Addiction: from biology to policy. David Nutt FMedSci Imperial College London

Transcription

1 Addiction: from biology to policy David Nutt FMedSci Imperial College London

2 What is addiction? From Latin addictio = enslaved a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences,

3 Addictions To drugs including alcohol and tobacco To gambling - money? Shopping sex internet +/- porn - food??? Work/research/learning/psychiatry??

4 Addictions To drugs including alcohol and tobacco Drugs and alcohol = biggest international trade in world To gambling - illegal drugs 2nd only to oil? Shopping sex internet +/- porn - food? UK costs > 50bill per year

5 Drug related deaths - UK 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 1,400 1,200 1, ,000 0 Tobacco Alcohol Opiates Source: Smoking and drinking among adults, Office for National Statistics Drug Misuse Declared: Findings from the 2010/11 British Crime Survey England and Wales. Home Office Estimates of the Prevalence of Opiate Use and/or Crack Cocaine Use, 2009/10: Sweep 6 report. The Centre for Drug Misuse Research 5

6 More than 20% of all male deaths yrs due to alcohol Male deaths from alcohol by age band 2,500 30% Number of deaths 2,000 1,500 1,000 25% 20% 15% 10% % of all deaths by age group 500 5% Age group Wholly attributable conditions Partially attributable acute consequences Partially attributable chronic conditions % of all deaths by age group 0% Figure 1. Number (% of all deaths in each age group) of male deaths attributable to alcohol consumption by age and type of condition (2005) Alcohol the most common reason for death in men under 50

7 Half of all years olds are drunk once a month

8 The rise and rise of liver deaths 80% liver deaths due to alcohol British Liver Trust analysis of Office for National Statistics mortality statistics covering all deaths related to liver dysfunction covering ICD K70 76 and other codes including C22 24 (liver cancer), and B15 B19 (viral hepatitis), January 2009

9 The more you drink the more comorbid diseases you get ause-specific relative risk by alcohol consumption 5.0 Lip, pharynx, and oral cancer Oesophageal cancer Colon cancer Rectal cancer Ischaemic heart disease Relative risk This is the excuse for doing nothing! 0.0 Relative risk Liver cancer Laryngeal cancer Breast cancer Essential hypertension Injuries Men and women Men Women Relative risk Ischaemic stroke Haemorrhagic stroke Cirrhosis Non-cirrhotic chronic liver disease Chronic pancreatitis Alcohol (units/week) Alcohol (units/week) Alcohol (units/week) Alcohol (units/week) Alcohol (units/week) White et al. BMJ 2002;325(7357):191 8

10 Triangulating addiction Social factors Drug factors Addiction Brain mechanisms Personal biological factors

11 Elements of addiction Loss of control Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Withdrawal

12 Brain circuits of addiction (a) Red = reward prediction and pleasure No-Go Go Blue = cognitive control Green = motivation drive and salience attribution Purple = learning and memory (b) Normal brain Addicted brain Baler and Volkow 2006

13 Elements of addiction Loss of control Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Use/exposure Withdrawal Perpetuation/addiction

14 What do we know about use? Addictive drugs are usually pleasurable when first taken? Not tobacco, alcohol Pleasurable effects determined by dose speed of brain entry Withdrawal by duration and dose speed of clearance (CYP450 genes)

15 Reducing use reduces harm Use increases mortality: with alcohol consumption exponential rise Lifetime risk of death due to alcohol-related injury 18 Risk of death (%) Men Women Alcohol consumption (g/day) Rehm et al. Addiction 2011;106(Suppl 1):

16 Reducing high-end consumption has major impact on harms Lifetime risk of death due to alcohol-related injury 18 Risk of death (%) Men Women Reductions in high consumers big health benefits Alcohol consumption (g/day) Rehm et al. Addiction 2011;106(Suppl 1):

17 The Times 20 th March 2000 i.v. marks = faster inputs more addiction

18 Time course of heroin effects: short half-life; highs and withdrawal High Effect normal Withdrawal 24 Time (hours) 48

19 Methadone reduces the chaotic effects of heroin and blocks on-top use High Slower and lower high Longer action Effect W/drwl Time (hours) Buprenorphine better blockade and extended action of up to 3 days

