Jurnal Metilphenidate

1. http://www.cesar.umd.edu/cesar/drugs/ritalin.pdf >> pdf Ritalin2. http://www.ncbi.nlm.nih.gov/pubmed/19445548

Paediatr Drugs. 2009;11(3):203-26. doi: 10.2165/00148581-200911030-00005.

Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents.Garnock-Jones KP1, Keating GM.

Author information

1Wolters Kluwer Health mid R: Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA. [email protected]

AbstractAtomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to

atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year.

3. http://www.ncbi.nlm.nih.gov/pubmed/18555941

Clin Ther. 2008 May;30(5):942-57. doi: 10.1016/j.clinthera.2008.05.006.

Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review.Findling RL1.

Author information 1Case Western Reserve University, Ohio, USA. [email protected]

Abstract

BACKGROUND:Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children.

OBJECTIVE:This article reviews the literature on the development and use of medications for the treatment of ADHD in children.

METHODS:A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children. The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included.

RESULTS:Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T(max), C(max), and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine (P = 0.039).

CONCLUSIONS:Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.

4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476488/

Subst Abuse Rehabil. 2015; 6: 61–74.

Published online 2015 Jun 17. doi:  10.2147/SAR.S50807

5. PMCID: PMC4476488

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidenceKenneth M Dürsteler,1,2 Eva-Maria Berger,1 Johannes Strasser,1 Carlo Caflisch,2 Jochen Mutschler,2 Marcus Herdener,2and Marc Vogel1

Correspondence: Kenneth M Dürsteler, Center for Addictive Disorders, Psychiatric University

Clinics Basel, Wilhelm Klein-Strasse 27, 4012 Basel, Switzerland, Tel +41 61 325 51 25, Fax +41

61 325 53 64, Email [email protected]

Author information   ▼  Copyright and License information   ►

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Introduction

Since the 1980s, the use of cocaine has emerged as a significant public health problem globally. According to the United Nations Office on Drugs and Crime (UNODC), in 2012 there were 17 million cocaine users (range 13–20) worldwide.1 Cocaine has been estimated to be the second most used illicit drug in North and South America, the Caribbean, Southern Africa, and Western and Southern Europe.2,3 In Europe, cocaine is the most popular illicit stimulant drug. It is estimated that approximately 2.2 million young adults aged 15–34 years (1.7% of this age group) used cocaine in the last year.3 However, as elsewhere in the world, there is great variability across Europe; high estimates of cocaine use are restricted to a number of countries, with UK, Spain, Ireland, the Netherlands, and Denmark ranking at the top concerning prevalences of lifetime and past-year cocaine use.3 Wastewater analyses from 42 cities also revealed large regional differences in cocaine use in Europe.4 Considering longer-term trends in cocaine use, declines have been observed after a peak in 2008 for most European countries, especially for those where cocaine use is widespread.3

Cocaine use is associated with a variety of psychiatric conditions and with negative physical and psychosocial consequences.5 Among others, these include cardiovascular and neurological disorders, psychotic symptoms, blood-borne infections (eg, HIV, HBV, HCV), unintentional injuries, violent behaviors, and premature death.6–12 According to epidemiological data, cocaine users show a four-to-eight times higher mortality rate than their age–sex peers in the general population.13 Although many consumers use cocaine occasionally, some develop a more compulsive pattern of use and become dependent on cocaine. It has been estimated that 6%–7% of those who use cocaine for the first time will develop a dependence syndrome within the first year of use and about one-fifth will meet dependence criteria by the age of 45 years.14 Cocaine dependence is a chronic mental

disorder characterized by high rates of relapse, which may occur after many months or even years of abstinence. It has a significant impact because of its onset in younger age and contributes substantially to burden of disease.15 Cocaine accounts for a substantial proportion of treatment admissions for substance use disorders. According to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), cocaine was cited as the primary drug for 14% of all reported persons entering specialized drug treatment in 2012 (55,000), and 18% of those entering treatment for the first time (26,000).3 Differences exist between countries, with approximately 90% of all cocaine patients being reported by Germany, Spain, Italy, the Netherlands, and the UK, which account together for just over half of the EU population.

Comorbid attention deficit hyperactivity disorder (ADHD) is common among cocaine-dependent patients, and substance-using patients in general.16,17 Furthermore, substance use is prevalent in parents of children with ADHD,18 and children of substance-using adults are at an elevated risk for ADHD.19 Dopaminergic deficits as well as executive dysfunction have been demonstrated in both disorders,20,21 which may share common genetic risk factors.22 Individuals may also, at least initially, use cocaine as self-medication for symptoms related to ADHD.23

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Current status of treatment for cocaine dependence

The treatment of cocaine dependence still remains a great challenge. After almost 3 decades of intense research, there is no well-established effective medication available, nor is any medication approved for cocaine dependence by any medication’s regulatory authority. The primary interventions with evidence of efficacy are behavioral approaches. For instance, contingency management (CM) which provides incentives (eg, vouchers, cash) for drug-free urine samples or other desired behaviors (eg, treatment attendance) has proven effective in reducing cocaine use and fostering abstinence during treatment, even in difficult-to-treat patients.24,25 However, it is not clear whether CM leads to long-term abstinence, as its effects tend to subside after treatment.24,26 Another effective intervention for patients committed to reducing or eliminating their cocaine use is cognitive-behavioral therapy (CBT).27,28 Its goal is abstinence through functional analysis of high-risk situations for cocaine use and the development of effective coping strategies through skills training. Yet, the impact of behavioral approaches is limited for several reasons. Among others, they require substantial investments in care delivery systems and trained professionals to implement the interventions.29 Moreover, cognitively more demanding interventions, such as CBT, do not suit all patients,30,31 and patient commitment is important for CBT success.32–34 Overall, behavioral treatments alone have moderate effect sizes in terms of abstinence and retention,27,28,35 underscoring the continuing need for effective pharmacotherapies for cocaine dependence.27,36

One plausible pharmacotherapeutic approach to treat cocaine dependence is agonist-replacement, or substitution, therapy, which is already effectively used in the treatment of opioid37,38 and tobacco39,40dependence. As the term implies, a pharmacologically similar agent is thereby substituted for the abused substance with the goal to reduce the cycle of compulsive substance use and its associated harms. This qualitative review addresses the rationale for the use of methylphenidate (MPH) as a substitution medication and its clinical potential for the treatment of cocaine dependence.

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Methods

We performed a MEDLINE search using the following key terms (all without quotation marks): “cocaine use”, “treatment”, all in combination with the term “methylphenidate” and the Boolean operator “AND”. The search produced 144 results published from 1965 through September 2014. Two of the authors also scanned the references of the studies to identify additional citations that were not captured in the search. For the review, we included studies on treatment of patients with cocaine abuse/dependence with MPH to improve cocaine use. With this strategy, we identified eight case reports/open-label studies and six randomized controlled studies. In addition, we selectively considered preclinical and human laboratory data where appropriate.

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Rationale for MPH as a potential substitute for cocaine

The replacement approach for cocaine dependence posits that substitution with a cross-tolerant agent may suppress cocaine craving and withdrawal symptoms and/or block the euphorigenic effects of cocaine.41,42Ideally, such a compound would mimic the positive effects of cocaine without inducing craving, ie, should likely have a slow onset and long duration of action to minimize drug abuse liability.41,43 However, substitution therapies may also function as positive reinforcers and can therefore be used as reinforcing stimuli in CM strategies to decrease cocaine use and promote more adaptive behaviors.44

A valid target for a cocaine substitute is the dopamine system, as cocaine is thought to exert its reinforcing properties primarily by blockade of the presynaptic dopamine transporters.45 This inhibits dopamine reuptake, elevating extracellular dopamine levels within the mesolimbic “reward” system, especially in the nucleus accumbens.45–47 While acute inhibition of dopamine uptake by cocaine consistently results in increased dopamine activity, chronic cocaine intake leads to dysregulation of striatal dopamine signaling.48–50 Compounds that directly or indirectly modulate dopamine to reverse alterations associated with cocaine use may therefore prove beneficial as treatment agents.51 However, though likely necessary, enhancement of the dopamine system may not be sufficient to treat cocaine dependence,52,53 as other neurotransmitter systems such as serotonin and norepinephrine mediate the reinforcing effects of cocaine.54

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MPH

MPH, a piperidine derivate, was first synthesized in 1944 and marketed by Ciba-Geigy Pharmaceutical Company as Ritalin.55 Initially indicated for various conditions (eg, chronic fatigue, depressive states, disturbed senile behavior, or psychosis associated with depression),56 MPH is mainly used today for the treatment of ADHD and, to a lesser extent, sleep disorders (eg, excessive daytime sleepiness, narcolepsy).42When used as indicated, this stimulant drug is well tolerated and remarkably safe with a minimal side effect profile as demonstrated in disparate patient populations,56,57 especially also in those with ongoing cocaine use.31,58–60 In line with the stimulant-like effect profile of MPH, common side effects include insomnia, decreased appetite, dry mouth, increased heart rate, headache, nervousness, nausea, and dizziness.31,55Where potentially more serious side effects occur, they have been found to be reversible with dose reduction or drug discontinuance.56,61 Today, various immediate-release (IR) and sustained-release (SR) preparations of MPH are available under several brand names in multiple forms for oral and transdermal administration.

