1 From Brain Mechanisms to New TreatmentsAddiction: From Brain Mechanisms to New Treatments SSA York 2016 David Nutt FMedSci Edmond J Safra Professor of Neuropsychopharmacology Imperial College London

2 Health Warning: Please don’t lie about my research and funding

3 Triangulating addictionSocial factors Addiction Personal biologicalfactors Drug factors Brain mechanisms

4 Elements of addiction Pleasure Wanting Memory Reduce suffering MeaningLoss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Meaning Habit Withdrawal Nutt: Drugs without the hot air

5 Elements of addiction Pleasure Wanting Memory Reduce suffering MeaningLoss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Meaning Habit Withdrawal I tried to drown my sorrows in alcohol, but they learned to swim - Frida Kalho

6 Elements of addiction Tatum O’Neal Pleasure Wanting MemoryLoss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Meaning Habit Withdrawal The only time I felt whole was on heroin Tatum O’Neal

7 Possible neurotransmittersNoradrenaline Dopamine Endorphins Dopamine GABA/glutamate Loss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Habit Meaning Dopamine Withdrawal Endorphins 5HT? Multiple – drug related Nutt: Drugs without the hot air

8 Stopping use? Endorphins 5HT? Dopamine Wanting ?NoradrenalineGABA/glutamate Loss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Habit Meaning Dopamine Withdrawal Endorphins 5HT? Multiple – drug related

9 Stopping use Block the drug getting to its binding siteAntagonists - 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 Sodium oxybate, baclofen for alcohol Varenicline for tobacco

10 Dopamine: The midbrain dopamine system may be a common reward system for stimulants – but ? other drugs Movement Basal ganglia (Parkinson’s) Planning and control Frontal lobes Reward learning Drug abuse DA Adapted from Stefan et al

11 For stimulants dopamine = reward Volkow et al 1999concelt that increasesin DA in nucleus accumbens are key to reinforcing effects of psychostimulants Increases in dopamine in limbic regions has been hypothesised to underlie the reinforcing effects of psychostimulant DAT knockout mice still find cocaine and MP reinforcing though lots in animal studies that activation of DR are impt not in humans - impt since drug development targeted to this healthy controls but used dose of MP which cocabusers said = cocaine 0.025, 0.1, 0.25, all reduced raclo binding intensity of high sign correlated with DA released - only sign at highest doses MP induced changes in D2 receptors availability were sign correlated with MP-induced changes in high for DAT study : lack of high is due to not enuf increase in DA if decrease raclo bing by 15% get a high regardless of dose of MP given so occupanych of D2 recpetos is better indication than DAT blockade MP will be dependent on dopamine cell firing thus is a relationship between high, release of DA Volkow et al 1999

12 But not all drugs release dopamine Heroin 50mg i. vBut not all drugs release dopamine Heroin 50mg i.v. gives a good “high” 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:

13 But there is NO release of dopamineNo difference in 11C-Raclopride binding +/- opiate agonist & to controls 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:

14 Not all drugs of abuse result in detectable increases in dopamine in manNutt et al Nature Reviews Neuroscience 2015

15 Dopamine and human addiction What we can be sure ofOnly stimulants reliably release dopamine (Volkow etc) Dopamine-rich areas esp n accumbens respond to stimulant drugs + their drug cues and reward - why ?motivation Dopamine promoting drugs eg agonists and L-DOPA in Parkinson’s can lead to addiction-like compulsive behaviour Dopamine receptor and uptake blockers have disappointingly little therapeutic value  exception = bupropion (Zyban) in smoking

16 Dopamine and addiction- other roles?So – dopamine for reward? – no or anticipation? – no or habit? - probably or impulsivity/compulsivity? - maybe Or something else ? urges/motivation/excitement/mood ? psychotic experiences

17 No change in DRD2 binding but lower receptor number predicts “urges”Controls Gamblers Controls Gamblers No change in DRD2 binding but lower receptor number predicts “urges” r=-.87, p=.005 (partialling for age) r=-.88, p=.004 (partialling for age)

18 Imaging opioid receptors in addictionDensity of brain receptors in relation to symptoms Measuring endorphin release

19 Increased mu opioid receptors in alcoholism and correlation with craving Alcohol-dependent patients (left ventral striatum) 35 30 25 20 15 10 5 Craving (OCDS) 1.2 1.4 1.6 1.8 2.0 2.2 2.4 Opiate receptor availability (V3”) r=0.55, p=0.04