20 Speeding up cocaine Leaf Powder [HCl] Crack [freebase]

21 Speed of brain entry predicts stimulant abuse High abuse Low abuse

22 Treatment targets? Loss of control Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Use/exposure Withdrawal Perpetuation/addiction

23 Possible neurotransmitters Dopamine GABA/gluta mate Loss of control Noradrenaline Dopamine Endorphins Pleasure Reduce suffering Memory impulsivity Meaning Wanting Compulsion Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

24 Stopping use? Dopamine GABA/gluta mate Loss of control?noradrenaline? Dopamine Pleasure Reduce suffering Memory impulsivity Meaning Wanting Compulsion Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

25 Stopping use Block the drug getting to its binding site Antagonists - naltrexone for heroin (low compliance) (Dopamine reuptake blockers failed for cocaine) Vaccines nicotine, cocaine (under study) Block elements of drugs effects Opioid antagonists for alcohol nalmefene naltrexone? Prevent loss of control Substitution therapy Methadone, buprenorphine for heroin GHB, baclofen for alcohol Varenicline for tobacco

26 Dopamine and addiction What we know In preclinical studies many drugs release dopamine coc >>others (DiChiara) low DRD2 receptor number predicts impulsivity and intake of cocaine but not opioids (Dalley) and similar findings in primate (Nader)

27 dopamine = reward? Increases in brain dopamine are associated with reward effects of psychostimulants in humans Volkow et al 1999

28 But not all drugs release dopamine Heroin 50mg i.v. gives a good high 4000 AUC Change from Baseline (+/- St. Err) [ *[ +[ Sleepy Urge Crave Gouched Withdrawal High Rush Placebo Hydromoprhone Heroin + p<0.05 paired t-test vs. placebo * p<0.05 unpaired t-test heroin vs hydromorphone Daglish MRC, Williams TM, Wilson SJ, Taylor LG, Eap CB, Augsburger M, Giroud C, Brooks DJ, Myles JS, Grasby P, Lingford- Hughes AR, Nutt DJ [2008] Brain dopamine response in human heroin addiction. Brit J Psychiatry 193: PMID:

29 But No difference there is NO in 11 release C-Raclopride of dopamine binding +/- opiate agonist & to controls C_Raclopride BP Right Putamen Right Caudate Right Vent. Striatum Left Putamen Left Caudate Left Vent. Striatum Placebo Hydromorphone Heroin Control Daglish MRC, Williams TM, Wilson SJ, Taylor LG, Eap CB, Augsburger M, Giroud C, Brooks DJ, Myles JS, Grasby P, Lingford- Hughes AR, Nutt DJ [2008] Brain dopamine response in human heroin addiction. Brit J Psychiatry 193: PMID:

30 Dopamine and addiction What we know In humans Only stimulants reliably release dopamine (Volkow etc) Dopamine-rich areas esp n accumbens respond to stimulant drugs to drug cues and reward Dopamine promoting drugs eg agonists and L-DOPA in Parkinson s can lead to addictive-like behaviour Dopamine receptor and uptake blockers have little therapeutic value exception = bupropion (Zyban) in smoking

31 Behavioural pattern of drug use predicts effects of dopamine-acting drugs in stimulant users? Behavioural endophenotype a) Behavioral performance b) Task-related brain activation during drug-word Stroop during drug-word Stroop low compulsive stimulant users highly compulsive stimulant users low compulsive stimulant users highly compulsive stimulant users Amisulpride Placebo Pramipexole Ersche and Robbins

32 Possible neurotransmitters Dopamine GABA/gluta mate Loss of control?noradrenaline? Dopamine Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

33 Unlearning addiction? Addiction is a form of learning - Can we unlearn? - Via enhanced glutamate - D-cycloserine D-cycloserine to augment erasure of addiction? Based on anxiety research in rats (Davies) where D- cycloserine can accelerate erasure (overwriting) of fear memories in humans (Ressler) by enhancing glutamate function

