Module 3 - Addiction Flashcards
What are the alcohol recommendations?
Men : 3-4 units/d Women : 2-3 units/d >2 alcohol free days 2016 UK advice: Men & Women : 14 units/week Binge : 2x daily guidelines men : 8+ women : 6+
What is harmful substance use?
Actual damage should have been caused to the mental or physical health of the user in the absence of diagnosis of dependence syndrome.
Addiction more likely if faster onset/faster brain entry of drug.
What is dependence syndrome?
A strong desire or sense of compulsion to take the substance
Difficulties in controlling substance taking behaviour in terms of its onset, termination, or levels of use
A physiological withdrawal state when substance use has stopped or been reduced
Evidence of tolerance: need to take more to get same effect
Progressive neglect of alternative interests
Persisting with substance use despite clear evidence of overtly harmful consequences
DSM-5: a continuum between abuse and dependence called substance use disorder
Kohn 2004 Less than 10% patients with alcohol dependence are treated.
What are the different models of addiction?
Incentive –Sensitization Model (Robinson and Berridge, 1993)
Addiction renders systems hypersensitive (“sensitized”) to drugs and drug-associated stimuli via the Mesolimbic dopaminergic system.
These sensitized systems mediate a component of reward termed incentive salience or “wanting” (not pleasure or “liking”). The cue becomes overvalued and resistant to devaluation: a “motivational magnet” that activates a “hedonic hotspot”.
Drug-induced sensitization of brain systems (DA) that mediate incentive-salience causes drugs and drug-associated stimuli to become compulsively “wanted”
The activation of the sensitized system can occur both implicitly or explicitly. Challenges: Applied to stimulants primarily and Harder to show in man
Physical dependence - negative reinforcement
Some drugs produce physical dependence and withdrawal symptoms upon cessation of drug-taking.
Withdrawal symptoms are produced by the body in order to compensate for the unusual effects of the drug. Withdrawal symptoms are generally the opposite of the effect produced by the drug. Addicts continue to use drugs in order to avoid withdrawal. Over time, drugs no longer have the same rewarding effects - they merely allow the person to feel “normal.”
BUT not all abused drugs generate withdrawal symptoms (cocaine, amphetamine).
Different drugs produce different withdrawal symptoms with different neural bases.
Once dependent you should continue taking drug, but people spontaneously stop.
Once drug-abstinent and withdrawal symptoms gone, users should not relapse, but they do.
No explanation as to why people take drugs in the first place.
Volkow’s diagram between control, drive, reward and memory and output.
Another Volkow diagram: addicted brain has less activity of the anterior cingulate cortex, inferior prefrontal cortex and lateral orbiofrontal cortex andmore activity int he medical orbitofrontal cortex. The medial OFC increases glutamate to the nucleus accumbens and ventral tegmental area. From here, there is reduced DA to the ACC, inferior PFC and lateral OFC and less GABA to the dorsal striatum and motor cortex (so there is increased output).
The final component is from the amygdala and hippocampus. The activity here is also increased, with more glutamate, corticotrophin-releasing factor, NA, and kappa receptors for the NAcc and VTA. These regions are involved with binge/intoxication, withdrawal/negative affect and preoccupation/anticipation. Also voluntary to habitual use of drugs (Everitt)
Discuss how the dopaminergic system is affected by drugs of abuse:
Hijacked by some, including alcohol and nicotine. But not opioids, THC.
DA release by amphetamine almost 7x that of food, 5x of sex. Nicotine and morphine are similar to levels for sex, cocaine is 2x food.
Alcohol, opiates, nicotine increase dopamine neuron firing in VTA
Cocaine, Amphetamine
block reuptake
but amphetamine enhances release of DA too.
Increases in dopamine levels in striatum are associated with reinforcing effects of stimulants in man.
Volkow - Modafinil increased DA activity with no changes in behaviour.
Hypothesised that low levels of D2 receptors predispose subjects to use drugs
genetic data is controversial
involvement of D2 receptors levels in reinforcing responses to drugs in man also not demonstrated BUT is in Volkow 1999
Eg. Morgan 2002 separate monkeys and then together - subordinate monkeys took more cocaine (statistically significant) initially, over 1 year they became more similar in habits. Environmental risk>D2 binding?
We also found that, over a 1-year period in which cocaine intake increased steadily, D2 receptor availability decreased irrespective of what the initial levels of D2 receptor availability were for each monkey (figure 1b). Nader 2006
Highly impulsive rats have lower D2/D3 receptors – particularly in ventral striatum and consume more cocaine Dalley 2007. More self-administration but Impulsivity does not predict acquisition or heroin self-administration, its escalation or relapse after extinction McNamara.