It is well established that MPH enhances cognitive performance not only in individuals with ADHD or those who have suffered traumatic brain injury, but also in healthy human volunteers, eg, on tasks that are sensitive to frontal lobe damage.56,62,63 In line with this, MPH has been found to improve higher-order aspects of neurocognitive functioning in cocaine-dependent individuals.63–65 This suggests that MPH therapy could potentially reverse neural alterations and cognitive deficits resulting from chronic cocaine use, thereby making patients more amenable to behavioral interventions.66 The wake-promoting properties may also be positive in cocaine-using individuals, in particular regarding the known deterioration in sleep architecture associated with acute cocaine abstinence.67

However, MPH, like amphetamine and cocaine, can also elicit reinforcing effects and tolerance. Thus, it has the potential for abuse, misuse/diversion, and dependence, which limits its clinical use.68–70 While its abuse potential appears low when administered as indicated, which is especially the case for SR formulations, the misuse and diversion of MPH seems a more widespread problem.71–73 Usually, this misuse is associated with efforts to increase concentration and attention, often in competitive academic environments.74,75

Neurochemical profile of MPH

Although MPH is structurally related to amphetamine, the two stimulants differ in their neurochemical mechanisms of action.76 Amphetamine causes dopamine release into the synaptic cleft and secondarily blocks catecholamine reuptake.77–79 In contrast, MPH, like cocaine, acts as a monoamine reuptake inhibitor; it binds to presynaptic dopamine and noradrenaline transporters, thereby increasing the extracellular catecholamine concentrations.45,80–82 However, the monoaminergic pharmacology of MPH and cocaine is

profoundly different from that of conventional monoamine reuptake inhibitors (eg, bupropion, mazindol).83Based on a wealth of data, Heal et al83 have recently concluded that the unusual, stimulant profile of MPH and cocaine is not mediated by reuptake inhibition alone. They propose that MPH allosterically modulates the function of the dopamine reuptake transporter to reverse its direction of transport, resulting in a firing-dependent retrotransport of dopamine into the synaptic cleft. Cocaine and MPH may therefore act as “inverse agonists” of the dopamine transporter (DAT), and this mechanism may be the major contributor to their pharmacobehavioral actions, especially when given at high doses and by routes that promote rapid entry into the brain.

Although the exact mechanism by which cocaine and MPH exert their euphorigenic effects is not fully clear, brain imaging studies have shown that both drugs are very similar in terms of their action at the DAT.84–86When administered intravenously, the in vivo potency of MPH at the DAT in the human brain is equivalent to that of cocaine.87 Moreover, the spatial and temporal distributions of intravenous (iv) MPH in the human brain are almost identical to those of iv cocaine, with the striatum showing the highest concentrations and time to reach peak uptake corresponding to 2–10 minutes for both drugs.88 Although the effects of iv MPH and cocaine overlapped considerably in that latter study, the two drugs differed markedly in their pharmacokinetics. The peak concentration of MPH in the brain was maintained for 15–20 minutes, whereas for cocaine it was maintained only for 2–4 minutes. MPH also cleared much more slowly from the striatum than did cocaine, with half-peak clearance of MPH taking about four to five times longer than that of cocaine (20 minutes). For both drugs, the fast uptake in the striatum paralleled the “high” experience but only for cocaine did the decline in the “high” correspond to the brain clearance rate. In contrast, for MPH, the “high” decreased as rapidly as for cocaine despite significant striatal binding of the drug, suggesting that acute tolerance to the reinforcing effects of MPH had occurred. The slow brain clearance of MPH may therefore limit its abuse potential, which would be favorable for a cocaine substitute.89 However, study data indicate that even when 80% of the DAT sites are occupied by MPH, this blockade does not prevent the subsequent “high” induced by a second iv injection of MPH given 60 minutes later.90

According to the rate hypothesis, the strength of euphorigenic effects is proportional to the rate of drug binding to its site of action; thus, routes of administration which produce faster brain uptake are more reinforcing.91 MPH has been found to be up to 100-fold more potent when administered intravenously than orally.83 In brain imaging studies that evaluated the relationship between MPH-induced dopamine increases and their reinforcing effects when equivalent levels were established for iv and oral MPH, only iv MPH elicited a “high”.92,93 The peak level of DAT blockade for clinically relevant doses of MPH, although delayed at approximately 1 hour, was about the same as that observed with iv MPH that induced a “high”.94However, even when doses of iv MPH are administered that produce significant DAT blockade, they are not always perceived as reinforcing, suggesting that DAT blockade, although necessary, is not sufficient to produce the “high”.92

Behavioral effects profile of MPH

Preclinical and human laboratory studies suggest that the stimulant-like behavioral effects of MPH are virtually indistinguishable from those induced by cocaine when both drugs are delivered by the same route of administration. For example, both drugs function as reinforcers in animals and humans under a variety of laboratory conditions.68 When delivered intravenously, MPH, like cocaine, maintains high rates of operant responding in rats, and long access to MPH results in an escalation of intake similar to cocaine.95 Injections of iv MPH also sustain self-administration in squirrel monkeys.96 Furthermore, drug discrimination studies in rodents indicate that MPH at higher doses fully substitutes for the cocaine cue.52,97 In laboratory studies examining the reinforcing effects of cocaine in rats pretreated with intra-peritoneal MPH, higher doses of MPH decreased cocaine intake but not responding to cocaine.97 However, 8-month treatment with oral MPH significantly reduced the rates of cocaine self-administration in rodents, suggesting that MPH pretreatment may alter cocaine reinforcement.98

With respect to the euphorigenic properties of MPH, subjective-effects studies of oral MPH in human adults have provided mixed results. In some studies, single doses up to 60 mg MPH tended to increase ratings of activity, arousal, concentration, intellectual efficiency, energy, anxiety, and talkativeness in healthy volunteers with no history of substance dependence, but not those of “drug liking”, “euphoria”, or “high”.94,99,100 Other studies, in contrast, found increased ratings of “good effects” and “drug liking” in non-drug-using volunteers after administration of oral MPH 40 mg.71,101–103 However, SR formulations of MPH are associated with less or lower ratings of “good effects” as compared to the IR formulation.71

In laboratory studies with cocaine-experienced volunteers, oral MPH 15–90 mg also produced ratings of “drug liking” and “stimulation” similar to those reported for oral cocaine.104 Moreover, single doses of intranasally administered MPH (10, 20, 30 mg) yielded dose-dependent increases in ratings of “good effects” and “high” in recreational stimulant users.105 After injections of iv MPH (0.5 mg/kg), both drug-naïve and cocaine-using volunteers experienced a “high”.106 Cocaine users reported that the “high” induced by iv MPH was similar to that of iv cocaine but lasted longer and was associated with more physical effects, ie, “stimulated more the body than the brain”.106 MPH injections also consistently induced cocaine craving in these cocaine users, while, in another experiment, oral IR MPH doses up to 60 mg increased neither cocaine craving nor subjective ratings that could suggest abuse potential in cocaine-dependent participants.107Furthermore, oral MPH in supratherapeutic doses was found to generalize to the cocaine cue in cocaine users who have been trained to discriminate between placebo and 200 mg oral cocaine; relatively high rates of cocaine-appropriate responding were also observed with MPH 30 mg.104

In two human laboratory studies assessing the effects of MPH treatment on iv cocaine,58,60 cocaine-dependent volunteers with and without adult ADHD were maintained on 0, 40, and 60 mg/day or on 0, 60, and 90 mg/day oral SR MPH. Both of these studies included a fixed cocaine dosing schedule. During each maintenance phase, a dose–response

function was determined for iv cocaine (0–50 mg). Maintenance on MPH significantly attenuated cocaine-induced increases in “good effects” and “desire for cocaine” ratings; these effects, however, were limited to the lower cocaine doses. In addition to the fixed dosing of cocaine, the first of these studies also included a choice experiment, in which seven cocaine-dependent patients with concomitant ADHD were maintained on 0, 40, and 60 mg/day oral SR MPH.58 The reinforcing effects of iv cocaine (0, 16, and 48 mg/70 kg) were assessed using a procedure wherein participants sampled a dose of iv cocaine (16 or 48 mg/70 kg) and were then given five opportunities to choose between it and two tokens, each exchangeable for US$2. As compared to placebo treatment, substitution with 60 mg/day MPH reduced the choice of the higher iv dose significantly from four to two times.

Overall, clinical laboratory studies largely support MPH as a treatment for cocaine addiction. To our knowledge, however, there are no studies on how cocaine users experience MPH in naturalistic settings.

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Clinical studies on MPH as a substitute for cocaine

A number of case reports, open-label studies, and controlled trials have addressed the clinical potential of MPH for the treatment of cocaine dependence in various patient populations (Table 1).