34 Our pilot study in Mean AUQ Score alcoholics Watson et al 2011 Mean AUQ Score D- Cycloserine group- craving scores Base line Day 1 Day 2 Day 3 Exp 1 Pre Exp 1 Post Exp 2 Pre Exp 2 Post Exp 3 Pre Exp 3 Post Exp 4 Pre Placebo group- craving scores Day 1 Day 2 Day 3 Exp 4 Post Base line Exp 1 Pre Exp 1 Post Exp 2 Pre Exp 2 Post Exp 3 Pre Exp 3 Post Exp 4 Pre Exp 4 Post

35 Endorphins and opioid receptors Dopamine GABA/gluta mate Loss of control Noradrenaline Dopamine Endorphins Pleasure Reduce suffering Memory impulsivity Meaning Wanting Compulsion Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

36 Endogenous opioids system may be a major aspect of addiction Heroin mu opioid receptor Mu Receptor KO mice have reduced heroin alcohol - cocaine intake (Keifer) Increase in brain opioid receptors in humans (and rats) - Cocaine, opiate and alcohol withdrawal Opioid antagonists naltrexone and nalmefene Reduce heroin use Reduce alcohol relapse Reduce alcohol intake Challenge is getting patients to take them depots

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38 Increase in opiate receptor availability in the brain in early abstinence from alcohol and opiates * Receptor Availability (Vd) Control alcohol dependent opiate dependent n = 28 n = 11 n = 10 Subject Type Bristol studies Williams et al Brit J Psychiatry 2007 ENP 2009 B 11C-diprenorphine * : significantly different to control p<0.05

39 In alcohol dependence opioid receptor PET binding correlates with craving craving score r=0.785 p=0.012 Volume of distribution L Anterior Cingulate R Anterior Cingulate [11C] diprenorphine VD Early withdrawal - Ant cingulate Williams et al 2009 Also in cocaine [Volkow, Zubietta] and opioid dependence [Williams] Total craving score Late withdrawal 3 months?recovery Ant cingulate

40 Nalmefene (mu receptor antagonist) reduces heavy drinking days in alcohol dependence Adjusted change from baseline in monthly HDD (FAS, OC, MMRM) Nalmefene Placebo Adjusted mean and 95% CI * * * * * * Baseline Nalmefene: 19.4 Placebo: 19.6 Month HDD=heavy drinking days; FAS=full analysis set; OC=observed cases; MMRM=mixed-effect model repeated measure; CI=confidence interval Mann et al. Biol Psychiatry Epub ahead of print

41 And improves liver enzyme profiles Study 801 (randomised: 403 patients; nalmefene=242, placebo=161) GGT ALAT Placebo Nalmefene GGT, UI * ALAT, UI * Study month Study month *p<0.05 vs placebo; GGT=Gamma-glutamyl transpeptidase;alat=alanine-aminotransferase Adapted from Karhuvaara et al. Alcohol Clin Exp Res 2007;31:

42 How drugs may work in alcohol dependence Acamprosate Nalmefene/Naltrexone? Decrease pleasure? Reduce loss of control Cues/triggers drink lapse relapse Disulfiram (fear of bad effects) Disulfiram (feel sick) Nutt DJ and Lingford-Hughes A (2008) Addiction: the clinical interface. Brit J Pharmacol 154:

43 Possible neurotransmitters Dopamine GABA/gluta mate Loss of control Noradrenaline Dopamine Endorphins Pleasure Reduce suffering Memory impulsivity Meaning Wanting Compulsion Habit Endorphins 5HT? Dopamine Withdrawal GABA alcohol Multiple drug related

44 GABA Major inhibitory neurotransmitter in brain Receptors are target for alcohol, benzodiazepines, GHB, other sedatives Molecular site of alcohol action is known in 3 rd transmembrane region Jung and Harris 2006 J Neurochem

45 GABA-A receptor subtypes Molecular complexity being unraveled x x x x x x x x What subtypes involved in addiction? McKernan and Whiting x

