Title: Brain Science or Sociology, what is the best approach to addiction
1 Brain Science or Sociology, what is the best
approach to addiction?
Yette Boris Glass Foundation Lecture Keele Oct
2007
David Nutt Prof of Psychopharmacology Bristol
University
2Addiction 3 elements
Social factors
Addiction and its treatment
Personal biologicalfactors
Drug factors
Brain mechanisms
3What do people get from using psychoactive
substances?
- Subjective changes
- Pleasure/relief of pain/escape
- Sleep/tranquillity
- Energy
- Empathy/social interactions
- Understanding/insights/meaning
- But .. problems when on and when coming off
4What can neuroscience tell us?
- How and where the drugs work in the brain
- Why they cause addiction/dependence
- Withdrawal mechanisms
- Also promise options for elucidating individual
risk factors e.g. vulnerability genes
5What neuroscience cant tell us! ? Yet?
6Drug-related science
- Kinetics how fast drug get in and out of the
brain - Dynamics what they do in the brain
7Changing cocaine
8Kinetics Speeding up brain entry
Faster brain entry ? more effects ? more
addiction
9Smoking opium 1850s
10Changing morphine
- Brain effects
- fast medium slow
- heroin morphine codeine
- lipophilic ? morphine in brain ? hydrophilic
Mu opioid receptors
Heroin is a prodrug of morphine ?into brain
faster ? a better hit
11Codeine is also a prodrug of morphine
- Brain effects
- fast medium slow
- heroin morphine codeine
- lipophilic ? morphine in brain ? hydrophilic
Mu opioid receptors
Codeine slower entry much less addictive
12Kinetics affect the UK drug class
- Amphetamine sulphate/HCl
- High melting point cant be smoked
- ? Oral intake
- class B unless in ampoules for iv injection
- Methamphetamine HCl
- Low melting point CAN be smoked
- ? faster and stronger brain effects
- more addiction and psychosis ? class A
13Harm is determined by route of use
- i.v. route
- infections (HIV, Hepatitis)
- thromboses
- sudden death (respiratory block)
- smoking (chasing the dragon)
- throat and lung disease
Should we encourage smoking heroin as a a
harm-reduction measure?
14- The search for the perfect route
- Christopher Wren 1665
- Wrens experiments were described in the
proceedings of the Royal Society. He injected a
dog with opium into a vein in the leg.
15Samuel Pepys, May 16th. 1664
- We to see an experiment of killing a dog by
letting opium into his hind leg. He and Dr.
Clerke did fail mightily in hitting the vein,
and in effect did not do the business after many
trials but with the little they got in and the
dog did presently fall asleep.
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19Spot the diagnosisiv injecting started 1920s
probably by accidentally hitting a vein when
injecting subcut
The Times 20th March 2000
20Time course of heroin effectsshort half-life
highs and withdrawal.
High
Withdrawal
21Each i.v.heroin injection can kill
Reduction in blood oxygen after heroin injection
22Methadone time course and action to block on
top heroin
Slower and lower high
High
Longer action
Effect
W/drwl
Time
24
48
(hours)
23Buprenorphine heroin long half life of
bup ? prolonged cover
Effect
normal
24
48
Time (hours)
Heroin weekend Buprenorphine 2-4mg
Buprenorphine 8-16mg
Buprenorphine stops on top heroin use
24Pharmacology of addiction - dynamics of drug
action
- Molecular mechanisms of most abused drugs now
understood - Leads for new treatment targets
- and ? understanding of genetic predisposition and
risk factors
25Neurotransmitters synapse and receptors
26Table 1. Molecular targets of drugs of abuse
? Inc Dopamine
27Imaging brain receptors in addiction
PET scanning
intravenous injection of radiotracer
28GABA-A receptors site of action of alcohol
and explanation of adaptation/tolerance
Human brain PET images 11C-flumazenil
healthy control alcohol
dependence
29Human Mu receptors - 11CCarfentanil
5
1
30Buprenorphine dose-dependently blocks mu
receptors - stops on-top use
Zubieta et al Neuropsycho- pharmacology
23326334, 2000
- Control and a matched heroin-dependent volunteer
- (placebo BUP 0, on BUP 2mg and on BUP 16mg
sublingual) - Occipital cortex BP 1 (no mu opioid receptors)
31Increase in opiate receptor availability in the
brain in early abstinence from alcohol and
opiates.
B
significantly different to control plt0.05
Control alcohol dependent opiate
dependent n 28 n 11
n 10
Bristol studies Williams et al Brit J
Psychiatry 2007
32Altered opioid receptors may be a major aspect of
addiction
- Evidence for increase in brain receptors in
humans (and rats) during - Cocaine withdrawal NIDA
- Opiate withdrawal Bristol
- Alcohol withdrawal Berlin, Bristol
- May reflect more receptors
- Or less endorphins
- May explain why treatments such as naltrexone and
nalmefene work - ? reset this
33Dopamine and addiction The midbrain dopamine
system may be a common drug reward system
Planning and control
Movement Basal ganglia (Parkinsons)
Frontal lobes
DA
Reward learning Drug abuse
Adapted from Stefan et al
34Dopamine receptor number may explain which humans
enjoy cocaine?