Table 1

Overview of case reports and clinical trials addressing methylphenidate as a treatment for cocaine dependence

Case reports

Khantzian23 was the first to report a case of a woman who presented a childhood history suggestive of ADHD and whose chronically excessive cocaine use was endangering her life. He started her on MPH 15 mg three times per day (tid) after a 6-day cocaine binge that had ended only 5 hours prior to her therapy appointment. Within 1 day, she began to experience normal appetite and sleep. Her mood had improved significantly and her cocaine craving had disappeared. She experienced one minor relapse in the first year as confirmed by urinalysis and continued weekly therapy sessions. A 2-year follow-up of this patient was presented 1 year later as the case of “Mrs B” in a series of case reports108 that described three cocaine-

dependent patients who shortly after beginning treatment with MPH showed a reduction in cocaine use. Medication was started at 15 mg tid in two patients and 5 mg four times per day in one patient. Doses were then increased up to a maximum of 70 mg/day. All three patients remained abstinent from cocaine for at least several months up to 2 years. Moreover, MPH improved symptoms of depression in one patient; in another, enhanced concentration and less violent behavior was stated; and, in the third patient, agitation, compulsive gambling, and interest in pornography decreased. The authors concluded that these cases lent support to the self-medication hypothesis of Khantzian.23 This hypothesis posits that an individual’s choice to use a particular drug depends to some degree on the drug’s effect on subjective painful affects or unpleasant emotional states which may or may not be associated with a psychiatric disorder.23

Two other successful case reports have appeared more recently. Imbert et al109 report the case of a male patient with cocaine dependence and adult ADHD who was also addicted to gambling and compulsive sex. Medication with the aim of improving ADHD symptoms and cocaine dependence was started with SR MPH 18 mg/day and increased to 54 mg/day. ADHD symptoms decreased after 2 weeks and craving for cocaine disappeared after 1 month of treatment. The patient stayed abstinent from cocaine and alcohol and quit gambling and compulsive sex, as shown in a 1-year follow-up. The other report110 depicts the case of a cocaine- and alcohol-dependent borderline illiterate man with difficulties in attention, restlessness, and hyperactivity during childhood. Treatment was started with SR MPH 36 mg/day and reduced to 27 mg/day. The patient described the treatment as “a miracle” since he felt much better after only 1 day of medication. Apart from one minor slip, the patient had stayed abstinent from cocaine for 8 months at the time of writing the report.

In another series of case reports,111 five male cocaine users without ADHD received MPH to treat cocaine dependence. MPH was started at doses of 20 or 40 mg/day, which were individually increased up to 100 mg/day. MPH treatment lasted between 2 and 5 weeks before it was discontinued in all patients due to increased cocaine craving and use. Initially, most patients experienced a short duration of positive medication effects, but they rapidly built up tolerance to MPH. Furthermore, patients stated that MPH lacked the desired “rush”, which might also have led to the increased cocaine craving and use. The authors concluded that treatment with MPH is not successful in cocaine-dependent patients without comorbid ADHD.

Open-label studies

The first open-label study that investigated the effectiveness of MPH as treatment for both cocaine use and ADHD included 12 cocaine-dependent outpatients with adult ADHD.112 Doses from 40 to 80 mg/day were used in this 12-week study, in which ten participants remained for at least 8 weeks, while eight of them completed the study. The most common side effects reported were dry mouth, increased heart rate, agitation, and jitteriness. No participant discontinued the study due to side effects. Participants showed significant improvement in all ADHD symptoms (except mood lability) of almost 50% on psychometric

measures. Cocaine craving and use had decreased significantly when the first 2 study weeks were compared to the last 2 weeks. Seven of the eight study completers were reachable for a follow-up 3 months later: three who still received MPH were cocaine-abstinent, as were two who were no longer treated with MPH, while two provided cocaine-positive urine samples.

Castaneda et al113 addressed a subgroup of cocaine-dependent patients who reported how cocaine had had a paradoxically calming effect on them at the beginning of their cocaine use. All these patients were diagnosed as having adult ADHD, which led the authors to conclude that these cocaine-dependent patients might have self-medicated their ADHD symptoms with cocaine, for which they report additional evidence in their study. Nineteen outpatients with adult ADHD and cocaine dependence in full remission were enrolled to this year-long, open-label, prospective study, which aimed at minimizing the risk of medication abuse or cocaine relapse. Before treatment for ADHD could be started, patients had to be abstinent from cocaine for 6 months or longer. Several medications were introduced for ADHD treatment in an order inversely related to their expected degree of stimulant effects and were replaced when the medication did not substantially improve ADHD symptoms after 2 weeks or after having doubled the dose. Treatment was viewed as fully effective when it decreased initial ADHD symptoms for a minimum of 12 months. Medications were administered in the following order and starting doses: fluoxetine 20 mg, bupropion 100 mg, pemoline 37.5 mg, SR MPH 20 mg, dextroamphetamine 10 mg, and methamphetamine 15 mg. Therapy with a long-acting stimulant (mostly SR MPH) alone or combined with fluoxetine or bupropion was most effective in suppressing ADHD symptoms. Fully effective treatment responses were achieved in 18 out of the 19 participants. The applied treatment strategy was found to be highly effective for treating ADHD symptoms, with cocaine use occurring only in four out of the 19 patients (two slips, two relapses).

Somoza et al114 also hypothesized that MPH could be safely and effectively used for the treatment of individuals with comorbid ADHD and cocaine dependence (mostly crack use). IR MPH was started at 20 mg/day and increased to a dose of 20 mg tid. Of the 41 outpatients enrolled in this 10-week, open-label study, 19 were rated as being compliant due to MPH plasma levels and ratings of the staff. Seventy percent of the participants completed the study. A significant difference in study retention was found between compliant and noncompliant participants. MPH was concluded to be safe with a minimum of side effects which were not serious and did not persist on a moderate or severe rating. With respect to cocaine use, study results showed that only participants reported to be compliant benefited from MPH. Compared to 0% of the noncompliant participants, 37% of the compliant stayed abstinent from cocaine during the study. A comparison of baseline and endpoint ADHD measures, however, revealed that ADHD symptoms had improved significantly in all participants, irrespective of compliance.

Randomized controlled trials

Five double-blind, randomized, and placebo-controlled trials on the efficacy of MPH as replacement therapy for cocaine dependence have been published so far. One other

randomized but single-blind trial115 was excluded from this review as its main focus does not lie on the management of cocaine dependence. Grabowski et al59 were the first to investigate this treatment approach in 49 cocaine-dependent outpatients with no other major mental health disorders who were randomized to receive either MPH or a placebo. After a 2-week intake period, a dosage of MPH 45 mg/day was administered during the 11-week treatment phase. There was no between-group difference in study retention, with 24 participants completing the trial. Study results showed no adverse effects of MPH and no increase of cocaine use. However, there was also no significant difference in cocaine use between the study groups; both groups continued to use cocaine. With respect to self-report items (eight items from Side Effects Questionnaire assessing direct drug effects) the two groups differed in the items “eating less”, “drowsy”, and “more energy”, suggesting that the MPH but not the placebo group noticed a direct effect of medication.

Dürsteler-MacFarland et al31 evaluated the feasibility, tolerability, and efficacy of MPH and cognitive-behavioral group therapy (CBGT) for cocaine dependence in patients prescribed diacetylmorphine. Sixty-two cocaine-dependent, diacetylmorphine-maintained patients participated in this dual-site, double-blind, placebo-controlled trial with four treatment arms. They were randomly assigned to receive MPH or placebo, each of which combined with either CBGT or treatment as usual for 12 weeks. After a baseline week, IR MPH 30 mg two times per day (bid) and placebo in identical capsules were administered under supervision. Manual-guided CBGT consisted of 12 weekly sessions in groups of five to seven patients. Primary outcome measures were cocaine-free urine samples, retention in pharmacologic treatment, and adverse effects. Urine cocaine screens were performed thrice weekly. Seventy-one percent of participants completed the trial. MPH was well tolerated with similar retention rates compared to placebo. No serious MPH-related adverse effects occurred. However, without reaching statistical significance, participants receiving MPH reported more side effects than those receiving placebo; these occurred at the beginning of the trial and disappeared soon after. The most common reported side effects were insomnia, dry mouth, hyperactivity, loss of appetite, and cardiac palpitations. There was a significant decline in self-reported amount and frequency of cocaine use in all groups, but data showed no significant change in cocaine-free urine samples. MPH did not provide an advantage over placebo in reducing cocaine use. In contrast to positive results obtained in other samples, this study does not support a role for CBGT for treating cocaine dependence in this patient group. There were no signs of additive benefits of MPH and CBGT.

ADHD is a common psychiatric comorbidity among cocaine-dependent individuals, with prevalence rates of up to 30% in some studies.116 Based on the self-medication hypothesis,23 other controlled trials have therefore evaluated the efficacy of MPH treatment for adult ADHD and comorbid cocaine dependence. The assumption hereby is that MPH might have a beneficial effect on ADHD symptoms which would also lead to a decline in cocaine use. Schubiner et al61 addressed this hypothesis in 48 cocaine-dependent patients with adult ADHD in a 12-week double-blind, placebo-controlled trial after a baseline week. MPH doses were titrated from an initial dosage for the first 2 or 3 days (10 mg tid) to a

second dosage level (20 mg tid) for the next 4 to 5 days to the target dose of MPH 30 mg tid by day 8. Retention in the study did not differ by group; 45% of the MPH and 58% of the placebo group completed the study. However, participants from the placebo group were less likely to drop out before the end of study week 4 than those from the MPH group. Reported side effects were generally high before the medication phase and remained so throughout the trial. Intensity of insomnia and sadness in the MPH group were higher at baseline and during the study than in the placebo group. A dose reduction was required in 25% of the participants receiving MPH; however, none of them discontinued the trial due to adverse side effects. The study demonstrated the safety of supratherapeutic doses of MPH in cocaine-dependent patients with adult ADHD. Although MPH did not decrease cocaine use or craving, it improved subjective reports of ADHD symptoms as compared to placebo.

