“Brain Drain”: Drug-Induced Loss of Brain Function Dr. Sandra Welch Professor Virginia Commonwealth University Photo courtesy of the NIDA Web site.
Download ReportTranscript “Brain Drain”: Drug-Induced Loss of Brain Function Dr. Sandra Welch Professor Virginia Commonwealth University Photo courtesy of the NIDA Web site.
“Brain Drain”: Drug-Induced Loss of Brain Function Dr. Sandra Welch Professor Virginia Commonwealth University Photo courtesy of the NIDA Web site. From A Slide Teaching Packet: The Brain and the Actions of Cocaine, Opiates, and Marijuana. We Have Generated A Lot of Evidence Showing That… Prolonged Drug Use Changes the Brain and In Fundamental and Long-Lasting Ways AND… We Have Evidence That These Changes Can Be Both Structural and Functional BRAIN IMAGING Positron Emission Tomography Magnetic Resonance Imaging Illustration used with permission, courtesy of Lydia V. Kibiuk and the Society for Neuroscience. Brain Maturation from Ages 5 to 20 Copyright ©2004 by the National Academy of Sciences Gogtay, Giedd, et al. (2004) Proc. Natl. Acad. Sci. USA 101, Photo courtesy of the NIDA Web site. From A Slide Teaching Packet: The Brain and the Actions of Cocaine, Opiates, and Marijuana. Dopamine Pathways striatum frontal cortex hippocampus Functions •reward (motivation) nucleus •pleasure,euphoria accumbens •motor function (fine tuning) •compulsion •perserveration •decision making substantia nigra/VTA Serotonin Pathway raphe Functions •mood •memory processing •sleep •cognition For Example… We Know That Despite Their Many Differences, Virtually All Abused Substances Enhance Dopamine (neurotransmitter) Activity (particularly related to pleasure, motor, and cognitive function • Other pathways also involved! Accumbens 1100 1000 900 800 700 600 500 400 300 200 100 0 AMPHETAMINE Much greater DA DOPAC Activity than any HVA Other drug of abuse -causes neurotoxicity 250 NICOTINE 200 Accumbens Caudate 150 100 Accumbens COCAINE DA DOPAC HVA 300 200 100 0 5 hr 250 % of Basal Release 1 2 3 4 Time After Amphetamine % of Basal Release 400 0 % of Basal Release % of Basal Release Effects of Drugs on Dopamine Release 0 1 2 3 4 Time After Cocaine Accumbens 5 hr ETHANOL Dose (g/kg ip) 200 0.25 0.5 1 2.5 150 100 0 0 1 2 3 hr 0 Time After Nicotine Source: Di Chiara and Imperato 0 1 2 3 Time After Ethanol 4hr 200 % of Basal DA Output NAc shell 150 100 Empty 50 Box Feeding 200 150 100 15 10 5 0 0 0 60 120 Time (min) 180 ScrScr BasFemale 1 Present Sample 1 2 3 4 5 6 7 8 Number Scr Scr Female 2 Present 9 10 11 12 13 14 15 16 17 Mounts Intromissions Ejaculations Source: Di Chiara et al. Source: Fiorino and Phillips Copulation Frequency DA Concentration (% Baseline) Natural Rewards Elevate Dopamine Levels FOOD SEX Common Underlying Neurobiological Factors Can Be: Neurochemical (imbalance of neurotransmitters) Structural/anatomical (same regions and pathways) Genetic (inherited factors that compromise function) Drugs of abuse can cause symptoms that mimic most forms of mental illness because they alter the same neurotransmitters that are altered in mental illnesses. Drug Disorder Cocaine and Methamphetamine Schizophrenia, paranoia, anhedonia, compulsive behavior Stimulants LSD, Ecstasy & psychedelics Alcohol, sedatives, sleepaids & narcotics PCP & Ketamine Anxiety, panic attacks, mania and sleep disorders Delusions and hallucinations Depression and mood disturbances Antisocial behavior Chronic use of some of these drugs of abuse may alter the way the brain functions, making persons particularly susceptible to mental illness People With Comorbid Mental and Addictive Disorders Have a Double DoubleBrain Disease Mental Disorder Comorbid Disorders Addictive Disorder Outline of talk: Alcohol - a depressant Cocaine - a stimulant MDMA and Club Drugs - stimulants Marijuana Inhalants Opioids Alcohol Abuse and Alcoholism Important neurotransmitters in the reward pathway for alcohol Dopamine Opioid Serotonin GABAA Glutamate well-being, arousal, reward rewarding and reinforcing behavioral inhibition inhibitory excitatory Overview: Statistics on teen drinking Short- and long-term effects of alcohol Statistics on Teen Drinking Monitoring the Future (MTF) reported that in 2007, nearly one in five 8th graders, more than one in three 10th graders, and nearly one in two 12th graders had a drink in the past month. Teen Statistics (cont.) From National Survey on Drug Use and Health (2005): 10.9 million users ages 12-20 7.2 million “binge drinkers” Short-term Effects Slower reaction times/reflexes Heavy sweating Blurry vision Nausea and vomiting Lowered reasoning ability Short-term Effects (cont.) Poor motor coordination Slower heart rate/breathing