Monkeys with shorter latency are assumed to be more impulsive and were quicker to approach novel objects. These monkeys then became subordinates.
What happens when the dopaminergic system is continuously or often stimulated by drugs, the brain gets depleted in dopamine and dopaminergic function is reduced.
associated with irritability, low mood - Reduced DRD2 cocaine, methamphetamine, alcohol.
Overall reduction: 10% in Alcohol and 12% in Cocaine studies.
And show blunted amphetamine induced dopamine release
NB: for opioids, nicotine, cannabis – robust consistent reductions in dopamine receptor levels have NOT been found.
decreased DA brain function in addicts - reduced baseline DA flow
decreased DA responsiveness would make cocaine less reinforcing - did get less of a high than in normals
the blunted response to Mp in cocaine addicts does not support an enhancement of DA release involved in reinforcing effects of cocaine in man
thalamus is part of relay between orbitofrontal cortex and nucleus accumbens Volkow 1999
Amphetamine-induced DA release blunted in cocaine addicts and “high DA transmission is associated with treatment response”
Martinez 2007
11C-PHNO binding: no differences between control & alcohol dependent groups except increase in hypothalamus Erritzoe 2014
Stimulant and Gambling: Correlations implicate D3 receptor levels in motivation, impulsiveness and risky decision-making
Schulz - if there is a cue, more DA to cue and if there is no reward after the cue, DA neuronal firing decreases.
Cocaine cues increase dopamine levels in the dorsal but not ventral striatum Volkow
What imaging is available for addiction?
fMRI exploits changes in magnetic properties of the blood - BOLD signal is the ratio change in oxyhaemoglobin to deoxyhaemoglobin in the venous blood vessels of the brain (indirect measure of neuronal activity) (More oxyhaemoglobin leads to less dephasing and more signal)
PET: glucose metabolism decreased in cocaine user
MAO B decreased in smoker
DA transporters decreased in meth user
Raclopride: D2 receptors decreased in cocaine -> fewer receptors available and therefore more used and more DA activity.
Mitchell 2012 - alcohol also releases endogenous opioids (in orbitofrontal cortex and nucleus accumbens and ventral striatum.) (reduces
11C-carfentanil
binding in PET)
MRI - alcohol damaged brain show some atrophy and enlarged ventricles.
Magnetic Resonance Spectroscopy (Hermann) - excessive central glutamate and after lorazepam/diazepam treatment for 2 weeks, glutamate levels back to healthy controls.
Magnetic Resonance Spectroscopy - Acamprosate did the same (Umhau)
11C-DASB- and 18F-altanserin-PET for MDMA and serotonin receptor 2A and SERT.
fMRI: Neural Activation Patterns of Methamphetamine-Dependent Subjects During Decision-Making Predict Relapse Paulus 2005 and Attenuated Insular Processing During Risk Predicts Relapse in Early Abstinent Methamphetamine-Dependent Individuals Gowin 2014
fMRI Response to Alcohol Pictures Predicts Subsequent Transition to Heavy Drinking in College Students Dager 2014 (compared with other risk factors (e.g., alcoholism family history, impulsivity), BOLD response best predicted escalating drinking amount and alcohol-related problems)
How does GABA and opioids interact with DA?
Opioids inhibit GABA which inhibits DA.
GABA neurotransmission in VTA is via:
GABA-B receptor
Substances release natural endorphins (also released by exercise) which inhibits GABA so more DA firing. Opioid antagonists, eg. naltrexone, prevent DA firing.
Colasanti - amphetamine releases endogenous opioids. Mitchell 2012 - alcohol also releases endogenous opioids (in orbitofrontal cortex and nucleus accumbens and ventral striatum.) (reduces
11C-carfentanil
binding in PET)
Heinz 2005 - In alcohol dependence: increased opioid target/receptor availability is associated with greater craving for alcohol.
Not found in alcoholics abstinent for longer but do have blunted amphetamine induced opioid/b-endorphin release
No difference in opioid receptor availability in pathological gamblers Mick 2015 but did see blunted beta-endorphin.
Associated with impulsiveness (Love) and social play and stress.
Stress results in activation of hypothalamic-pituitary-adrenal axis and rise in cortisol.
Opioids modulate hypothalamic function and B-endorphin is released by pituitary with ACTH.
What pharmacotherapies are available for alcohol dependence?
Malcolm 2000 - multiple previous detoxifications associated with less responsive treatment and cognitive impairment Duke 2003
Substitution - benzodiazepines.
DA-ergic agonists (eg. bromocriptine, disulfiram (inhibits aldehyde dehydrogenase so there is a build up of acetaldehyde and nausea, vomiting, flushing, headache, palpitations, hypotension, but not if psychosis, severe liver or cardiac disease or epilepsy, also increases DA by inhibiting DA-beta-hydroxylase and therefore NA reduces), methylphenidate, amphetamine, bupropion (DAT reuptake blocker) to reduce dysphoria and irritability.
