dependence Stimulants seminar shahid sadoughi university of medical sciences Esfand 1393 M Yassini MD M Yassini MDyazd medical sciences university yassiniardyahoocom 1 refrences ID: 571055
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Pharmacotherapy of amphetamine-type stimulant dependence
Stimulants seminar shahid sadoughi university of medical sciencesEsfand 1393M Yassini MD
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
1Slide2
refrences
Drug and Alcohol Review (September 2013), 32, 449–460 Comprehensive textbook of psychiatry2009 Kaplan and sadockNeurobiology of Addiction Koob, Michel Le MoalSynopsis of psychiatry 2015
Kaplan and sadock
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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objectivesThis
review describes the rationale and targets for pharmacotherapies for abuse or dependence on ATS reviews the extant evidence for select agentsdiscusses emerging
pharmacogenetic dataproposes
directions for future work
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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underlying mechanisms for pharmacotherapy
alter the neurobiology of reinforcement or reward from the drugattenuate the negative reinforcing effects of withdrawal from and craving for the drug
Ameliorate comorbid psychiatric vulnerabilities that co-occur and that can interfere with recovery.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Methamphetamineeffect
increases extracellular levels of monoamines both byblocking presynaptic reuptake Stimulating the release of
catecholamines through the disruption of vesicular storage
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Rewarding effect of methamphetamine
mediated by neurotransmitter systems including dopamine, serotonin and norepinephrine dopaminergic system a favoured
target for pharmacotherapy
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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neuroadaptationsInitial positive
and rewarding subjective effects of methamphetamine dull in quality with repeated use of the drug, signalling development of a series of neuroadaptationsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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neuroadaptations
Koob and Le Moal [16] characterise this process as the increasing recruitment of anti-reward processes, including- hypoactivity in the dopaminergic system-
alterations in hypothalamic–pituitary–adrenal axis functioning
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Evaluated medications
AgonistsantagonistsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com11Slide12
antagonistsblock
the action of the agonist to attenuate or eliminate the positive reinforcing effects of acute methamphetamine intoxication.compete with endogenous monoamines but have no intrinsic activity at the receptor siteNaltrexone in other addiction
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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agonists
bind to and trigger responses from receptors involved in the addiction process, often mimicking the action of monoamines involved in the reinforcement, withdrawal symptoms and motivational aspects of methamphetamine or amphetamine usepromote early abstinence by providing
a modest level of subjective effects but may have their greatest
impact in
minimizing
withdrawal and
negative affective
symptoms
.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Antagonists strategies
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com14Slide15
Naltrexone
an opioid receptor antagonistopioid receptors partially modulate dopaminergic effects and may act as a relevant pharmacological target.encouraging but await confirmation in several clinical trials that are currently underway
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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mixed dopamine and serotonin antagonist
Risperidone in small samples of methamphetamine-dependent adults showed acceptability and decreases in weekly methamphetamine usequetiapine and risperidone equally reduced
bipolar symptoms and drug cravings, with reductions in cravings associating
with reductions in stimulant use
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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mixed dopamine and serotonin antagonist
However, in non-dependent volunteers in the human laboratory, neither haloperidol nor risperidone attenuated the euphorigenic effects of methamphetamine
dampening rationale for further evaluation
of dopamine
antagonists.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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aripiperazoleiatrogenic
effectExacerbation of drug useAttenuate psychotic symptomsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com18Slide19
Agonist strategies
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com19Slide20
Agonist therapies produce
behavioral and neurobiological effects that are comparable or identical with the drug of addictionM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Dexamphetamine
Increase extracellular levels of dopamine through a carrier mediated exchange at presynaptic vesicles. In a small unblinded
randomised trial, Shearer demonstrated initial
safety and feasibility
of dexamphetamine
replacement therapy
(60 mg/day) for injecting
amphetamine dependent individuals.
The
study was
underpowered
to detect
treatment differences
, but no serious
adverse events
were observed
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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methylphenidate
Additional support for an agonist approach is provided by Tiihonen 20-week, randomised, double-blind, placebo-controlled trial of aripiprazole, methylphenidate or placebo among participants dependent upon injection use of amphetamine
participants assigned to the 54 mg/day slow-release methylphenidate condition (n = 17) had significantly
fewer amphetamine-positive
urine samples than
placebo
treated
patients
(n = 19; odds ratio = 3.77; 95%
confidence interval
1.55, 9.18).