35Dopamine receptors in addiction
Low D2 receptors
Increased pleasure from abused drugs
36Drug abuse especially stimulants and alcohol
downregulates dopamine receptors
Low D2 receptors
Increased pleasure from abused drugs
Drug abuse
37Dopamine can help explain social aspects of
addiction also
genes
Low D2 receptors
Increased pleasure from abused drugs
Drug abuse
Environment e.g. early deprivation
38Social dominance in monkeys dopamine D2
receptors and cocaine self-administration
Morgan, et al. 2002.
39Where in the brain is addiction localised?
- Different areas of the brain subserve different
functions - PET/SPECT and fMRI scanning can now test these
theories
40Regional increases in brain glucose metabolism
associated with cocaine craving Grant et al
(1996) Proc. Natl. Acad. Sci. USA, 9312040-12045
41Brain reactions to drug stimuli
Increase in rCBF in anterior cingulate gyrus and
amygdala Video stimuli of cocaine related images
or nature video Changes also found in temporal
pole and orbito-frontal cortex
Childress et al. (1999) Am. J. Psychiatry
42Brain activation to opiate stimulus in heroin
addicts
Region of activation covering left anterior
cingulate and medial pre-frontal gyri All
subjects (n12) Activation centered on Talairach
co-ordinates -10,46,24 mm Peak t 4.52 (plt0.005)
Daglish et al Am J Psychiatry 2001 158 1680-1686
43Brain activation related to craving
- Region of activation in left orbito-frontal
cortex - Subjects who craved during the experiment (n8)
- Peak t 5.19 (plt0.05 corrected for multiple
comparisons)
Daglish et al Am J Psychiatry 2001 158 1680-1686
44Brain regions of addiction
- Same as those involved in other processes
- Anterior Cingulate ? arousal and attentional
processes - Orbitofrontal cortex ? response/impulse control
and motivational learning
45Brain regions of addiction
- Same as those involved in other processes
- Anterior Cingulate ? arousal and attentional
processes - Orbitofrontal cortex ? response/impulse control
and motivational learning - Theory addiction is excessive activation of
normal functional behavioural circuits
highjacked by drugs -
- More rather than different
46Brain changes are long lasting
- The size of effect in L Anterior Cingulate
increases with longer abstinence - Daglish et al 2001
47The future of addiction science scenarios
2025The following will happen or be available
(from the Foresight report)
- Total genome sequencing at birth ? genes for
- Vulnerability to addiction
- Treatment response
- Adverse effects ? safer use of recreational
drugs?
48Genetic polymorphisms can predict drug actions
and consequences
Cognitive effects of amphetamine
Ecstasy abuse
5-HT transporter ss alleles associated with
depression
Roiser, et al 2005 Am. J. Psychiatry
49The COMT gene predicts the effect of amphetamine
on cognitive flexibility
Cognitive effects of amphetamine
Ecstasy abuse
val/val ? faster metabolism Less dopamine
Mattay et al 2003 PNAS
50Cannabis psychosis and COMT genotypeCaspi et al
2005 Biological Psychiatry
Percentage of individuals meeting diagnosed with
schizophreniform disorder at age 26 NB
schizophrenia diagnostic rates 1
51Issues with the Caspi paper
What protects the remaining 86?
Only 6 people
? Protective if never use
? No effects in older group
52Is COMT important?
- COMT variants differ in a number of ways
- val/val more exploratory met/met more
cautious ?warrior v- worrier phenotypes - val/val less pain sensitive ? as release more
endorphins
53Effect of COMT val158met genotypes determine
endorphin release to pain
Zubieta et al., Science, 2003
54COMT Genotype predicts effects of Nicotine
Replacement Therapy
Off NRT
On NRT
Met/met
Val/val
Munafò et al. (in press)
55Scientific scenarios 2025The following will
happen or be available
- Total genome sequencing at birth ? genes for
- Vulnerability to addiction
- Treatment response
- and adverse effects ? safer use of recreational
drugs? - Understanding molecular processes of learning and
memory - ?potential for unlearning treatments for
addiction
56Potential addiction treatmentsfrom other
research areas
- New learning anti-learning drugs
- e.g. D-cycloserine other glutamatergic agents
Cognitive Enhancers as Adjuncts to Psychotherapy
Use of D-Cycloserine in Phobic Individuals to
Facilitate Extinction of Fear
Augmentation of Exposure Therapy With
D-Cycloserine for Social Anxiety Disorder
Ressler et al 2004
Hofmann et al 2006
57Potential addiction treatmentsfrom other
research areas
- New learning anti-learning drugs
- e.g. D-cycloserine other glutamatergic agents
Cognitive Enhancers as Adjuncts to Psychotherapy
Use of D-Cycloserine in Phobic Individuals to
Facilitate Extinction of Fear
Augmentation of Exposure Therapy With
D-Cycloserine for Social Anxiety Disorder
Ongoing trials in alcohol and nictoine dependence
Ressler et al 2004
Hofmann et al 2006
58Scientific scenarios 2025The following will
happen or be available
- Total genome sequencing at birth ? genes for
- Vulnerability to addiction
- Treatment response
- and adverse effects ? safer use of recreational
drugs? - Understanding molecular processes of learning and
memory - ?potential for unlearning treatments for
addiction - Vaccines against most addictive drugs
59Targeting the Drug Rather Than the Brain
60Targeting the drugs, not the receptors
Capillary Blood Flow
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62Blood
Brain
63Effects of Antibody Titer onBrain Nicotine
Concentration
1.5
Two nicotine vaccines in phase 3 trials
Serum Antibody Concentration (ELISA O.D.)
