent stimulus for relapse is a “free” (non contingent) “priming” injection of the training drug – Just as a single drink, smoke, sniff can establish a relapse in detoxified addicts • In animals, “cross-priming” from one class to another has been widely demonstrated – ie. priming with cocaine can lead to opiate self administration and vice versa – Stewart J: Reinstatement of heroin and cocaine self administration in the rat by intracerebral application of morphine in the ventral tegmental area Pharmacol Biochem Behav 1984: 20 917 -923
Cross Addiction risks DA agonists trigger relapse to both cocaine and heroin self administration This fact is known by drug dealers who cut heroin with cocaine Ref: Shaham Y. Effects of opioid and dopamine receptor agonists on relapse induced by stress and re-exposure to heroin in rats Psychopharmacology 1996: 125; 385 -391
Stress Triggers relapse Individuals exposed to stress are more likely to abuse alcohol and other drugs or undergo a relapse Kosten TR et al: A 2. 5 year follow-up of depressions life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 1986; 43 -739 Sinha R et al Psychological stress, drug-related cues, and cocaine craving. Psychopharmacology 2000; 152: 140 -148 Shaham Y Immobilization stress-induced oral opioid self administration and withdrawal in rats: role of conditioning factors and the effects of stress on relapse to opioid drugs Psychopharmacology. 1993: 11; 477 -485
How about doctors? • Physicians become addicted at the same rate as the rest of the population – Prevalence rates (between 10 -15%) – Increased risk for use of “legitimate” drugs • Availability, availability – Differences between subspecialties reflect availability issues • I. e. anesthesiologists preferred drug is fentanyl
Physician Risk Factors: Divorce • Rates are 10 -10% higher than the general population • Physicians are career-driven • Training requires the mastery of the art of delayed gratification • Macho Mentality – “we notice you’re married – that could be a problem - most of our interns divorce - this is a trial by fire and we mean to keep it that way” » Ref: Sotile WM et al The Medical Marriage: a Couple’s Survival Guide New York. Carol Publishing, 1996
Profile of High-Risk Physician • • • Driven Competitive Compulsive Individualistic Ambitious Often a graduate of a “prestige” school • Frequent mood swings • Drug and/or alcohol problem • Non-life threatening but annoying physical illness Ref: Ross M: Suicide among physicians: a psychological study. Dis Nerv Syst 1973; 34: 145 -150
Physician Risk Factors: Suicide • Physician suicide rate is estimated to be between 28 -40 per 100, 000 • Compared to general population rate of 12. 3 per 1000, 000 • No difference between gender or specialties • Most common cause of death for young physicians (26%) • Physicians complete suicide at twice the expected rate (know-how) – Ref: Council on Scientific Affairs: Results and implications of the AMAAPA Physician Mortality Project, Stage II. JAMA 1987; 257: 2949 -53
Physician Suicide • No difference between specialties • More than one-third of physicians who committed suicide had a drug problem sometime in their lives • 42% were seeing a mental health professional at the time of death Ref: Council on Scientific Affairs: Results and implications of the AMA-APA Physician Mortality Project, Stage II. JAMA 1987; 257: 2949 -53
Physician Suicide • Blamed themselves for their illness • Personality style: more critical of themselves and others • Talked about killing themselves before suicide • Reported more emotional problems prior to age 18 • Had more draining patients than colleagues Ref: Council on Scientific Affairs: Results and implications of the AMA-APA Physician Mortality Project, Stage II. JAMA 1987; 257: 2949 -53
Time Course of Addiction: the more potent the drug, the faster the course Sufentanyl Morphine/meperidine Fentanyl Alcohol (Slopes are proportional to the addictive potential for each drug)
Risk of Impairment in CA MDs in Diversion Program 1989 Medical Specialty % of MDs in Diversion Anesthesia 5. 0 17. 4 Emergency Med 2. 8 6. 5 13. 6 25. 1 Thoracic Surgery 0. 4 OBGYN 6. 1 6. 0 Psychiatry 6. 9 6. 5 Surgery 6. 1 4. 9 Plastic Surgery 1. 0 0. 3 Dermatology 1. 7 1. 2 16. 2 11. 3 Pediatrics 7. 2 4. 5 Neurology 2. 7 1. 6 Radiology 4. 9 2. 8 Ophthalmology 3. 1 1. 6 Pathology 2. 5 1. 2 18. 2 7. 4 General/ Family Practice Internal Medicine Other
Warning Signs in Addicted Colleagues • Unusual changes in behaviors – Mood swings – Irritability • Signs of loneliness and isolation – Withdraw from family, friends, leisure activities • Denial – When directly confronted may become defensive, vehemently rejecting accusations • Domestic strife, fights, and arguments • Wear long sleeves in warm weather • Addicts near to be near drug source: for a professional addicted to narcotics, this means long hours in the hospital, even when off duty. For alcoholics, this means frequently calling in sick. Alcoholics may disappear without explanation to bars or hiding places to drink secretly • Unexplained overspending, legal problems, gambling, extramarital affairs, work problems
Warning Signs in Addicted Colleagues • Decreased Libido • Pills, syringes, alcohol bottles found around the house • Bloody swabs or tissues found at home • May develop the habit of locking themselves in the bathroom or other rooms while they are using drugs • Frequent smell of alcohol on breath • Pinpoint pupils • Evidence of withdrawal, especially sweats and tremors • Weight loss and pale skin • Untreated addicts are found comatose • Untreated addicts are found dead
Physician Recovery • Physicians recover from addiction at a rate of between 70 -85% • This is twice the rate of the general population
Outcome of Non-Opioid Addiction in Anesthesia Residents Menk EJ et al; Success of Reentry into Anesthesiology Training Programs By residents With a History of Drug Abuse. JAMA 263(22) pp. 3060 -3062. 1990
However: • It may require a change of environment to reduce the relapse risks associated with availability
Outcome of Opioid Addiction in Anesthesia Residents Menk EJ et al; Success of Reentry into Anesthesiology Training Programs By residents With a History of Drug Abuse. JAMA 263(22) pp. 3060 -3062. 1990
Useful Reading • Gardner E - What we have learned about addiction from animal models of drug selfadministration Am J Addict 2000; 9: 285 -313 • Sapolsky R Glucocorticoids and hippocampus in neuropsychiatric disorders Arch Gen Psychiat Vol 57 10/2000 • Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10: 201 -217, 2001 • Duman, R. A Molecular and Cellular Theory of Depression: Arch Gen Psychiat: July 1997 • Effective Medical Treatment of Opiate Addiction. NIH Consensus Statement 1997 Nov 17 -19; 15(6): 1 -38.
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