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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modafinile
nonamphetamine-type stimulant with wake-promoting properties and cognitive-enhancing effectsincreases dopamine availability in nucleus accumbensDespite disappointing findings, some enthusiasm still exists for modafinil
in its current form or one of its enantiomers, R-
modafinil
,
as a
treatment for
psychostimulant
dependence
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Bupropion
Although not considered an agonist, bupropion functions as a mild stimulant and antidepressant.Bupropion is a non-selective inhibitor of the dopamine and norepinephrine transporters
also acts as an antagonist
at nicotinic acetylcholine
receptors
Bupropion increases dopamine transmission in
both the
nucleus
accumbens
and the prefrontal
cortex
encouraging but await confirmation
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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In sum
dopamine-enhancing medications have demonstrated the most consistent effects on reducing methamphetamine use when evaluated in placebo controlled randomized trials. One of the challenges t
o continued work using this strategy is that pure agonists have
abuse liability,
which elicits concerns that
limit impact
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Serotonergic medications
marketed serotonin-specific reuptake inhibitors may be ineffective for treating methamphetamine dependence.compounds in development that have selective activity at specific
serotonergic receptors may be efficacious approaches. Indeed
,
one such
medication,
mirtazapine, has demonstrated
some promise
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Mirtazapine
is a pharmacologically distinctive antidepressant with sedative and anxiolytic properties that enhances both noradrenergic and serotonergic activity.Its actions on the serotonergic system are different from those of selective serotonin reuptake inhibitors, including enhanced
transmission of 5-HT1A receptors and blockade of 5-HT2 and 5-HT3
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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GABAergic mechanisms
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com29Slide30
GABA system
interacts with dopaminergic processes, and its activation exerts an inhibitory effect on the reward system.This feature suggests that GABA agents may have some efficacy in attenuating the
reinforcing effects of stimulants.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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vigabatrine
Increases brain GABAAttenuate cocaine, nicotine, heroine, alcohol and amphetamine induced increases in extracellular nucleus accumbens dopamine as well as drug seeking behaviors associated with this biochemical changes in animals
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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GABAergic agents
Gabapentine has no effects on methamphetamine use, treatment retention or drug craving.topiramate appeared to facilitate abstinence during the second half of the trialBaclofen, tiagabine have shown some promise In preclinical studies and early clinical studies
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Other agents
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com33Slide34
Tricyclic antidepressants
Some positive results in early treatment with minimally drug dependent patientsLittle or no use inducing abstinence in moderate or severe casesDesipramine as most effective
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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dilantine
One study found 300mg a day of dilantine reduced cocaine use This study requires furthur replication M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Cocaine vaccine
Cocaine binding antibodies Reduce the reinforcing effects of cocaine in animal modelsCatalytic antibodies Accelerate the hydrolysis of cocaineM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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disulfiram
Inhibitor of dopamine beta dehydroxylate enzymeIncreases level of dopamine by slowing the breakdown of synaptic dopamineIncrease cocaine levels several foldCo administration of cocaine and disulfiram
make more negative response including anxiety, restlessness and paranoia so decreases cocaine use
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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conclusion
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com38Slide39
Complex disease
Numerous pharmacotherapies have been assessed in randomized, placebo-controlled trials but most have failed to demonstrate efficacyDependence on long-acting stimulants represent a complex disease of staged neuroplasticity
involving multiple brain systems
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Optimal pharmacological targets
dopaminergic system—the principle focus in addiction medication research—is dependent on competent functioning of the GABA system and cholinergic interneuronsDetermining optimal pharmacological targets is
difficult
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Agonist replacement therapies
Although the preponderance of findings from clinical trials have been negative, not all results have been disappointing.Agonist replacement therapies show some promise. Concerns, however, have been raised regarding public health implications of
widespread implementation of this strategy
.
Additionally
, agonist
therapies will
likely require significant
behavioural
support
and
oversight in order to deliver robust public
health benefits
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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bupropionNIDA has completed
a second, confirmatory trial of bupropion, and if results are similar to existing studies, support would exist for use of the medication as a pharmacotherapy.M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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novel mechanisms
Shoptaw and Heinzerling are assessing ibudilast, a phosphodiesterase inhibitor that may attenuate the cascade of methamphetamine-induced
glial activation and
release of cytokines
upon
initial abstinence
.
A
Phase I trial is being completed
Phase II trial of the compound
not finished
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Mirtazapinedemonstrated
promise in a preliminary study being assessed in a larger trialM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com44Slide45
Varenicline
a partial agonist at alpha-4, beta-2 nicotinic acetylcholine receptors is being examined as a pharmacotherapy following promising pilot data and encouraging results with both cocaine and alcoholevidence suggests involvement of the cholinergic system in the neurochemical effects of
methamphetamine use the reinstatement of methamphetamine MA-seeking in animal models
reduced
subjective effects of methamphetamine
in a
human laboratory study
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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N-acetylcysteine
Promising preclinical and human laboratory studies with cocaine have stimulated interest in N-acetylcysteine as a pharmacotherapy for methamphetamine dependence, though a Phase II trial is years away.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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D3 receptor
NIDA has recently signalled an interest in a dopamine D3 receptor for cocaine dependence M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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buspironeTwo
randomized controlled trials will evaluate buspirone as a relapse prevention treatment among cocaine-dependent patients being discharged from inpatient treatment facilities
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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Final word
After over 20 years of concerted effort to develop a broadly effective medication for MA dependence, no candidate has emerged.This highlights the need for new research methodologies,
better integration between basic and clinical sciences and
improved
collaboration between
government, industry and
academic researchers
.
M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com
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