1. Stimulants seminar shahid sadoughi university of medical sciences Esfand 1393 M Yassini MD M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 1

2.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 2

3.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 3

4.  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. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 4

5.  increases extracellular levels of monoamines both by - blocking presynaptic reuptake - Stimulating the release of catecholamines through the disruption of vesicular storage M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 5

6.  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 6

7.  Initial positive and rewarding subjective effects of methamphetamine dull in quality with repeated use of the drug, signalling development of a series of neuroadaptations M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 7

8.  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 8

11.  Agonists  antagonists M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 11

12.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 12

13.  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. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 13

14. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 14

15.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 15

16.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 16

17.  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 17

18.  iatrogenic effect  Exacerbation of drug use  Attenuate psychotic symptoms M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 18

19. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 19

20.  produce behavioral and neurobiological effects that are comparable or identical with the drug of addiction M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 20

21.  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 21

22.  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 22

23.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 23

24.  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 24

25. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 25

26.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 26

27.  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 27

28.  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 28

29. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 29

30.  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 30

31.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 31

32.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 32

33. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 33

34.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 34

35.  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 35

36.  Cocaine binding antibodies Reduce the reinforcing effects of cocaine in animal models  Catalytic antibodies Accelerate the hydrolysis of cocaine M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 36

37.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 37

38. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 38

39.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 39

40.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 40

41.  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 41

42.  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. M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 42

43.  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 43

44.  demonstrated promise in a preliminary study  being assessed in a larger trial M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 44

45.  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 M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 45

46.  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 46

47.  NIDA has recently signalled an interest in a dopamine D3 receptor for cocaine dependence M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com 47

48.  Two 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 48

49.  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 49

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