Levin et al117 compared the efficacy of SR MPH or SR bupropion to placebo in treating ADHD symptoms and additional cocaine use. The sample included 98 methadone-maintained patients with adult ADHD, of whom 53% also met criteria for cocaine abuse or dependence. Participants were randomly assigned to the MPH, bupropion, or placebo treatment. The 12-week study duration included a 2-week lead-in phase with placebo, a 2-week titration phase, and 8 weeks at stable doses. MPH was started at 5 mg bid with standard formula and increased to a maximum dose of SR MPH 40 mg bid. Bupropion was started at 100 mg/day and increased to a maximum dose of 200 mg bid. Overall, 69 participants completed the study; the groups did not differ in retention rates. The results showed a reduction of ADHD symptoms in all three study groups. However, there were no significant group differences, suggesting that neither SR MPH nor SR BPR is more effective than placebo in treating ADHD symptoms in these patients. In terms of cocaine use, subgroup analysis demonstrated a high proportion of cocaine-positive weeks across all groups throughout the trial, whereby active medication had no advantage over placebo in improving cocaine use. Nevertheless, no evidence of medication abuse was found and both medications were well tolerated with no adverse side effects. The most common side effects were fatigue and increased sweating. No group differences were observed with respect to side effects.

Another double-blind trial by Levin et al118 hypothesized that treatment with MPH would lead to greater improvement of ADHD symptoms and cocaine use than placebo. The sample consisted of 106 adult ADHD outpatients with comorbid cocaine dependence who participated in this 14-week trial (1 week placebo lead in, 2-week titration phase, and 11 weeks of medication treatment). MPH was started at 10 mg/day standard formulation and increased to a maximum dose of 60 mg/day of SR MPH (40 mg in the morning and 20 mg in the afternoon). Retention in treatment did not differ between groups. Eighty-nine participants, of whom 47 completed the trial, remained at least 4 weeks in the study. A variety of side effects were reported across both groups but there were no significant group differences. The most frequently reported side effects were headache, gastrointestinal upset, diarrhea, and insomnia. Most of the participants reported at least a 30% decrease in ADHD symptoms. However, in contrast to Schubiner et al,61 this study did not find a significant difference between the groups. Although there was no substantial improvement in cocaine abstinence in

either group, those receiving MPH had a reduced likelihood of cocaine use over time. A secondary analysis showed no improvement in cocaine use for participants in the placebo group, regardless of ADHD response. However, in the MPH group, the likelihood of submitting cocaine-positive urine samples decreased by 36% over time for ADHD responders compared to under 10% for ADHD nonresponders, suggesting a beneficial effect of MPH treatment in this group.

To summarize, all double-blind, placebo-controlled trials confirmed that the administration of up to MPH 90 mg/day to cocaine-dependent patients with or without adult ADHD and/or with simultaneous diacetylmorphine or methadone maintenance is safe and does not increase cocaine use or craving. However, in contrast to most open-label studies, the more rigorously controlled studies were not able to show a substantial decrease of cocaine use through MPH treatment.

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Discussion

Overall, the findings from human laboratory and clinical studies assessing the clinical potential of MPH as an agonist medication for cocaine dependence are inconclusive. Controlled laboratory studies have shown that MPH can be safely administered in combination with cocaine without relevant clinical consequences and that MPH substitution reduces some of the positive effects of cocaine.58,60,107 With one exception,111 the available case reports23,43,108,109 and open-label studies112–114 also suggest that substitution with MPH might be a safe and effective treatment intervention in cocaine dependence, especially in those with comorbid ADHD. In contrast, randomized controlled trials do not provide evidence for the effectiveness of MPH as replacement therapy, at least in those patients who do not additionally suffer from ADHD; yet, they have demonstrated that MPH is well tolerated and remarkably safe with minimal side effects in active cocaine users.31,59,61,117,118 However, there are several explanations for the negative results of these trials which should be considered when discussing the potential of MPH as a substitution therapy for cocaine dependence and planning further studies. The negative findings may in part be due to relatively small sample sizes, the dose and formulation of MPH used, the duration of MPH treatment and time point of its initiation, as well as patient characteristics.

A general problem of randomized controlled trials is that there are upper limits of dosing. These limits may not adequately approximate the cocaine use patterns in naturalistic settings. The MPH doses administered in the trials so far might be too small to be effective. In fact, laboratory data indicate that higher doses of MPH more effectively attenuate cocaine’s positive subjective effects and decrease choices for cocaine over money in cocaine users.58,60 Some evidence also suggests that chronic cocaine use decreases sensitivity to dopaminergic medications.49 This means that dosing at the high end of the recommended range or above would be required to be effective in cocaine dependence. These doses,

however, might be much higher than those commonly used for the treatment of ADHD and may increase the risk for side effects and especially for severe adverse events.61,119 Even at dosages of 90 mg/day, MPH did not show advantage over placebo in terms of cocaine use.61 Hence, MPH in therapeutic doses may be best suited for low-to-moderate severity of cocaine dependence. Connected to the cocaine users’ decreased sensitivity to dopaminergic medications, the duration of treatment and the time point of treatment initiation may also be critical determinants for effectiveness. Time to maximal reduction in cocaine use can vary considerably and may take several months. Such a delay between treatment initiation with MPH and reduction in drug use has been reported for amphetamine-dependent participants receiving a terminal dose of 54 mg/day of extended-release MPH.120In that study, 18 weeks of MPH treatment were required to significantly reduce amphetamine use. Furthermore, treatment with MPH in randomized controlled studies was induced while participants were using cocaine. A different approach would be to start MPH treatment after participants have achieved an initial period of abstinence from cocaine (eg, via CM intervention) and to assess time to relapse and relapse rates over a longer period of time.

A recent brain imaging study has found that deficient dopamine transmission in cocaine users is associated with failure to respond to behavioral treatment.121 If deficient dopamine transmission predicts poor response to behavioral interventions, then MPH replacement therapy could potentially reverse this deficit.43 In fact, brain imaging data suggest that MPH may ameliorate various neural dysfunctions in mesocorticolimbic regions and improve neurocognitive deficits found in cocaine users.64,65,122–126 In one study, for example, a single oral dose of 20 mg MPH normalized hypoactivation in the anterior cingulate cortex and improved behavioral measures of response inhibition.123 Moreover, Li et al65 have shown that MPH in cocaine-dependent individuals is associated with robustly decreased reaction time in the stop signal task, suggesting improvements in inhibitory control. Cognitive improvements were thereby positively correlated with inhibition-related activation in the medial frontal cortex, an area associated with motor inhibitory control. MPH has also been found to attenuate brain reactivity of cocaine-dependent participants to cocaine-related cues in a brain imaging study.126 These findings highlight another mechanism by which MPH might be beneficial in the treatment of cocaine dependence, as intact dopamine signaling is required for responding to natural and therapeutic contingencies.121 However, the potential of MPH to increase the effects of behavioral interventions warrants further well-designed studies.

Interestingly, MPH treatment in cocaine-dependent patients with ADHD who respond positively to the medication in terms of ADHD symptoms is associated with a significantly greater increase in the number of cocaine-negative urine samples compared to those who respond poorly.118 It is well known that variability in drug pharmacokinetics and pharmacodynamics are largely influenced by an individual’s genetic profile. Properly assessed genetically driven functional changes in the DAT could help determine which patients could benefit from MPH for cocaine dependence.51,127 Individuals with variable number tandem repeats of the SLC6Q3 gene 3′-untranslated region polymorphism of DAT1

have been found to have altered responses to drugs, with the 10/10 repeat responding poorly to MPH. An example of a study of a predictive genetic biomarker in cocaine dependence has recently been published,128 but there are no data available for MPH treatment in cocaine dependence.

Some randomized controlled trials31,117 described above were conducted in polysubstance users maintained on methadone or diacetylmorphine. This may have influenced the results; smaller doses of MPH may be less effective in poly-drug users or effects of ongoing substance use and potential withdrawal symptoms may have interfered with the studies. However, opioid withdrawal symptoms should be minimized or absent in patients on stable opioid maintenance. Furthermore, concomitant use of other substances is highly prevalent in cocaine users, and this population should therefore be included in the research on the effectiveness of a substitution approach for cocaine addiction.