20 * : significantly different to control p<0.05Increase in opiate receptor availability in the brain in early abstinence from alcohol and opiates. * B * : significantly different to control p<0.05 Morphine – red delta in nuc acc / striatum Ethanol reduces mu in nuc acc & striatum. Turchan Get both down & up relgaulation seen Chen finds decreased mu opioid receptor funcx with alcohol NB not same as recepotrs - Increased in nuc acc & putamen – cowne – fawn-hooded. Control alcohol dependent opiate dependent n = n = n = 10 Bristol studies Williams et al Brit J Psychiatry 2007

21 Alcohol consumption induces endorphin release in the human orbitofrontal cortex and nucleus accumbens Left In non-dependent alcohol drinkers following alcohol consumption (~24 g) p<0.001; n=25; P=posterior; A=anterior Mitchell et al. Sci Transl Med 2012;4(116):116ra6

22 Endorphins theory of addictionStimulants  dopamine (? Gambling) Alcohol  endorphins Heroin  mu receptor stimulation reward /loss of control  addiction X

23 Endorphins theory of addictionStimulants  dopamine (? Gambling) Alcohol  endorphins Heroin  mu receptor stimulation reward /loss of control  addiction X X Nalmefene and naltrexone block this in alcoholism

24 Memory neurotransmitters?Noradrenaline ? Dopamine Dopamine GABA/glutamate Loss of control Pleasure Compulsion Memory impulsivity Wanting Reduce suffering Habit Meaning Dopamine Withdrawal Endorphins 5HT? Multiple – drug related

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

26 Imaging human - a5 GABA-A receptors 11C-Ro a selective tracer Anterior cingulate cortex N accumbens Note – not in the rat accumbens where is a2 Hippocampus Lingford-Hughes et al 2002 J Cereb Blood Flow Metab

27 11C-Ro15 4513 binding in n accumbens reduced in alcoholicsAnd in heroin addicts too May  loss of control when confronted with or use drug One-tailed t-tests of the hippocampi. Graphs show mean and spread. As expected, control groups have greater means and a smaller spread. The right hippocampus reaches significance at p<0.05, but the left does not quite. With the same means and SDs, a power analysis shows that only a small number (perhaps 3) more subjects in either group would mean significance in the left hippocampus. L Nuc Accumbens t = 4.18; p < 0.01 R Nuc Accumbens t = 4.23; p < 0.01 Lingford-Hughes et al Journal of Psychopharmacology

28 Abstinence is not enoughAmy Winehouse’s death due to acute alcohol poisoning in relapse Blood alcohol 450 mg/% = 5.5 x legal driving limit

29 Philip Seymour Hoffman Feb 2014Relapse after 23 years abstinence Philip Seymour Hoffman Feb 2014

30 How to prevent relapse? = The ICCAM Platform New Drugs to Treat Addiction: Can a Knowledge of Brain Mechanisms Help? Imperial College London: David Nutt (PI), Anne Lingford-Hughes, Laurence John Reed, Louise Paterson and John McGonigle Cambridge University: Trevor Robbins, Barry Everitt, Ed Bullmore, Karen Ersche, Jeff Dalley and Franklin Aigbirhio Manchester University: Bill Deakin, Rebecca Elliott and Anna Murphy. Imanova: Ilan Rabiner and Rexford Newbould GSK: Pradeep Nathan

31 ICCAM Platform – Mechanisms of RelapseReward Sensitivity Response Inhibition Network (fMRI) Emotional Responses Assessment Candidate Target  Antagonist Naltrexone Dopamine D3 Antagonist Neurokinin 1 Antagonist Placebo Preclinical Spontaneously Impulsive Model Paterson et al 2015 Journal of Psychopharmacology

32 Anticipation of reward Monetary Incentive delay taskventral striatum Cue Delay Target Feedback ITI Cue 8 - 12 seconds Reward > neutral Z > 4

33 X Y X Y Y X Y X X   Impulsivity: Go/No-go Task putamen Inferiorfrontal gyrus X Y X Go Y Go Y Go  No-go > go Z > 5 X No-go Y Go 1 second trials X Go X Go  No-go

34 Emotional processing taskSelected neutral and aversive images from IAPS - did not choose any images with alcohol/drug Neutral + Aversive + amygdala Aversive > neutral Z > 4

35 Nalmefene and MID task during alcohol intoxication fMRISignificant decrease in globus pallidus and putamen and in brain stem Nutt and Lingford-Hughes – in prepn

36 Pleasure Wanting Memory Reduce suffering Meaning Habit WithdrawalAddiction is a complex, multifaceted and enduring 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 Compulsion Memory impulsivity Wanting Reduce suffering Meaning Habit Withdrawal

37 Thanks and questions Further readingAll proceeds to DrugScience.org.uk Follow me on twitter