Objectives Participants will: Recognize the difference between Substance abuse and Dependency Learn basic principles of the neurobiology of addiction Recognize

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

Lifetime Prevalence, mental health and addictive disorders

• Alcoholism (dependency & abuse) - 13.7%

• Phobias - 12.6%

• Drug Abuse/Dependence - 6.1%

• Major Depression - 5.1%

• Antisocial Personality - 2.5%

• Obsessive Compulsive Disorder - 2.5%

• Panic Disorder - 1.5%

• Schizophrenia - 1.0%

• Mania - 0.4%

ECA Community Study

Ref: Burke et al: Age of Onset of selected mental Disorders

in five community populations-Arch Gen. Psychiat 511-518

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

WOD

’75 ’81 ’85 ’91 ’99

use

Perceived harm

availability

NIDA: Monitoring the Future Study (1999)

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% 8th graders

• 24% 10th graders

• 34% 12th graders


Meet Adult Criteria for Alcohol Use Disorder

• 9% adolescent girls• Up to 20% adolescent

boys

CSAT TIP 32: Treatment of Adolescents with Substance Use DisordersOnline: 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% 8th graders• double the rate since 1991


Heroin Use in Past 12 months


Perceived risk of sniffing heroin


Disapproval of Sniffing Heroin


Smoke Cigarettes Daily

• 20% high school seniors


Why do some people Why do some people become addicted while become addicted while

others do not?others do not?

VulnerabilityVulnerability

Complex genetic factors play a roleIn animals and people

Complex genetic factors play a roleIn 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 Ratsnot 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 self-administration

• 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(suppl1):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(suppl1):82-84

2.5

0

unpleasant response

pleasant response

DA Receptor Levels and Response to MPHIn People

low receptor levels MPH pleasant high receptor levels MPH unpleasant

Ref: Volkow, ND, Wang, G-J, Fowler, JS, Logan, J, Gatley, SJ, Gifford, A, Hitzemann, R, Ding, Y-S, Pappas, N. Brain dopamine D2 receptor levels predict reinforcing responses to psychostimulants in humans. Am J Psychiatry, September 1999.

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 cAMP 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 LevelsEffects of Drugs on Nucleus Accumbens Dopamine LevelsEffects of Drugs on Nucleus Accumbens Dopamine LevelsEffects of Drugs on Nucleus Accumbens Dopamine Levels

Amphetamine

DA

0 5h

DA

0 5h

Cocaine

Morphine

3h

Nicotine

5h

Timothy P. Condon, Ph.D. Addiction as a Brain Disease: New Implications for Research and PracticeConnecticut Statewide Addiction Medicine/Psychiatry Grand Rounds September 20, 2001

Source: Di Chiara and Imperato

Natural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine Levels

0 60m 120m 180m

Empty Box

Feeding

FOOD

Nac DA

Intromissions

SEX

Ref: Fiorino and PhillipsRef: Di Chiara et al.

Timothy P. Condon, Ph.D. Addiction as a Brain Disease: New Implications for Research and PracticeConnecticut Statewide Addiction Medicine/Psychiatry Grand Rounds September 20, 2001

Nac DA

• 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 D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14:169-177, 1993

Receptor agonists•Opiates•Cannabinoids•Nicotine

Transporter Ligands•Cocaine•Amphetamine•Methylphenidate

Ion Channel Ligands•PCP•Alcohol

Initial Protein Targets for some drugs of abuse

• 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.

Molecular Biology of AddictionBeyond Initial Cellular Targets:

Transcription Factor CREB (cAMP response element-binding protein) and its target BNDF

This is your brain

This is your brainThanks to BDNF

Think of it like fertilizing and pruning your rose bushes

Intracellular Targets

Ca++

Change in Gene Expression

Receptor

CREB

BDNF

Adaptations in neural function

PKA / protein kinases

cAMP / Second Messengers

Adenyl cyclaseGs

Target Genes

Ca dependentkinases

Ion Channels

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 cAMP 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 FosB– Exerts opposite effects – May contribute to sensitized responses to drug

exposure


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


• 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


The switch from acute to chronic addiction

Drug => Synaptic => transmission

signaling => pathways

neuronal => activity

Persistent behavioral abnormalities


The switch from acute to chronic addiction

Drug => Synaptic => transmission

signaling => pathways

neuronal => activity

Persistent behavioral abnormalities

Acute effects chronic molecular and cellular adaptation

CREBAdenyl Cyclase type 8Tyrosine HydroxylaseDynorphinMany others

FosB

GluR2Cyclin dependent kinase-5Many others

Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

This is your brain

This is your brainAfter 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

DECREASED • Eating• Sleeping• Reproductive activity

INCREASED• Restless activity in familiar environments• Avoidance behaviors

Behavioral Effects of Chronic Stress Hormones (CRF)

Physiological changesSupporting flight or fight responses

Bloodstream

CORTISOL

CRF

Anterior Pituitary

INHIBITORYSIGNAL

HypothalamusHypothalamus

STRESS

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 re-

growth 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, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci.

1985;5:1222-1227.

Stress

Glucocorticoids

BDNF

Neuronal DeathAtrophy

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, McCarthy 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.


• 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.


• Depression, particularly stress-associated cases, may result from the atrophy or death of vulnerable pyramidal neurons in the CA3 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 CA3 neurons


• BDNF is reported to enhance the growth of serotonin and NE neurons, as well as to protect these neurons from neurotoxic damage


CREB Cakes

• expression and function of the transcription factor cAMP response element-binding protein (CREB) is increased by different types of antidepressant treatments, suggesting that CREB is a common postreceptor target for antidepressants


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 cAMP-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


• 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


This is your brain

This is your brainafter 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; 43-733-739

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, 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 AMA-APA 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

Fentanyl

Morphine/meperidine

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 % of MDs in Diversion

Anesthesia 5.0 17.4

Emergency Med 2.8 6.5

General/ Family Practice 13.6 25.1

Thoracic Surgery 0.4 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

Internal Medicine 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

Other 18.2 7.4

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

Relapse26%

Died4%

Success70%

RelapseDiedSuccess

Menk EJ et al; Success of Reentry into Anesthesiology Training Programs By residentsWith 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

Relapse49%

Died17%

Success34%

RelapseDiedSuccess

Menk EJ et al; Success of Reentry into Anesthesiology Training Programs By residentsWith 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 self-administration 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.

Documents

Objectives Participants will: Recognize the difference between Substance abuse and Dependency Learn basic principles of the neurobiology of addiction Recognize