Several studies on cocaine dependence suggest a differential treatment outcome by sex.129 Moreover, the menstrual cycle and levels of gonadal hormones can influence dopamine function, subjective effects of stimulants, and responsiveness to potential treatments.130 Because, typically, cocaine dependence is more prevalent in males, female patients are less often enrolled in studies, and this is also the case for the studies described here. Correspondingly, the results may be more representative of male cocaine users. None of the studies on MPH in cocaine dependence reported sex-specific effects; however, the number of enrolled females may have been too small to conduct these analyses. Future studies should take sex-specific effects and menstrual cycle into account.

Although there is no evidence from randomized controlled trials that MPH is superior over placebo in reducing cocaine use in cocaine-dependent patients without ADHD, clinical experience suggests that MPH might be beneficial for some patients when treatment is appropriately tailored to the individual patient.23,43,108,109 Therefore, substitution therapy with MPH appears to be viable, with risks outweighed by benefits in carefully selected, monitored, and motivated patients. In these cases, SR or newer extended-release preparations of MPH are generally to be preferred over IR formulations for purposes of behavioral safety. However, further research is required to determine optimal treatment models (initiation after achieving a period of cocaine abstinence or during active cocaine use), effective and safe doses, and length of treatment. From these points of view, further well-designed studies are needed to better evaluate the clinical potential of MPH as possible treatment for cocaine dependence. Future trials should be conducted in larger samples of clinically and genetically well-characterized participants, over a longer duration and with higher doses of supervised MPH administration, best combined with CM, likely the most robust behavioral intervention available for cocaine dependence followed by CBT.

5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462776/

Int J Prev Med. 2015; 6: 52.

Published online 2015 Jun 4. doi:  10.4103/2008-7802.158181

PMCID: PMC4462776

Reduction of Methylphenidate Induced Anxiety, Depression and Cognition Impairment by Various doses of Venlafaxine in RatMajid Motaghinejad, Manijeh Motevalian, Andia Ebrahimzadeh,1 Setare Farokhi larijani,1 and Zohreh Khajehamedi2

Correspondence to: Dr. Majid Motaghinejad, Department of Pharmacology, School of Medicine, Iran University of Medical

Sciences, Tehran, Iran. E-mail: ri.ca.smut.izar@dajenihgatom-M

Author information   ▼  Article notes   ▼  Copyright and License information   ▼

Received 2014 Oct 28; Accepted 2015 Apr 5.

Copyright : © 2015 Motaghinejad M.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

AbstractGo to:

INTRODUCTION

Methylphenidate (MPH; Ritalin) is an agent with a neural stimulant activity, which administrated for the treatment of attention - deficit/hyperactivity disorder in children.[1,2] Chronic abuse of MPH and its neurochemical and behavioral consequence in adult and children remain unclear.[3] Mechanism of MPH is that it binds the dopamine, norepinephrine, and lesser extent serotonin transporter and inhibit reuptake of these amine into synaptic terminals, thus stimulates their receptors.[3,4] This agent functionally and pharmacologically is similar to amphetamine and cocaine.[5,6] MPH has a high potential for abuse and addiction due to its pharmacological similarity to cocaine and amphetamines.[7,8] Some unpleasant property of stimulant therapy may emerge during durable therapy, but there is the very little research of the chronic effects of MPH. Chronic administration of MPH can induce behavioral alteration such as anxiety and depression-like behavior in the animal model experiment.[7,8,9] The behavioral change, which observed after chronic abuse of to MPH consists of increases in depressive-and anxiety-like behaviors and also cognition (learning and memory) impairment.[2,7,8] Experimental studies have demonstrated the potential effect

of MPH and other amphetamine-like agent on brain development and functional change, this study showed that chronic usages of MPH has a role in neurodegeneration of some parts of brain cells such as hippocampus and cerebral cortex, which was responsible for cognition and anxiety.[10,11]

Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI), which was used for management of depression and anxiety.[12] Many previous studies demonstrated that this agent can be effective as sedative and anxiolytic agent.[12,13] Previous studies also demonstrated that venlafaxine due to its effect on both serotonin and norepinephrine can act as a complete antidepressant with low side-effect on the brain.[13,14] This studies showed that this agent can interfere with some major neurotransmitters such as serotonin, norepinephrine, and dopamine, and this mechanism is responsible for some of its applications such as anxiolytic, antidepressant and neuropathic pain relief.[15,16] These studies suggested that because venlafaxine has both anxiolytic and antidepressant effect, thus itis one of the best choices in situations where there are both anxiety and depressive depression like as amphetamine and other psychostimulant abuse.[13,14] A previous study demonstrated that venlafaxine can potentate and increase motor activity, and it has not side effect on cognition activity.[17] Venlafaxine has been demonstrated to be neuroprotective and can act against some neurotoxin and neurodegenerative agents.[18,19] It also can be effective in the treatment of alcoholic and other drug abuse.[20] Our previous study demonstrated that venlafaxine can be effective against morphine dependency and can be effective as pain killer and anxiolytic in the withdrawal period.[15] Many studies demonstrated that serotonin (5-HT) and a number of serotonergic receptor agonists have anxiolytic and antidepressant effect, these results suggest that the serotonergic agent can be effective against methamphetamine-induced anxiety and depression.[21] Furthermore, it was demonstrated that the adrenergic system has a major role in depression, anxiety, and cognition.[22] Co-administration of venlafaxine with some neurotoxin can diminish this harmful agent effects in some parts of the brain especially in the area, which serotonin and dopamine have protective role.[20] The aim of the study was to evaluate the possible role of pretreatment with venlafaxine, as SNRI, on the modulation of MPH induced stress, anxiety, depression, motor activity and cognition impairment.

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METHODS

Animals

A total of 48 adult male Wistar rats, weighing between 250 g and 300 g, were provided from the animal house of Iran University of Medical Sciences. They were housed in an adjusted temperature (22 ± 0.5°C) with 12-h light/dark cycle and had free access to food and water. Our experimental protocol was approved by the Ethical Committee of Research Deputy of Iran University of Medical Sciences.

Drugs

Methylphenidate and Venlafaxine was purchased from Sigma-Aldrich Co. All agents were freshly prepared just before use.

Experimental design

Group 1, received normal saline (0.2 ml/rat) for 21 days and served as control group. Group 2, received MPH (10 mg/kg i.p.) for 21 days. Groups, 3, 4, 5 and 6 concurrently were treated by MPH (10 mg/kg) and venlafaxine at doses of 25, 50, 75 and 100 mg/kg as i.p. respectively for 21 days. On day 22, elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were used to investigate the level of anxiety and depression in animals. In addition between days 17 and 21, Morris water maze (MWM) was used to evaluate the effect of MPH on spatial learning and memory. On 16th day, some standard behavioral methods such as EPM, OFT, FST and TST were used to investigate anxiety and depression level of experimental animals. In addition, a standard behavioral protocol by Morris water maze was applied to evaluate spatial learning and memory in animals between 17th and 21st days.

Behavior tests

Open field test

Open field test used as a standard test for assessment of anxiety and locomotor activity in rodents. For the performance of the test, an apparatus used with bottom divided to 16 equally spaced squares bordered by opaque high walls of 65.90 cm. All parts of the bottom were painted with black color, except the 6 mm broad white lines that divided the ground into 16 squares. During the experiment all parts of the room except for the open field were kept dark, the apparatus was illuminated by a 100 W bulb that focused on the field from a height of about 110 cm from the ground. For assessment of anxiety and locomotors activity, each animal was centrally positioned in the field for a maximum of 5 min to monitor the following behaviors.

Ambulation distance: Frequency with which the rat crossed one of the grid lines with all four paws

Line crossing (ambulation) distance: Distance which rat crossed of the grid lines

Center square entries: Frequency with which the rat crossed one of the red lines with all four paws into the central square

Center square duration: Duration of time the rat spent in the central square

Rearing: Frequency with which the rat stood on their hind legs in the maze.

Forced swim test

Forced swim test, frequently used for evaluation of depressant like behavior in rodents. The apparatus is composed of a transparent plexiglass cylinder with 30 cm diameter and 65 cm height, which filled with water up to 30 cm. The day before the experiment, in order to have adaptation of animals, all animals were individually located to swim for a period of 15 min, On the day of experiment, animals were positioned individually for a period of 6 min in plexiglass cylinder, filled with water. The swimming duration was 6 min. Swimming activity is a marker of nondepressive behavior.

Elevated plus maze

Elevated plus maze is another test, which used for assessment of anxiety in experimental animals. The equipment includes two opposite arms 60 cm × 20 cm, which joined with a central square (10 cm × 10 cm), this apparatus form was a plus sign. Two arms were kept open while other arms were closed with 40 cm elevated walls. All parts of apparatus were kept in 50 cm height above the ground. All subjects were situated individually in the center of the maze in front of a closed arm. The time which animal spent on the open arms were recorded during 5 min for each rat. Spent more time in open arm considered as non-depressive behavior.

Tail suspension test

In this test, animal hang up from tail with tape, which stick to 4/5 of the tail length and suspended from a metal rod, which was fixed 50 cm above the surface area. The duration of immobility and heave of animal was recorded for 5 min period. Immobility is considered as depressive-like behavior.