rate Increased blood pressure Anxiety/restlessness Lower inhibition Short-term Effects (cont.) Mental confusion Memory loss Coma Death from respiratory arrest Long-term Effects Nervous system Muscles Lungs Liver Long-term Effects (cont.) Sexual organs Brain Heart Esophagus/stomach Drug and Alcohol Intoxication MARKEDLY Disrupt Brain Function: Effects of alcohol intoxication on brain metabolism sober intoxicated (0.1 mg%) Studies on Teen Drinking "I used to worry about my short attention span - but not for very long." - Strange de Ji Studies on Teen Drinking Early drinking onset is associated with increased risk of alcoholism NIAAA Comorbidity with alcoholism Drug abuse (opioids, cocaine, cannabis) nicotine addiction antisocial personality disorder major depression anxiety disorders bulimia nervosa Alcoholism and Nicotine Addiction Heavy smokers > 20 cigarettes / day 70% of alcoholics 10% of the general population Structure and Functional Consequences of Intoxication Structural damage to the brain resulting from chronic alcohol abuse can be observed in different ways: •Results of autopsy show that patients with a history of chronic alcohol abuse have smaller, less massive, and more shrunken brains than nonalcoholic adults of the same age and gender. •The findings of brain imaging techniques, such as CT scans consistently show an association between heavy drinking and physical brain damage, even in the absence of chronic liver disease or dementia. •Brain shrinking is especially extensive in the cortex of the frontal lobe2 - the location of higher cognitive faculties. •The vulnerability to this frontal lobe shrinkage increases with age. After 40 some of the changes my be irreversible, but some changes are not reversible at any age! •Repeated imaging of a group of alcoholics who continued drinking over a 5-year period showed progressive brain shrinkage that significantly exceeded normal age-related shrinkage. Moreover, the rate of shrinkage correlated with the amount of alcohol consumed. In Adults, Emotional Self Regulation Is Normally Implemented By A Neural Circuit Comprising Various Prefrontal Regions… Sexual Arousal Condition & Subcortical Limbic Structures Attempted Inhibition Condition Attempted Inhibition Condition Source: Beauregard, M. et al., Journal of Neuroscience 21 RC165, 2001. Effects of Alcohol Intoxication on Brain Glucose Metabolism (Marker of Brain Function) Decreases prefrontal cortex cingulate gyrus Increases amygdala Alcohol decreases activity of areas involved with control and increases activity of areas involved with emotional reactivity Fetal Alcohol Syndrome >10% of children exposed in utero to alcohol toxicity 7-14 drinks/wk (particularly > 5/occasion) can cause moderate fetal damage FAS: growth deficiency, abnormal facies, mental retardation, attentional and behavioral problems FAE: learning disabilities, intellectual impairment, behavioral problems Your Brain on Drugs: Cocaine 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 Photo courtesy of Nora Volkow, Ph.D. Mapping cocaine binding sites in human and baboon brain in vivo. Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, Macgregor RIR, Hitzemann R, Logan J, Bendreim B, Gatley ST. et al. Synapse 1989;4(4):371-377. Your Brain After Drugs Normal Cocaine Abuser (10 days) Cocaine Abuser (100 days) 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. Important neurotransmitters in the reward pathway for stimulants Dopamine well-being, arousal, reward Opioid rewarding and reinforcing Serotonin GABAA Glutamate behavioral inhibition inhibitory excitatory Drug Use Has Played a Prominent Role in the HIV/AIDS Epidemic In Several Ways Disease Transmission IV Drug Use Drug User Disinhibition Leading to High Risk Sexual Behaviors Progression of Disease In Addition to Increasing the Risk of HIV Transmission Some Psychoactive Drugs May Also Accelerate HIV Progression Effects of Cocaine Combined with HIV Infection In Vivo 105 8 6 4 * 2 HIV RNA copy no. CD4: CD8 ratio 10 * 104 103 102 0 Control Cocaine Control Cocaine Roth, M.D. et al., The Journal of Infectious Diseases, 185, pp. 701-705, 2002. Acceleration of HIV Degeneration of Dopamine Cells With Cocaine Seronegative HIV HIV + Drug Drugs Have Long-term Consequences Photo courtesy of NIDA from research conducted by Melega WP, Raleigh MJ, Stout DB, Lacan C, Huang SC, Phelps ME. Amphetamine and the Hallucinogen DOI Produce Different Protein Profiles in Brain Normal AMPH DOI The Memory of Drugs Front of Brain Amygdala not lit up Amygdala activated Back of Brain Nature Video Photo courtesy of Anna Rose Childress, Ph.D. Cocaine Video CEWG Advance Report NIDA Community Epidemiology