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CSAM-SCAM Fundamentals BioPsychoSocial Approaches to Addiction Presentation by: Kathryn J. Gill PhD -Associate Professor, Psychiatry Department, McGill University -Psychotherapist and Researcher, Addictions Unit, McGill University Health Centre Disclosures/Warnings Fundamentals: BioPsychoSocial Approaches to Addiction No current funding from pharmaceutical or medical device companies Psychotherapist at the Addictions Unit, McGill University Health Centre, and in private practice Tenured professor, McGill University with undergraduate, graduate and postgraduate teaching duties Addiction research funded by Canadian Institutes of Health Research https://muhc.ca/addictions_unit/profile/addictions -unit [email protected] Overview Alcohol, drugs, new psychoactive substances Addiction –What are the signs and symptoms? How does it develop? What are the effects of drugs/alcohol on the brain? What are the implications for treatment? Vulnerability to addiction - the roles of genetics and environment http://www.emcdda.europa.eu/ Addictions Unit Department of Psychiatry McGill University Health Centre 6 new substances — 25I-NBOMe, AH-7921, methoxetamine, MDPV, 4,4′-DMAR and MT-45 are currently undergoing risk assessment Harms related to substance use disorders (SUD) Social Effects • family violence/child neglect • isolation/lack of social support • job loss, legal issues, poverty • increased emergency room visits Physical/Brain Effects • HIV, HCV • liver toxicity, sleep problems • neurocognitive & brain deficits (decrease in receptors, neurotransmitters) • increased depression, anxiety, psychosis (Keil et al., 2015; Goldstein et al., 2011; McClure et al., 2009 Costs of SUD in Primary Care (Quebec) (Gill et al., 2016) $7,000 $6,000 +68% $5,000 +34% +145% $4,000 $3,000 $2,000 $1,000 $972 $1,303 $1,984 $4,854 $2,871 $4,827 $0 Other a) SU-RC SUD+ $7,000 $6,000 -10.3% $5,000 $4,000 +90.2% -8.5% $3,000 Average annual per patient RAMQ costs (± SEM) for medical services (a) and pharmaceuticals (b) at two time points over a 3 year period for SURC and SUD+ groups $2,000 $1,000 $2,791 $2,553 $3,079 $5,855 $4,228 $3,792 $0 Other SU-RC T1 b) T2 SUD+ N=2794 Addiction – What are the signs and symptoms? How many started the day with a cup of coffee or tea this morning? What drug did you consume? Xanthines – caffeine and/or theophylline Do you think coffee and tea are addictive? regular use leads to subjective sensation of needing a lift/energy/break + preference for caffeinated forms strong pharmacological effects - increases alertness, energy, concentration via brain adenosine receptors produces physical dependence. Withdrawal symptoms (headache, fatigue, nausea, poor concentration, irritability, increased muscle tension begin 12–24 hours after stopping; peak by 20–48 hours) Reinforcing complex - coffee Warmth conditioned cues Colour, smell, taste Taking a break Pick me up – stimulant Reduction in withdrawal – fatigue, headache Tobacco Smoking Single largest preventable cause of illness and mortality in the world Many of you have patients that are current smokers What drug are they consuming? nicotine + harmane/norharmane (known to inhibit brain enzymes that regulate the level of the neurotransmitters dopamine and serotonin acetaldehyde (effects neurotransmitter release) preservatives, pesticides, mould retardants, humectants, polycyclic aromatic hydrocarbons (carcinogens) Why can’t they just stop? Pleasure and Reward Reinforcing Complex - tobacco smell, taste sound (lighter or match) conditioned cues cigarette shape & colour cigarette package oral sensations, inhalation/exhalation (calming) pharmacological effects of tobacco smoke time out, taking a break relief from withdrawal (anxiety, fatique) Rewarding Effects of Tobacco Primary effects of tobacco constituents Pleasure EEG desynchronization Arousal, enhanced attention, improved task performance Muscle relaxation Increased levels of catecholamines, vasopressin, growth hormone, ACTH, cortisol, prolactin, beta-endorphin Decreased spinal reflexes Reduced hunger Increased metabolic rate, Lipolysis, increased free fatty acids LDL, HDL Heart rate acceleration, BP coronary vasoconstriction Reduced anxiety, depression ? May be due to compounds in smoke that inhibit Monoamine Oxidase? Physical Dependence Withdrawal Discomfort Tobacco Withdrawal Irritability, restlessness, hostility Difficulty concentrating; impaired task performance Drowsiness Sleep disturbance Anxiety Headaches Hunger, weight gain Cravings or strong urges to smoke Depression - Smoking is correlated with a history of childhood depression and smoking cessation is associated with increased depressive episodes. (Niemelä et al., Childhood antecedents of being a cigarette smoker in early adulthood, 2009) - Smoking is very high among those with anxiety, mood and personality disorders, as well as psychosis and all forms of substance dependence Why is it difficult to quit? "He stated