Morris water maze task

Morris water maze was composed of a circular black-colored water tank (150 cm in diameter and 85 cm in height) which was set up in the center of the small room. This apparatus was divided into four quadrants (North, East, West and South). The tank was filled by water to the height of 50 cm. The operator stay in the North-East part of the room. A platform disk with 12 cm diameter (made of Plexiglas), which is invisible was inserted 1 cm beneath the surface of the water. In the first 4 days of the experiment, which called training procedure the platform was constantly located in one of the quarter. An automated infrared tracking system (CCTV B/W camera, SBC-300 [P], Samsung Electronic Co., Ltd., Korea) recorded the position of the animal in the tank. The camera was mounted 2.3 m above the surface of the water.

Handling

Before the start of experiment, on the first day, rats were located on the tank that was filled with water, room temperature (25 ± 2°C) and the operator guided the rat for swimming to

reach to the platform placed quarter. The platform was located on South-West quarter of the tank.

Training procedure

Some distinguish landmarks (such as picture, window, door, etc.) as set up in the extra maze in the room for spatial cues for learning of platform's position for animals. The position of the platform was settled in the Southwest quarter of MWM tank with 25 cm distance from the edge of the tank, and 1 cm beneath the surface of the water. Each rat was experimented for four trials in a day. Each animal was tested randomly from four quarters (North, East, West and South). If the rats found the platform within the 60 s, the trial was automatically stopped by computer. In this experiment, two parameters were evaluated.

Time to find the hidden platform which was called escape latency

Time to find the hidden platform which was called escape latency., and Distance traveled to the hidden platform which was called traveled distance were recorded.

On the 5th day, probe day, platform was removed and animal was thrown into water from one of the above-mentioned directions (East) and the percentage of presence of animal in the target quarter (South-West quarter) was recorded.

Statistical analysis

The data were analyzed using GraphPad PRISM v. 6 Software and averaged in every experimental group and expressed as means ± standard deviation. Then the differences between control and treatment groups were evaluated by ANOVA. To evaluate the severity of behaviors, the differences among averages in each group were compared using the Tukey test at a significant level (P < 0.05).

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RESULTS

Results of open field test in control and treatment groups

As shown in Table 1 rats under treatment by MPH (10 mg/kg) had less rate of central square entries and also spent less time in the central region of the OFT in comparison with negative control group (P < 0.05). Our study indicates that venlafaxine inhibited this effect of MPH in a dose-dependent manner and increased the frequency of central square entries and also time spent in the central region of the OFT in MPH treated group. This difference was statistically significant in comparison with MPH (10 mg/kg) treated group (P < 0.05) [Table 1].

Table 1

Effect of various doses of venlafaxine on open field exploratory and anxiety like behavior in rat under treated by 10 mg/kg of MPH

Negative control animals in comparison with MPH (10 mg/kg)-treated group has a higher frequency of rearing and longer ambulation distance in OFT (P < 0.05). Also, animals treated by venlafaxine (25, 50, 75 and 100 mg/kg) caused a significant increase in ambulation distance in MPH (10 mg/kg) treated group. This increase was statistically significant in comparison with group receiving MPH (10 mg/kg) alone (P < 0.05) [Table 1]. Also, Venlafaxine at high dose (100 mg/kg) caused a significant increase in rearing in MPH (10 mg/kg) treated animals. This increase was statistically significant in comparison to group administrated by MPH (10 mg/kg) alone (P < 0.05) [Table 1].

Results of forced swim test in control and treatment groups

Animals in MPH treated group (10 mg/kg) compared to negative control group had less swimming time in FST (P < 0.05) [Figure 1], While venlafaxine in all doses inhibited this effect of MPH and increased swimming time, however venlafaxine just in doses of 75 and 100 mg/kg can increase significantly the time of swimming compared to the group receiving MPH (10 mg/kg) alone (P < 0.001) [Figure 1].

Figure 1

Swimming time (seconds) in forced swim test in control group, and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise. All data are expressed as mean ± standard deviation (n = 8). ***P ...

Results of elevated plus maze in control and treatment groups

Negative control group spent more time in open arms of EPM in comparison to group under treatment by 10 mg/kg MPH (P < 0.05) [Figure 2]. The result of our study indicated that animals treated with venlafaxine with doses of 50 and 75 mg/kg remarkably increased the presence of animal in open arm of EPM with P < 0.05 as opposed to the MPH (10 mg/kg)

treated group, while in dose of 100 mg/kg of venlafaxine, this significant level was P < 0.001 in contrast with MPH (10 mg/kg) treated group [Figure 2].

Figure 2

Duration of time spent in open arms (seconds) in elevated plus maze test in control group and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise. All data are expressed as mean ± standard ...

Results of tail suspension test in control and treatment groups

Duration of immobility in MPH (10 mg/kg) treated group was significantly increased compared to animals in the control group in TST (P < 0.05). Decrease in the immobility due to venlafaxine with doses of 75 and 100 mg/kg was statistically significant in comparison with rats receiving 10 mg/kg of MPH (P < 0.001) [Figure 3].

Figure 3

Duration of time stayed in immobility (seconds) in tail suspension test in control group and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise. All data are expressed as mean ± standard ...

Evaluation of escape latency and traveled distance during training days in the Morris water maze

Escaped latency and traveled distance during 4 days training in the MWM for group under treatment by MPH with dose of 10 mg/kg was statistically significant compared with negative control group (P < 0.05) [Figures [Figures4 4  and and5]. 5 ]. Although venlafaxine in all doses inhibited MPH induced reduction in escape latency and traveled distance but this effect of venlafaxine was not noteworthy as opposed to MPH (10 mg/kg) treated group [Figures [Figures4 4  and and5 5 ].

Figure 4

Average of escape latency in control group and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise across all training days using Morris water maze in rats. Data are shown as means ± standard ...

Figure 5

Average of traveled distance in control group and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise across all training days using Morris water maze in rats. Data are shown as means ± ...

Evaluation of swimming speed during training days

The swimming speed was not altered during training trials in any of the animal groups, suggesting that exposure to MPH (10 mg/kg) alone or in combination with venlafaxine with doses of 25, 50, 75 and 100 mg/kg did not cause any motor disturbances [Figure 6].

Figure 6

Average of swimming speed in control group and groups under treated by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise across all training days using Morris water maze in rats. Data are shown as means ± standard ...

Evaluation of percentage presence in target quarter in probe trial

Results indicated that there was a significant increase in percentage of the presence of animals in target quarter in MPH treated group (10 mg/kg) in comparison with negative control group (P < 0.05) [Figure 7]. Also, venlafaxin at all doses used could diminish this effect of MPH, but this effect in any of the doses had not visible/noticeable difference in comparison with MPH (10 mg/kg) treated group [Figure 7].

Figure 7

Percentages of time spent in target quarter in probe trial in control group and groups by 10 and 20 mg/kg of MPH and 10 and 20 mg/kg of MPH in combination with forced exercise across all training days using Morris water maze in rats. Data are shown as ...

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DISCUSSION

This study demonstrated that various doses of venlafaxin can alter MPH induced anxiety, depression, and but not the learning and memory disturbances. MPH administration caused an increase in anxiety and depression-like behavior in FST (swimming) and EPM (open arm entry). MPH in various doses can also alter behavioral parameters in OFT (central area entry, central area duration, ambulation distance and rearing). MPH in a dose of 20 mg/kg deteriorates learning and memory. MPH is a neural stimulant which was used for management of hyperactivity in attention-deficit/hyperactivity disorder in children. This agent acts like amphetamine derivatives, like methylen-dioxymethamphetamine. MPH binds the dopamine, and to a lesser extent the norepinephrine transporter, and inhibits reuptake of dopamine and norepinephrine into presynaptic terminals. Because of similarity to cocaine and amphetamine, abuse of MPH increased in recent years in adults.[20,23] However, the chronic neurobehavioral and neurochemical consequences of it remains unclear.[23] Venlafaxine is an antidepressant of the SNRI class. It is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder and vasomotor symptoms.[12]