Workgroup 25th Anniversary Meeting MDMA & Club Drugs Seattle Minneapolis Boston New York Newar k Philadelphia Detr oit Chicago San Fra ncisc o Denv er St. Louis D.C. Los Angeles Phoenix San Diego Honolulu Atlanta Austin Ne w Orleans Miami • Consequences UP in 13 of 20 cities • More routine settings: home and school • More concomitant and sequential abuse “Ecstasy” may not be MDMA Methyl Salicylate, Caffeine 90% DXM MDMA MDA These are some of the “Ecstasy” pills tested by the dancesafe organization (www.dancesafe.org) MDMA Users (N=55) Selected other drugs used - last three months Ketamine Methamphetamine Inhaled cocaine Inhaled nitrites (poppers) Viagra GHB Anabolic steroids LSD Mushrooms Marijuana Injected last three months Enrolled in drug treatment program- ever % 69 56 55 53 38 24 13 13 7 76 11 15 MDMA Brief Historical Overview 1912 1950s MDMA was synthesized (Merck) U.S. army studied as potential agent in psychological warfare 1970s MDMA used in psychotherapy – “penicillin for the soul” 1985 MDMA became illegal in the U.S.; 1988 in the Netherlands 1990s… Still limited knowledge of prevalence of use, levels of risk and consequences EFFECTS OF MDMA USE PHYSIOLOGICAL Sensatory awareness Loss of appetite Nausea Muscle ache Tachycardia Hypothermia Cardiological complications Liver damage PSYCHOLOGICAL Euphoria • Anxiety, depression, and panic attacks Depersonalization Paranoia Psychotic experiences Cognitive deficiencies, e.g., memory loss and decreased planning ability Settings of Use The settings at which MDMA is being used Are diversifying according to all presenters And these include: Raves and concerts Clubs and bars House parties At home with friends or other private settings MDMA Administration Intranasal Bumpers Inhale “bumps” from the back of the hand Other paraphernalia such as spoons, pen caps Oral Pills and capsules Anal Insertion “Booty bumping” HIV Risks 24 percent of current MDMA users in NIDA studies are HIV positive. Unsafe sex reported but is almost always attributed to other drugs such as methamphetamine. Unwanted sexual attention (rape) and sex has been reported in the context of MDMA use. Challenges - Prevention Prevention messages regarding MDMA use have had little effect among all age groups. Other drugs such as GHB are seen as more dangerous, have become stigmatized, and use has reduced. While MDMA is not perceived as a safe drug, it is seen as much safer than other drugs. Effect of MDMA on cerebral blood flow: A SPECT and MRI study Baseline 2 Weeks Post MDMA Highest Dose Lowest Dose L. Chang Psychiat Res (2000) 98: 15) Rat Hippocampus (2 wks after 20 mg/kg; 2X daily, 4 days) • Result: long-term loss of nerve fibers 5-HT levels in monkey after MDMA (two 5 mg/kg daily for 4 days) • Result: -long-term loss of nerve fibers in monkeys 2 weeks 7 years (caudate nucleus) (Hatzidimitriou et al., J. Neurosci. 19 [1999] 5092) -some recovery Partial Recovery of Brain Metabolism and Function in Methamphetamine Abusers After Protracted Abstinence Short Abstinence % Metabolic Change Protracted Abstinence Improved memory correlates with thalamic recovery Adapted from Wang, Volkow, et al, (2004) American Journal of Psychiatry 161: 242-8 (scans unpublished) MOTOR FUNCTION • Slowed gait •Impaired balance • Impairment correlates with damage to dopamine system Implication: Brain changes resulting from prolonged use of psychostimulants, such as methamphetamine may be reflected in compromised cognitive and motor functioning Photo courtesy of the NIDA Web site. From A Slide Teaching Packet: The Brain and the Actions of Cocaine, Opiates, and Marijuana. Important neurotransmitters in the reward pathway for stimulants Dopamine Opioid Serotonin GABAA Glutamate well-being, arousal, reward rewarding and reinforcing behavioral inhibition inhibitory excitatory Important neurotransmitters in the reward pathway for stimulants Dopamine Opioid Serotonin GABAA Glutamate well-being, arousal, reward rewarding and reinforcing behavioral inhibition inhibitory excitatory Important neurotransmitters in the reward pathway for stimulants Dopamine Opioid Serotonin GABAA Glutamate well-being, arousal, reward rewarding and reinforcing behavioral inhibition inhibitory excitatory Dopamine D2 Receptors in Addiction Cocaine Meth Alcohol Food DOE/BNL, NIDA, ONDCP Reward System in Addiction More Cocaine Alcohol Food treated METH Ability to Experience Rewards Is Damaged Less Their Brains… Get Rewired by Drug Use Is There Recovery? • Good News: After 2 years some of the dopamine deficits are recovering • Bad News: Functional deficits persist • What does this mean??? … Is it worth the risk? Photo courtesy of NIDA. Don’t Worry Be Happy!