Stimulants seminar shahid sadoughi university of medical sciences Esfand 1393 M Yassini MD M Yassini MD.yazd medical sciences university. [email protected]

M Yassini MD.yazd medical sciences university. [email protected]

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PHARMACOTHERAPY OF AMPHETAMINE-TYPE STIMULANT DEPENDENCE

Stimulants seminar shahid sadoughi university of medical sciencesEsfand 1393

M Yassini MD


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REFRENCES Drug and Alcohol Review (September

2013), 32, 449–460 Comprehensive textbook of

psychiatry2009 Kaplan and sadock Neurobiology of Addiction Koob, Michel Le Moal Synopsis of psychiatry 2015 Kaplan and sadock


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OBJECTIVES This review describes the rationale and

targets for pharmacotherapies for abuse or dependence on ATS

reviews the extant evidence for select agents

discusses emerging pharmacogenetic data

proposes directions for future work


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UNDERLYING MECHANISMS FOR PHARMACOTHERAPY alter the neurobiology of reinforcement

or reward from the drug attenuate 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.


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METHAMPHETAMINEEFFECT increases extracellular levels of

monoamines both by- blocking presynaptic reuptake - Stimulating the release of

catecholamines through the disruption of vesicular storage


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REWARDING EFFECT OF METHAMPHETAMINE mediated by neurotransmitter systems

including dopamine, serotonin and norepinephrine

dopaminergic system a favoured target for pharmacotherapy


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NEUROADAPTATIONS Initial positive and rewarding subjective

effects of methamphetamine dull in quality with repeated use of the drug, signalling development of a series of neuroadaptations


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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


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EVALUATED MEDICATIONS Agonists antagonists


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ANTAGONISTS block 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 site

Naltrexone in other addiction


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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 use

promote early abstinence by providing a modest level of subjective effects but may have their greatest impact in minimizing withdrawal and negative affective symptoms.


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ANTAGONISTS STRATEGIES


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NALTREXONE

an opioid receptor antagonist opioid 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


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MIXED DOPAMINE AND SEROTONIN ANTAGONIST Risperidone in small samples of

methamphetamine-dependent adults showed acceptability and decreases in weekly methamphetamine use

quetiapine and risperidone equally reduced bipolar symptoms and drug cravings, with reductions in cravings associating with reductions in stimulant use


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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.


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ARIPIPERAZOLE iatrogenic effect Exacerbation of drug use Attenuate psychotic symptoms


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AGONIST STRATEGIES


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AGONIST THERAPIES produce behavioral and neurobiological

effects that are comparable or identical with the drug of addiction


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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


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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).


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MODAFINILE nonamphetamine-type stimulant with

wake-promoting properties and cognitive-enhancing effects

increases dopamine availability in nucleus accumbens

Despite 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


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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


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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 to continued work using this strategy is that pure agonists have abuse liability, which elicits concerns that limit impact


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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


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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


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GABAERGIC MECHANISMS


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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.


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VIGABATRINE Increases brain GABA Attenuate 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


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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 trial

Baclofen, tiagabine have shown some promise In preclinical studies and early clinical studies


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OTHER AGENTS


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TRICYCLIC ANTIDEPRESSANTS Some positive results in early treatment

with minimally drug dependent patients Little or no use inducing abstinence in

moderate or severe cases Desipramine as most effective


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DILANTINE One study found 300mg a day of

dilantine reduced cocaine use This study requires furthur replication


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COCAINE VACCINE Cocaine binding antibodies Reduce the reinforcing effects of cocaine in animal models Catalytic antibodies Accelerate the hydrolysis of cocaine


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DISULFIRAM Inhibitor of dopamine beta

dehydroxylate enzyme Increases level of dopamine by slowing

the breakdown of synaptic dopamine Increase cocaine levels several fold Co administration of cocaine and

disulfiram make more negative response including anxiety, restlessness and paranoia so decreases cocaine use


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CONCLUSION


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COMPLEX DISEASE Numerous pharmacotherapies have

been assessed in randomized, placebo-controlled trials but most have failed to demonstrate efficacy

Dependence on long-acting stimulants represent a complex disease of staged neuroplasticity involving multiple brain systems


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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 interneurons

Determining optimal pharmacological targets is difficult


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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


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BUPROPION NIDA 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.


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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


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MIRTAZAPINE demonstrated promise in a preliminary

study being assessed in a larger trial


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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 alcohol

evidence 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


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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.


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D3 RECEPTOR NIDA has recently signalled an interest

in a dopamine D3 receptor for cocaine dependence


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BUSPIRONE Two randomized controlled trials will

evaluate buspirone as a relapse prevention treatment among cocaine-dependent patients being discharged from inpatient treatment facilities


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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.


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Stimulants seminar shahid sadoughi university of medical sciences Esfand 1393 M Yassini MD M Yassini MD.yazd medical sciences university. [email protected]