he could give up smoking with ease, and in fact had done so hundreds of times" (Mark Twain) Why it is Difficult to Quit High Availability – Legal, relatively socially acceptable cheap, readily available - difficult to avoid cues, nonintoxicating – no deficits in performance Conditioning - Exposure to conditioned cues repeated hundreds of times per day (oral stimulation, inhalation, exhalation), associated with many activities Complex Pharmacological Effects short duration of action, rapid acute tolerance – promotes repeated self-administration, strong physiological dependence with unpleasant withdrawal long delay to negative medical consequences (lung, larynx, stomach, pancreatic cancers), cardiovascular disease Extrapolate to other drugs of abuse (alcohol, cocaine, heroin, cannabis) Many of the factors that make smoking a difficult habit to quit apply equally to other drugs of abuse + + strong intoxication and/or euphoria + ++ cortical suppression after chronic use (impaired control of impulsivity, decision making, planning) What are the effects of drugs/alcohol on the brain? The brain is hard-wired to respond to drugs of abuse Drugs of abuse resemble/activate or disrupt natural neurotransmitters in the brain Anandamide is an endogenous cannabinoid with a much shorter half-life, as well as lower efficacy and binding affinity for CB1 receptors in the brain compared to exogenous THC Animal Studies Drug Exposure has significant effects on: Release of neurotransmitters (DA, glutamate, GABA…) Structure of neurons and circuits (spine density, #synapses) Stress hormones and underlying brain structures Gene expression (striatum and frontal cortex) Epigenetic modification of genes - transgenerational (Vassoler) current research looking at ways to reverse stress and epigenetic effects – focus on neuroplasticity Human Studies -Brain Imaging Positron Emission Tomography - PET Dopamine Pathways striatum frontal cortex hippocampus substantia nigra/VTA nucleus accumbens Functions •attention, arousal •reward (motivation) •motor function •decision making Serotonin Pathways Functions raphe •mood •memory processing •sleep •cognition Issues with Dopamine-related Theory of Reward “Theory - drugs produce pleasure via dopamine release, and addiction may result from neurobiological changes to the dopamine system” Dopamine ≠ Pleasure or Euphoria Not all drugs of abuse release dopamine in humans (inconsistent imaging data). DA blockers or depletion do not affect euphoria or the high in humans, no therapeutic value Preclinical studies show that dopamine firing and release become tied to the cues preceding drug use – not the actual drug decreased DA D2 receptors following chronic drug abuse have been found, but not consistently. However Low D2 receptors may predict poor treatment response to behavioural therapy Dopamine and Incentive Motivation the mesolimbic dopamine pathway, which includes the NAcc, amygdala and hippocampus, is relevant for drug reward and for drug-related memories and conditioned responses Current hypothesis is that dopamine mediates the ‘incentive motivational’ value of reward Dopamine neurons label environmental stimuli with appetitive value, predict and detect rewards and signal motivating events leading to increased dopaminergic activity in response to salient cues Dopamine receptors (PET) PET images of D2 receptors and glucose metabolism in the brain With chronic cocaine abuse, there is decreased dopamine D2 receptors and decreased activity in the OFC, which is linked to compulsive behaviour and disinhibition (Volkow & Li, 2004) Alcohol-induced suppression of brain activity (PET Scan) Thanos et al., 2008 (Alc Res Health, 31:233-237) Recovery of function in chronic alcoholics Volkow et al. (Am J Psychiatry, 151: 171-183, 1994) Effects of chronic cocaine on the brain - PET High activity Non-user, normal brain Cocaine Abuser (10 days) Low activity Cocaine Abuser (100 days) From Volkow et al. Synapse 14:169-177 Drug-induced reduction of activity in the prefrontal (PFC) and orbitofrontal cortex (OFC) have effects on memory, decision making, inhibitory control, judgement, planning and behavioural control (Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Goldstein & Volkow, 2011) 2016 Discussion – What are the implications of frontal cortical dysfunction in terms of treatment planning? disorganization cognitive, attentional and memory deficits low motivation less compliant to treatment/medication regimens poor emotional regulation and decision making Diagnostic Criteria for a Substance Use Disorder Fundamentals: BioPsychoSocial Approaches to Addiction Addiction Definition – ASAM + CSAM “Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors…” DSM-5 ** Diagnostic Criteria For Substance Use Disorder (SUD) A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by 2 of 11criteria, occurring within a 12 month period Impaired control, compulsion to obtain and take the substance Detrimental effects on users and their close