Our previous study indicated that venlafaxine can be effective for the treatment of morphine dependency.[15] Previous studies demonstrated that venlafaxine significantly decreased the side effects and depression of cocaine dependency.[24,25] Also, another study suggested venlafaxine to be effective in the treatment of alcohol abuse, and furthermore it seems to be useful to decrease the severity of problems related to the alcohol use.[20] The results of this study demonstrated that MPH with a dose of 20 mg/kg cause a decrease in central square entry and time spent in Central Square in OFT. This study suggested that mentioned dose of MPH can induce a depressive-like behavior. Also our findings suggest that 20 mg/kg of MPH cause disturbance in ambulation distance and rearing, as a result, we can discuss that this doses of MPH cause disturb in the motor activity in test animals. We can discuss this results with effect of MPH on dopamine level in brain, many previous studies showed that dopamine has important role on brain motor function, these results indicated that dopamine receptor blockade or decrease in dopamine level by abuse of some drugs such as amphetamine, cocaine and other psycho-stimulants is responsible for disturbance in motor activity which appear in subjects with drug abuse. Probably by abuse of MPH the dopamine level decreased and thus motor activity was disturbed.[3,26,27] On the other hand, our results showed that venlafaxine in all mentioned doses decreased the type of depression in OFT and increased central square entry and time spent in the central square in rats treated by MPH. Also, venlafaxine can abolish the MPH-induced decrease in motor activity. This anti-depressant agent can increase ambulation distance in MPH treated rats. Our results can be compared

with a previous study, which demonstrated that venlafaxine as potent SNRI can alter depression-like behavior in OFT in rats.[28] Many previous clinical trials and experimental tests showed that venlafaxine can act as an antidepressant and modulate many depressive-like behavior in depressed patients and subjects showing drug withdrawal syndrome.[13,29,30] Venlafaxine also can improve motor activity and depressive-like behavior by increase in neurotransmitters such as adrenaline, serotonin, and dopamine, we can compare our data with this concept, which by administration of venlafaxine the disturbance of mentioned neurotransmitters induced by MPH were diminished.[16,27,31] Another study indicated that venlafaxine can be used for the treatment of methamphetamine craving in humans; this study suggests that this effect of venlafaxine mediated by its antidepressant activity.[32] It was demonstrated that venlafaxine could modulate the cortical excitability and improve motor activity and reaction speed, which greatly related to the increase of contralateral motor cortical excitability.[17] Our data are consistent with results showing venlafaxine enhancement of motor activity. Thus it can modulate motor activity disturbance, induced by drug abuse. Results of our data showed that MPH (10 mg/kg) decreases swimming period in FST, while venlafaxine in all doses used (25, 50, 75 and 100 mg/kg) decrease immobility and increase the swimming time (period) in FST. Venlafaxine due to its anti-depressive activity can increase serotonin and dopamine in synapses in the brain and modulate rats’ depressive-like behavior. We can compare our data with previous results, which supported the role of venlafaxine even at sub-therapeutic doses in affecting the result of FST and increase in swimming time (period). Our previous study demonstrated that venlafaxine can act as pain killer and antidepressant in morphine withdrawal syndrome, our previous data suggest that antidepressant and anti-anxiety effects of venlafaxine is the major reason for its use in management of withdrawal syndrome.[15] The present study indicated that MPH in mentioned dose can decrease the duration of time spent in open arms (seconds) in EPM and also can increase immobility behavior in TST, while venlafaxine in all doses used (25, 50, 75 and 100 mg/kg) can increase duration of time spent in open arms (seconds) in EPM in rats pretreated by MPH. Also, venlafaxine with the same doses can decrease immobility time in TST. We can argue these results with the basic concept that many antidepressant and anxiolytic compounds and agents could alleviate anxiety-and depression-like behaviors.[33] Several previous studies suggested that SSRIs and SNRIs antidepressants can modify anxiety and depression in experimental tests and clinical trials.[33,34] In our study, venlafaxine as potent SNRI alleviate MPH cessation induced anxiety and depression. Our study showed that MPH cause depletion of dopamine and serotonin and thus augmented anxiety and depression-like behavior after its cessation. In addition, we have found that venlafaxine by its antidepressant and anxiolytic effect inhibited the effect of MPH. Many previous studies demonstrated that venlafaxine can act as neuroprotective agent, this result suggested that venlafaxine can increase amount of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase and also brain-derived neurotrophic factor and BCl2 and decrease Bax in brain regions, in other words, MPH and other methamphetamine like compounds can increase Bax and oxidative marker such as malonil dialdehyde, Protein carbonyl and decrease antioxidant defenses.[18,19,35,36,37] We can suggest that venlafaxine by a protective

mechanism can alleviate MPH induced brain degeneration and induction of anxiety and depression. As mentioned before, our previous study also demonstrated that venlafaxine can reduce blood cortisol level in morphine withdrawal syndrome.[15] According to our findings, we can suggest that venlafaxine can act as a potent antidepressant and anxiolytic agent, which can be used in MPH and other drug abuse. Our study also alluded that chronic administration of MPH (20 mg/kg) can decrease escaped latency and traveled distance in MWM in learning time, this data suggested that MPH at mentioned dose can decrease learning activity and also in probe day, decreases percentage of presence in target quarter in MWM. And suggested that long-term injection of MPH can alter memory in the experimental animal model. This confirms the result of previous studies showing that chronic administration of MPH decreases learning and memory in immature rats.[38,39,40] Also, other study showed that Methamphetamine like compound caused the release of dopamine, serotonin and adrenaline in the brain and caused depletion of brain region from this amines, a consequence of this phenomenon is cognition impairment.[41] On the other hand, our data showed that venlafaxine at each of mentioned doses could not alter spatial learning and memory. Many previous studies indicated that venlafaxine and other SNRI and antidepressants have not significant effects on learning and memory. However some other studies demonstrated that this agent can improve cognition.[42,43]

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CONCLUSIONS

Overall, from obtained data we can conclude that chronic administration of MPH in adult rats caused an increase of anxiety and depression-like behavior and can disturb learning and memory activity. The results of the present study support the hypothesis that venlafaxine may be effective against MPH induced depression, anxiety and motor activity disturbance, but it has no effect against MPH induced cognition impairment. venlafaxine can be suggested for clinical use in patients with MPH abuse and suffering from its behavioral side-effects. These data could be helpful in human MPH abusers. However, further studies are required with human subjects.

6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462043/

Curr Neuropharmacol. 2015 Jan; 13(1): 5–11.

Published online 2015 Jan. doi:  10.2174/1570159X13666141210221750

PMCID: PMC4462043

Smart Drugs and Synthetic Androgens for Cognitive and Physical Enhancement: Revolving Doors of Cosmetic NeurologyPaola Frati,1,2 Chrystalla Kyriakou,1 Alessandro Del Rio,1 Enrico Marinelli,1 Gianluca Montanari Vergallo,1 Simona Zaami,1 and Francesco P. Busardò1,*

*Address correspondence to this author at the Department of Anatomical, Histological, Medico-legal and Orthopaedic Sciences,

Sapienza University of Rome, Viale Regina Elena 336 (00185) Ro me, IT; Tel: +39 06.49912622; E-mail: [email protected]

Author information   ▼  Article notes   ▼  Copyright and License information   ▼

Received 2014 Jul 30; Revised 2014 Oct 14; Accepted 2014 Oct 15.

Copyright ©2015 Bentham Science Publishers

This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License

(http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction

in any medium, provided the work is properly cited.

AbstractGo to:

INTRODUCTION

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence (intended as problem solving ability) in the absence of any medical indication [1, 2].

Currently, it represents one of the most debated topics in the neuroscience community. Human beings have always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. According to many, this continued demand for substances to improve cognitive skills is a typically human feature and therefore cognitive enhancement can be considered as the application of new scientific advances to achieve the age-old desire of self-improvement [3-5].

In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects [6].

The first aim of this paper is to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on

methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults.

Secondly, the authors will explore the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports.

Finally, a brief overview of the ethical considerations surrounding human enhancement will be examined.

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SMART DRUGS AS COGNITIVE ENHANCERS: THE EMBLEMATIC CASE OF METHYLPHENIDATE

Methylphenidate (Fig. 1 1 ) is a psycostimulant, present on the market with different trade names (e.g. Ritalin, Concerta, Methylin, Equasym XL). It was initially synthesized in 1944 by Leandro Panizzon and sold with the trade name of “Ritalin” by Ciba-Geigy Pharmaceutical Company in 1954 [7]. It was used at the beginning for the treatment of several conditions, such as: depressive states, psychosis associated to narcolepsy etc. [8]. Presently, methylphenidate is one of the most commonly prescribed drugs for the treatment of Attention deficit-hyperactivity disorder (ADHD) [9].

Fig. (1)

Chemical structure of Methylphenidate.

In order to understand the possible efficacy of this drug as a cognitive enhancer, a fundamental starting point is represented by its pharmacodynamics. Methylphenidate is a benzylpiperidine and phenethylamine derivative and it acts as a dopamine-norepinephrine reuptake inhibitor, by binding and blocking dopamine and norepinephrine transporters, which reuptake them within the presynaptic neuron after their release, although methylphenidate is most effective in modulating the levels of dopamine rather than norepinephrine [10, 11].

Numerous studies concerning the cognitive enhancing effects of methylphenidate on the normal brain have involved adult animals and humans [12-14]. At high doses (5–10 mg/kg), administered intraperitoneally in rats, there is an increase of the locomotor activity and an impairment of attention and performance, which affect those cognitive skills belonging to prefrontal cortex, whereas the intraperitoneal administration of low doses (0.5–2 mg/kg) improves cognitive performance and reduces motor activity. The administration of lower doses (0.25–1 mg/kg) of methylphenidate in healthy rats increases the attention skills without affecting the motor activity [15].

The potential effects of the psycostimulants (e.g. methylphenidate) and agents active on catecholamines, represent a plausible risk of cognitive enhancement. When the levels of dopamine and norepinephrine are optimal, they bind, showing a high affinity, respectively to D1-like receptor and α2 receptors, increasing the signal to noise ratio (S/N) in the prefrontal cortex. At higher doses, dopamine starts to bind to D2 receptors, while norepinephrine binds to α1 and β receptors; as a consequence there will be a reduction of S/N and the activation of neurons not involved in these tasks [16].