Withdrawal - Benzodiazepines reduce signs and symptoms of withdrawal +/- acamprosate. Carbamazepine (glutamatergic anticonvulsant) as alternative to benzodiazepine.
Abstinence -
Acamprosate (taurine derivative) is a partial agonist at the modulatory site and reduces NMDA activity via AMPA and mGluR5. Increases abstinence rates by double to <40% after 1 year. As effective as naltrexone (Jonas 2014)
D2 antagonists, eg. antipsychotics, to prevent ‘high’
Baclofen is typical GABA-B agonist which has been shown to improve abstinence rates in alcohol dependence (reduces self-admin of cocaine, cues, alcohol, heroin (Xi) Lots of RCTs show varied results, eg. BACLAD (68% vs 24% placebo) and ALPADIR (11.9% vs 10.5%)
Other drugs that increase GABA levels have similar effect
Tiagabine, vigabatrin, gabapentin, topiramate
Naltrexone (opioid antagonist) also used in pathological gambling, self-injurious behaviour, binge eating, kleptomania, compulsive sexual behaviour. (best in those with anxiety) Nalmefene (mu opiate antagonist, kappa partial agonist, blocks increase in kappa activity in dependence, reducing dysphoria, etc.) reduces drinking while drinking, as needed. Mann 2013
To prevent harm -
Vitamins, nutrition, neuroinflammation, reduce sharing of needles.
How does alcohol work on a molecular level?
Dopamine: mood altering, euphoria, positive reinforcement, craving. Low levels of DRD2 seen in stimulant & alcohol addicts.
Release of dopamine – blunted to none.
Can get ‘high’ without detectable increase in dopamine
Opioid: positive reinforcement, euphoria, craving
GABA-Bdz/GABA-A: ‘agonist’ : sedation, anxiolytic, amnesia, ataxia
Glutamate: NMDA ‘antagonist’, sedation, amnesia, withdrawal
a5IA (inverse agonist) reverses the alcohol induced impairment because stops GABA-A from decreasing memory. Nutt 2007
In the acute setting, it allows more Cl- through GABA-A receptors and antagonises NMDA to reduce Ca2+ flux excitation.
In chronic: NMDA receptors are upregulated (this is associated with memory impairment)
the GABA-A receptors become less efficient at allowing Cl- through.
This is from tolerance, but acutely drinking reverses the chronic effects temporarily.
Withdrawal:
Increased activity in NMDA receptor and Ca2+ influx via L-subtype Ca2+ channels -> hyper-excitability cell death. There is overall decreased GABA-ergic activity and decreased inhibition by the Mg2+ of the NMDA receptor.
Hermann - excessive central glutamate and after lorazepam/diazepam treatment for 2 weeks, glutamate levels back to healthy controls and acamprosate (Umhau)
In abstinent, still have cognitive function issues and showed morphological changes that were highest in the dorsolateral prefrontal cortex (DLPFC) of up to 20% but were noted also in the temporal cortex, insula, thalamus, and cerebellum.
What are the drug therapies for opiate addiction?
Substitution - Blocks “on top” heroin.
Full opioid agonist.
Buprenorphine is a partial mu agonist (kappa antagonist) with a long half life and prolonged cover.. No/less risk of fatal respiratory depression. Less dysphoria.
Zubieta 2000 - at 16mg, all mu opioid receptors occupied.
Melichar - no reduction in availability of opioid receptors in presence of methadone.
Why substitution? stop street use & reduces crime
reduce iv risks - stop HIV
keep in health care => psychosocial treatment
easier w/drawal when ready - flexible dosing
Withdrawal - mydriasis, restlessness, diarrhoea, dysphoria, insomnia, noradrenergic storm -> tachycardia, piloerection, sweating, rhinorrhoea, shivering because opioid inhibits conversion of ATP to cAMP so upregulation of the enzyme if chronic use and then when stop there is excessive NA.
Lofexidine for detoxification
Naltrexone for relapse prevention.
What drugs are available for cocaine, amphetamine, etc addiction?
Trials but nothing recommended.
Eg. Methylphenidate Enhances ACC Functioning and Reduces Impulsivity in Cocaine Addiction Goldstein 2010
Modafinil Improves Learning in Methamphetamine Dependence by Enhancing Neural Functioning Ghahremani 2011
What is a drug?