relations Development of tolerance and withdrawal ** Diagnostic and Statistical Manual of Mental Disorders, APA, 5th edition DSM-5 Diagnostic Criteria 1) use of larger amounts or longer period than intended 2) unsuccessful efforts to cut down or control use 3) long time spent obtaining or recovering from effects 4) craving 5) failure to fulfill major role obligations 6) continued use despite persistent social problems caused by the substance 7) social, occupational, or recreational activities given up 8) repeated use in hazardous situations 9) continued use despite persistent physical/ psychological problems caused by the substance 10) tolerance 11) withdrawal Sedative/Hypnotic and Anxiolytic Withdrawal Two (or more) of the following developing after cessation of alcohol use that has been heavy and prolonged autonomic hyperactivity (e.g., sweating, pulse rate >100), increased hand tremor psychomotor agitation and/or anxiety insomnia nausea or vomiting transient visual, tactile, or auditory hallucinations or illusions generalized tonic-clonic seizures Are some people more vulnerable to addiction? Vulnerability – Transition from use to abuse to dependence? USE REGULAR HEAVY ABUSE DEPENDENCE availability, cultural norms, sources of recreation/pleasure, drug expectancies, same-sex siblings peer influences, family attitudes (modeling), high risk taking behavior, sensation seeking family disruption/divorce familial antisocial personality disorder familial substance abuse (chaos, shame, violence, poverty, fetal exposure) familial mental illness (genetic factors, neglect, abuse, poor parental monitoring) Familial Risk Factors … genetic + intrauterine exposure + socialization + maltreatment + culture (traditions, religion, values) Parental substance dependence is associated with more risk factors including: mental illness in the parents impaired parental monitoring and control higher genetic loading more disruptive adverse childhood events (family violence, neglect, physical and sexual abuse, foster care) http://www.cdc.gov/ace/ Adverse Childhood Experiences (ACE) – within first 18 years of life ≥ 4 ACE categories = 4-12x risk of SUD 1. 2. 3. 4. 5. 6. 7. 8. 9. Emotional abuse Physical abuse Sexual abuse Emotional/physical neglect Mother treated violently Household substance abuse Household mental illness/suicide attempt Parental separation or divorce Incarcerated household member Is there a genetic vulnerability to addiction? COGA – Collaborative Study on the Genetics of Alcoholism Nine-centre study to detect and map genes for alcoholism (multiplex pedigrees) Measuring multiple related factors (alcoholism, alcohol metabolism, brain waves, personality traits, biochemical measures such as MAOB COGA has reported associations between alcoholism and the GABAA gene clusters on chr 4 (Edenberg et al. 2004), chr 5 (Dick et al., 2006) (Song et al. 2003; Dick et al. 2004) and chr 15 GABAA Genetics (Kumar et al., 2009) GABARA2 - a single SNP in the α2 subunit was associated with alcohol dependence in a large multigenerational pedigree (Edenberg et al 2004) Replicated in separate independent studies (Agrawal et al 2006; Bauer et al 2007; Soyka et al 2008) in some studies the GABARA2 has been linked to anxiety scores, ethanol withdrawal severity and sensitivity to alcohol COGA has suggested that alcoholism (and comorbid anxiety) MAY be related to a CNS dysregulation of the GABA system Other candidate genes under investigation alcohol/drug metabolism (ADH, ALDH, CYP4502E1) GABA (α2, γ3, rho subunits of GABAA , GAD2) MAO (promoter VNTR), COMT, nicotinic CHRNA4 Dopamine (receptors D2 , D3 , D4) + DAT) Serotonin (TPH1, TPH2, 5HT2A, 5HT1B + 5HTT) Opiate receptor OPRM1 (C118G, A118G polymorphisms) Genetic & Epigenetic Factors It is highly likely that genetic and epigenetic factors affect the transition from use to abuse For example, genes products could modify initial responses to drugs, rate of acute and chronic tolerance development, conditioned responses to cues, as well as the likelihood of developing physical dependence and the severity of withdrawal reactions Fundamentals: BioPsychoSocial Approaches to Addiction Addiction Risk (and Resilience) availability, cost, route, rate of onset, efficacy, tolerance, physical dependence Genetic s, family environment, co-morbid psych/med disorders, abuse/trauma Occupation, drug policy, peer group, culture, poverty, lack of opportunity The End Extra discussion slides 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Alcohol related conditions (ICD-9) Psychosis, alcoholic 291 Polyneuropathy, alcoholic 3575 Cardiomyopathy, alcoholic 4255 Gastritis, alcoholic, w/o haemorrhage 5353 Cirrhosis, fatty, alcoholic 5710 Hepatitis, acute, alcoholic 5711 Cirrhosis, liver, alcoholic 5712 Damage, liver, alcoholic, unspecified 5713 Foetal alcohol syndrome - Alcohol affecting foetus via placenta or breast milk 7607 Abnormal findings, alcohol in blood level 7903 Poisoning by alcohol 908 Personal history mental