1.0
150
100
50
Brain Nicotine (ng/g)
64Vaccination against cocaine
- Phase 2 trials for cocaine
- reduced cocaine ve urines (Martell et al 2005)
- Feasible for most other drugs
65Immunogen for Active Vaccination
Linker
Carrier Protein
Abused drug
- Drug abusers dont have antibodies to abused
drug - Abuse of drug wont boost or maintain antibody
titers - Boosting requires administration of immunogen
-
66Vaccination issues
- Addicts
- High risk groups
- genes/family history/behaviour?
- Children protection from birth ???
67Scientific scenarios 2025The following will
happen or be available
- Total genome sequencing at birth ? genes for
- Vulnerability to addiction
- Treatment response
- and adverse effects ? safer use of recreational
drugs? - Understanding molecular processes of learning and
memory - ?potential for unlearning treatments for
addiction - Improved imaging modalities resolves brain
circuitry of pleasure and addiction ?
intermediate brain phenotypes ? predicts
addiction vulnerability and treatment response - Vaccines against most addictive drugs
- After dependence established - ? As preventative
measure - New molecular targets ? new drugs? will
industry care, be encouraged to develop them?
68alcohol
Drug harm ranking
tobacco
Nutt et al Lancet 2007
69Social policy may have perverse effects
70Can we reduce the harms of alcohol?
In UK 1 death per day from alcohol poisoning,
3 with other drugs 5 from alcohol-related
RTAs
Nutt 2006 Journal of Psychopharmacology editorial
71How does alcohol work?
- Alcohol actions now becoming understood
- Enhances brains natural inhibitory
neurotransmitter GABA to calm the brain - And blocks glutamate excitation
- ? double whammy of excess sedation
anaesthetic
72 There are a large number of GABA-A receptor
subtypes in brain
GABA-A subunits family tree
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73GABAA subtypes - distribution in the brain
74Imaging human - a5 GABA-A receptors 11C-Ro
15-4513 - a selective tracer
Anterior cingulate cortex
Hippocampus
Lingford-Hughes et al 2002 J Cereb Blood Flow
Metab
75a5 Inverse Agonist selectively attenuates a5
GABAA receptor activity
a5IA
GABA
a5 GABAA receptor
- Whole-cell patch clamp recording in a mammalian
cell line - nanomolar affinity for the a5 receptor subtype
- high inverse agonist activity at the a5 receptor
subtype - little activity at other GABAA receptor subtypes
76?5IA reverses alcohols amnestic effect in humans
Max score 20 Normal control 8-10 words
Blood alcohol 130 mg
Plt0.001
Nutt et al 2007 Neuropharmacology in press
77Proof of concept of alcohol antagonist
- Could other effects be blocked by inverse
agonists at other GABA-A receptor subtypes? - Ataxia
- Aggression
- Liking
- Proves alcohol acts through the GABA-A system - ?
different subtypes ? different effects
78Could GABA enhancers make a safer alcohol ?
- Probably
- ? less liver/heart/brain toxicity
- - less aggression/ incoordination
- - reversible (antidote)
- But - who would do this since would need to be
licensed as a drug not a a foodstuff and no
illness to treat!
Nutt DJ. J Psychopharmacology 2006 commentaries
79Harm reduction approaches In USA increase in
drinking age from 18-21 over last decade has
saved 170,000 lives from RTAs
80A start in the harm reduction direction for the
UK?
Low alcohol beers/lagers used to reduce
intoxication in some countries E.g. Sweden,
NL See Nutt 2006 and Room 2006 Journal of
Psychopharmacology
81Fashion the most powerful means of social
change 1950s Quote from senior civil servant
it would be inconceivable that the Prime Minister
could be seen in public without a cigarette Why?
urbane, sophisticated, in the mode,
normal! 2000s Would be electoral suicide ..
dirty habit, lack of self-control, an addict!
82Credits The UK Foresight Brain Science
Addiction and Drugs project 2006