“a chemical which when taken produces physiological changes” - Nutt
Depressants
alcohol
opioids
benzodiazepines – barbiturates
GHB – GBL – Butanediol
ketamine
Stimulants
cocaine – crack
amphetamine – metamphetamine
MDMA - BZP
Psychedelics
LSD – psylocybin [mushrooms]
salvinorum
Cannabis
Class A medicine: opioid, methamphetamie, IV amphetamine
Class B medicine: Amphetamine, barbiturates, ketamine
Class C medicine: Benzodiazepines, GHB, buprenorphine, steroids, growth horme
Class A not currently medically recognised: cocaine, MDMA, LSD, psilocybin (crack cocaine never medical)
Class B not currently medically recognised: cannabis
Class C not currently medically recognised: clenbuterol (benzylpiperazine never medical)
A B C
possession 7 5 2 yrs
supply etc life 14 14 yrs
What are the possible harms caused by drugs?
Acute focal harm to self: Vomiting, Boerhaave, choking, death (alcohol), infection, skin popping (heroin)
Acute systemic harm to self: Infection, respiratory depression (opiates), hypothermia (ketamine, alcohol), hyperthermia (MDMA), cerebral oedema (MDMA), hyponatraemia (MDMA), confusion/delirium (ketaine), paranoia/delusional states (cannabis, cocaine, metamphetamine), anxiety attacks (all)
Chronic focal harm to self: Septum (cocaine), amphetamine tooth loss
Chronic systemic harm to self: withdrawal/dependency, cystic bladder (ketamine), Wernicke’s (alcohol), peripheral neuropathy (alcohol), malnutrition, liver disease/cirrhosis (khat and alcohol), hepatitis (MDMA), MI, stroke (cocaine, cocaethylene),
Harm to society: STI spread from date rape, foetal alcohol syndrome, disability in under 24yo (alcohol), most common reason for death in men <50yo, A&E admissions, £3 billion cost
What are the overall trends for cannabis and schizophrenia rates?
Hickman 2007: 20x increase cannabis users over last 40 years (Offending, Crime and Justice Survey, sample of approx. 10000, 74% response rate)
Frisher 2009 - schizophrenia hasn’t changed much in the last 20 years.
To prevent one case of schizophrenia one would have to prevent 5000 young men from ever smoking cannabis
Describe the effects of MDMA:
60-120mg
• Increased energy
• Euphoria emotional warmth (better relationship with therapist? Oehen 2013)
- positive memories are more vivid and and positive and emotional and no difference in recalling worst memories compared to placebo.
• Empathy toward others
• Distortions in sensory and time perception
• Paranoia
Acute administration of MDMA in ecstasy users decrease the accuracy of facial fear recognition (Bedi 2010), attenuates responses to threatening faces in the amygdala (Bedi 2009), and enhances responses to happy expressions in the ventral striatum (Bedi 2009).
Recall and tolerance of traumatic memories increase (Oehen 2013) - 12 patients, not statistically significant if use clinician-administered PTSD Scale but is if patient reported questionnaire
PTSD trials relatively successful (Miethofer 2013)
Holland, 2006: 1580 subjects from childhood to early adulthood, 14 year period; Confirmed that childhood anxiety and depression preceded later use of E (Huizink et al, 2006) BUT Canada, 2012: 3880 10th grade students (15 y old) followed up after 1 year; Both MDMA use (OR 1.7) and meth/amphetamine use (OR 1.6) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. (Briere et al, 2012)
Some studies have found that correction for sleep deprivation and disturbances removes the statistically indentified MDMA-intake related negative impact on mood (Scott 2013; Pirona and Morgan 2010; Huxster 2006).
But - serotonin depletion and therefore toxicity? Serotonin depletion not always associated with axonal death but not reactive gliosis, etc.
It inhibits SERT (serotonin transporter) in the presynaptic terminal, reducing serotonin transmission -> >1000% increase in serotonin, 200% DA. NE effects too.
SERT reversibility: ~212 days recovery time in striatum, similar in amygdala, thalamus, and midbrain, Cerebral SERT binding is reduced in MDMA users with a relatively short abstinence of 145 days
(Buchert 2003, Reneman 2001, McCann 20 but none in neocortex
ASL (MRI with arterial spin labelling to measure CBF)
Decrease CBF in right amygdala, hippocampal after MDMA (statistically significant) correlates with subjective intensity of effects
Left temporal pole activations increased with negative effects.
Decreased functional connectivity in medial prefrontal cortex and hippocampus (associated with rumination, Berman 2011) - associated with positive effects.
Boosting serotonergic function with SSRIs leads to decreased amygdala activation to negative emotional
faces. Acute adminstration of MDMA, oxytocin, as well as Cannabidiol (CBD) all have similar effect (Bedi 2008; Fusar-Poli 2009) BUT Acute tryptophan depletion
leads to increased amygdala activation when processing negative emotional faces. Chronic MDMA use has same effect (Laursen 2016)