problems V11 Health problems in family V614 Examination, for medico legal reasons V704 Special screening for alcoholism V791 Drug related conditions (ICD-9) Psychosis, drug 292 Polyneuropathy, due to drugs 3576 Pregnancy, complicated by drug dependence 6483 Pregnancy, management affected by suspected damage to foetus from drug 6555 Reaction and intoxication, drugs, specific to newborn 7794 Syndrome, drug withdrawal in new born 7795 Poisoning by hormones and other synthetic substitutes 962 Poisoning by Opiates and related narcotics 965 Poisoning by Sedatives and hypnotics 967 Poisoning by other central nervous system depressants and anaesthetics 968 Poisoning by psychotropic agents 969 Poisoning by central nervous system stimulants 970 Poisoning by drug primarily affecting the autonomic nervous system 971 Poisoning by other and unspecified drugs 977 Pimozide Effects in Humans Brauer & DeWit 1997 – The D2 antagonist pimozide did not change the subjective effects of amphetamine in human subjects Lack of efficacy of D2 antagonists (antipsychotics) on cocaine addiction • Three double-blind RCTs evaluated olanzapine for cocaine dependence – no positive results (Hamilton, 2009;Kampman etal.,2003; Reidetal.,2005) • Aripiprazole reduced cocaine use (Meini, 2011), but was shown to increase self-administration of smoked cocaine(Haney etal.,2011). • Meta-analysis of RCTs related to antipsychotics for cocaine or amphetamine dependence, found no efficacy over placebo (Kishi et al.,2013) Phytocannabinoids (from POT) Endocannabinoids (eCB) 2-AG Hanus, 2009 Burns et al. (2007) [18F]MK-9470, a positron emission tomography (PET)tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Definition of Disease/Disorder A disease/disorder is an abnormal condition of an organism that impairs bodily functions, associated with specific symptoms and signs. It may be caused by external factors, such as infectious agents, or it may be caused by a wide variety of internal dysfunctions (such as genetic mutations, autoimmunity, cancer cells, breakdown of a tissue/organ). In human beings, "disease" is often used more broadly to refer to any condition that causes pain, dysfunction, distress, social problems, and/or death. – Cocaine Metabolism I – Normally cocaine is degraded by plasma or liver esterases to Benzoylecgonine (50-70% of the cocaine is metabolized to this form). It is inactive on dopamine uptake, but has minor vasospastic effects In the presence of alcohol, cocaine is degraded by carboxyl esterase to another metabolite COCAETHYLENE – a pharmacologically active cocaine metabolite Compared to cocaine it has equal affinity for the dopamine transporter, lower LD50, greater effects on blood pressure and heart rate, greater hepatotoxicity (based on studies in cell culture and animals), and a longer half-life (~2 hours) 28 – Behavioural, biochemical and molecular changes induced by – chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex. Results: Mice in the crack-cocaine group exhibited hyper-locomotion and “escape jumping” that increased with drug exposure (blue) Levels of AEME were higher than levels of cocaine Expression levels of ΔFosB were upregulated in the crack-cocaine group and levels of CREB were downregulated CB1 receptors and cannabinoid degradation enzymes were downregulated Expression levels of receptors D1, D2, D3 and TH were significantly upregulated in the crack-cocaine group (red) There was a significant increase in DAT expression in the PFC of crack-cocaine mice, and a reduction in the levels of dopamine, DOPAC and HVA Areal, L. B., Rodrigues, L. C., Andrich, F., Moraes, L. S., Cicilini, M. A., Mendonca, J. B., . . . Pires, R. G. (2015). Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex. Behavioural Brain Research, 290, 8-16. doi: 10.1016/j.bbr.2015.04.036 – Behavioural, biochemical and molecular changes induced by – chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex. Discussion: The data demonstrate neurochemical changes in the dopaminergic and the endocannabinoid systems of the crack-cocaine exposed mice, and the authors suggest: AEME concentration was significantly higher than cocaine and its neurotoxic potential is much greater; this may be cause for the phenotypic differences observed between cocaine use and crack-cocaine use The downregulation of CB1 receptors and cannabinoid degradation enzymes – which may have be due to a crack-cocaine-induced increase in levels of anandamide – are possibly the cause of the deceased levels of dopamine and its metabolites in the PFC and further the significant increase of dopamine receptors and tyrosine hydroxylase They conclude that crack-cocaine addiction should be treated differently from cocaine addiction and indicate a potential candidate for some of crack’s addictive properties, though suggest that further research is required Varenicline: Efficacy Smokers treated with 1 mg Varencline, 150 mg Bupropion SR, or placebo twice daily over 12 week period Jorenby et al. 2006