46 GABA A subtypes - distribution in rat brain Predicted actions of alcohol Sedation, ataxia Anxiolytic Anxiolytic Learning, pleasure, memory impairing actions of alcohol

47 In hippocampus many 5 receptors are extrasynaptic provide tonic inhibition 1 2 5

48 5 Inverse Agonist selectively attenuates 5 GABA A receptor activity X40 5IA G A B A 100nA 90s 5 GABA A receptor % modulation of GABA EC Log [ 5IA] (M) -55 % Whole-cell patch clamp recording in a mammalian cell line nanomolar affinity for the 5 receptor subtype high inverse agonist activity at the 5 receptor subtype little activity at other GABA A receptor subtypes

49 5IA reverses alcohol s amnestic 14 effect in humans 12 number of words recalled Max score = 20 Normal control ~ 8-10 words 2 0 Placebo + alcohol Nutt et al 2007 Neuropharmacology P< IA +alcohol Blood alcohol = ~ 130 mg%

50 Proof of concept of alcohol antagonist Could other effects be blocked by inverse agonists at other GABA-A receptor subtypes? Ataxia Aggression Liking Could GABA enhancers make a safer alcohol? particularly if had antagonist (antidote) Could 5 receptors play an etiologic role?

51 Imaging human - 5 GABA-A receptors 11 C-Ro a selective tracer Note not in the rat accumbens where is 2 N accumbens Anterior cingulate cortex Hippocampus Lingford-Hughes et al 2002 J Cereb Blood Flow Metab

52 5 receptors in human brain highest density in accumbens 12 * * * Controls Alcoholics 7 VD Hippocampus_r Hippocampus_l Amygdala_r Amygdala_l Ant_TL_med_r Ant_TL_med_l Ant_TL_lat_r Ant_TL_lat_l G_paraH_amb_r G_paraH_amb_l G_sup_temp_r G_sup_temp_l G_tem_midin_r G_tem_midin_l G_occtem_la_r G_occtem_la_l Cerebellum_r Cerebellum_l Brainstem Insula_l Insula_r OL_rest_lat_l OL_rest_lat_r G_cing_ant_l G_cing_ant_r G_cing_post_l G_cing_post_r FL_mid_fr_G_l FL_mid_fr_G_r PosteriorTL_l PosteriorTL_r PL_rest_l PL_rest_r CaudateNucl_l CaudateNucl_r NuclAccumb_l NuclAccumb_r Putamen_l Putamen_r Thalamus_l Thalamus_r Pallidum_l Pallidum_r Corp_Callosum FrontalHorn_r FrontalHorn_l TemporaHorn_r TemporaHorn_l ThirdVentricl FL_precen_G_l FL_precen_G_r FL_strai_G_l FL_strai_G_r FL_OFC_AOG_l FL_OFC_AOG_r FL_inf_fr_G_l FL_inf_fr_G_r FL_sup_fr_G_l FL_sup_fr_G_r PL_postce_G_l PL_postce_G_r PL_sup_pa_G_l PL_sup_pa_G_r OL_ling_G_l OL_ling_G_r OL_cuneus_l OL_cuneus_r FL_OFC_MOG_l FL_OFC_MOG_r FL_OFC_LOG_l FL_OFC_LOG_r FL_OFC_POG_l FL_OFC_POG_r Region Lingford-Hughes et al 2010 Journal of Psychopharmacology

53 11 C-Ro binding in n accumbens reduced in alcoholics 13.5 nuc_accumb_l 13.5 nuc_accumb_r VD 10.5 VD Alcoholics Group Controls 7.5 Alcoholics Group Controls L Nuc Accumbens t = 4.18; p < 0.01 Lingford-Hughes et al 2011 Journal of Psychopharmacology R Nuc Accumbens t = 4.23; p < 0.01

54 Addiction is a complex, variable and multifaceted state Different elements with different behavioural and molecular mechanisms New treatments may require a more fine-grained analysis of these factors and clarity of processes across species Personalised treatment may be the best way forward Loss of control Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Withdrawal

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