The abuse of methylphenidate among adolescents can be particularly dangerous and numerous side effects can arise after a prolonged use of this drug (see Fig. 2 2 ). Moreover, methylphenidate has an important role in regulating dopamine/norepinephrine levels, which can alter the maturation process of the prefrontal cortex, deeply active during that period of life [17].

Fig. (2)

Possible side effects after chronic use of Methylphenidate.

Lee et al [18] observed the effects of repeated methylphenidate exposure on the locomotor diurnal rhythm activity patterns of female adolescent Sprague–Dawley (SD) rats, which were divided into 4 groups: control, 0.6 mg/kg, 2.5 mg/kg, and 10 mg/kg methylphenidate group. The results obtained showed that the repeated administration of 2.5 mg/kg and 10 mg/kg of this drug was able to modify the locomotor diurnal rhythm patterns, suggesting that these doses exert long-term effects.

Urban et al [19] treated juvenile and adult SD rats with methylphenidate, and the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex were examined. The results of this study showed that an intraperitoneal dose of 1 mg/kg, either single dose or chronic treatment produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, whereas exerting excitatory effects in adult rats. Minimum clinically-relevant doses (from 0.03 to 0.3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, however chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and more. According to this study the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults has been overestimated. Juvenile treatment with this drug could result in long-lasting, potentially permanent changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

Therefore, the dosage of methylphenidate and the age of the subjects in relation to prefrontal cortical plasticity remain the key points, which should be better investigated with further studies involving healthy subjects, in order to clarify several aspects still not entirely understood.

Although according to numerous reports, methylphenidate is widely abused as a cognitive enhancer among healthy subjects, especially young adults and teenagers, it is very difficult to determine the actual trend of abuse [20]. First of all, it is necessary to distinguish the illicit from therapeutic use among people affected by ADHD or other pathologies requiring methylphenidate as therapy.

According to the U.S. Department of Health and Human Services, in monitoring the Future National Survey Results on Drug Use, 1975–2006 [21], the use of methylphenidate among college students was 3.9% in 2006, whereas in young adults it was 2.6%. It is interesting to underline a slight decrease in the use of this drug in both categories between 2002 and 2006 (see Fig. 3 3 ). Moreover, these trends of use if compared to other phenethylamines commonly abused, such as amphetamines, show that methylphenidate is less used both in college students and in young adults.

Fig. (3)

Trends of use of methylphenidate compared to amphetamine during the years 2002-2006.

Numerous other studies have investigated the misuse/abuse of methylphenidate in healthy subjects, but because of different methodologies, type of studies and statistical analysis they cannot be uniformly compared; Babcock and Byrne [22] showed the results of a study, in which the use of methylphenidate in a small New England college was investigated. According to this study about 16% of the student population had used the drug for recreational purposes and it is the most common among students (aged 18–24 years).

Teter et al [23] carried out a larger study at the University of Michigan, by administering a questionnaire. About 3% of the students had used or abused methylphenidate, the survey was completed within a year. Males and females presented nearly the same percentages of misuse/abuse. In addition, an association between misuse and attendance at parties was found.

White et al [24] report in their research that 16.2% of students have misused or abused stimulants. Of this group, 96% identified Ritalin as their stimulant of choice. The frequency of abuse in more than 50% of misusers was 2-3 times per year, in almost 34% it was monthly (1-2 times/month) and in 15.5% it was weekly (2-3 times/week).

Despite not allowing for comparative analysis, the above reported studies highlight a wide misuse/abuse of methylphenidate as a cognitive enhancer among teenagers, college students and young adults.

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ANABOLIC ANDROGENIC STEROIDS MISUSE AND ABUSE

“Anabolic steroids” is the name given to synthetic variants of the male sex hormone testosterone. The comprehensive term for these compounds is anabolic-androgenic steroids (AASs): “anabolic” refers to muscle-building and “androgenic” refers to the increased male sexual features.

AASs can be used for clinical purposes in the treatment of several pathologies: several forms of anemia, acute and chronic wounds, severe burns, short stature, osteoporosis, hypogonadism (primary or secondary forms), AIDS wasting syndrome, catabolic states due to long-term corticosteroid therapy etc. [25-28].

Besides the numerous clinical applications of AAS, they are always more misused and abused by athletes as an ergogenic aid to improve their performance and/or physical shape [29].

Sports involving power production and strength training are the ones which commonly involve the use of AASs. Back in the 1950s, these compounds were used by a handful of professional athletes, but as they became more accessible and their use was extended to include also high school and college students [29-31]. Furthermore, as an ever increasing number of women use these compounds, the abuse of AASs can no longer be said to belong mostly to the male population [32].

The issue of AASs misuse and abuse creates some difficulties in order to make a proper and accurate estimation. Several aspects, such as the neurological effects of AASs are still under investigation. Moreover, in some cases, there is conflicting data, especially concerning psychological effects.

The abuser is placed under numerous influences and a very complex interconnection of forces, which cannot be ignored. The slogan “win at all costs” is the one that makes better this concept. Moreover, the significant appreciation of the society for winning athletes represents a further decisive factor for the consumption of these substances.

The issue of AAS use and abuse by athletes allows us to make numerous ethical considerations:

If on the one hand, the position of banning the use of AASs could be adopted, except for medical purposes, taking into consideration the numerous side effects associated with their use, on the other hand this stance may appear as “very parentalistic or paternalistic”, and it cannot be applied to “professional” athletes, who consider the use of AASs and their side

effects as an equal exchange in order to succeed in sport [33]. This view point can be significantly internalized by athletes who follow tough training programs for several years in order to progress in levels of certain competitive sports only to discover that many of their rivals are using AASs, forcing upon them a difficult choice; either to decide to use AASs or to participate at a known disadvantage, or to withdraw from competition.

Generally in sports, athletes train in order to be better than other competitors, thereby beating their opponents. This advantage can be achieved through fair play, competitiveness, professional foul, or through the use of performance enhancing drugs like AASs [33]. This raises an ethical issue; if all athletes in a particular sport decide to consume AASs, would that not produce a fair competitive setting? The fairness would depend on whether all athletes were using a similar typology and quality of drugs [34]. If one argues that participants are free to choose to take part in competitive sports and are therefore free to use AASs or not, in spite of the possible side effects, then surely it can be regarded as an athlete’s right to choose [33-35].

Many argue that using AASs allows an athlete to perform beyond the natural limits of the human body. The counter argument could be that the widely accepted use of coaches, vitamins, or weight training, already pushes athletes beyond their natural limits [33]. Athletes are already able to perfect their performance as a result of scientifically prepared training programs. However, if it is agreed upon that sport is a test of character and greatness within the natural limitations of man, then AASs use would be seen as wrong because competitors would no longer be within this human state but in a pharmacologically-induced state [33].

AASs are able to modify the mood through numerous mechanisms [36-38]. Testosterone and AASs can act as a central monoamine oxidase inhibitor (MAOI).Therefore, AASs are considered mood enhancers, investigated in subjects affected by depression. Vogel et al [39] confronted the antidepressant effects of amitriptyline (range: from 75 mg/d to 300 mg/d) with those of mesterolone (range: from 100 mg/d to 550 mg/d) in a double-blind design with 34 male patients suffering with depression. According to this study [39] both drugs had a similar effect in diminishing the depressive symptoms and at the same time the mesterolone caused far less side effects than amitriptyline.

The neurologic and psychiatric consequences due to AAS abuse reported in adolescents and young adults require a careful evaluation.

Irving et al [40] performed a study in 4746 middle and high school students, in order to assess the prevalence of AAS use and to identify social, environmental and behavioral aspects concerning the health of students using these drugs. The results obtained show that AASs were more commonly used by males (5.4%), whereas the prevalence of use in females was 2.9%. In males, an association between AAS use and “poorer self-esteem and higher rates of depressed mood and attempted suicide, poorer knowledge and attitudes about health, greater participation in sports that emphasize weight and shape, greater parental concern about weight, and higher rates of disordered eating and substance use”, was found. In female

students, the association between AAS use and the condition above reported was weaker, even if numerous common aspects between the two groups were highlighted.

Another study [41] conducted on 3054 high school students showed the association between the frequency of AAS use among students and high-risk behaviors, suggesting that AAS use is more a contributor to a "risk behavior syndrome" than a former of an isolated behavior.

Several cases reporting psychiatric symptoms in subjects using AASs are described in the literature [28,  42 -44].

Thiblin et al [44] reported eight suicidal cases involving males aging from 21 to 33 years old, with a present or previous history of AAS use. In 5 cases, suicide was committed during the use of AAS, whereas in 2 cases it was committed after 2 and 6 months respectively following AAS discontinuation. Only in one case it was not possible to establish whether the subject was using or had recently stopped the use of AAS. In 5 males, their relatives had observed the onset of depressive symptoms associated to AAS discontinuation. In 4 cases, following a long use of AASs, the development of a depressive syndrome was noticed. Hypomania-like symptoms appeared in 2 cases right before committing suicide.

Only 1 out of the 8 cases examined by Thiblin et al [44] had developed suicidal thoughts prior to the consumption of AASs, however, the presence of suicidal risk factors, regardless of the use of anabolic steroids, was found in all cases. According to the authors of this study, psychiatric symptoms and conflicts because of a prolonged use of AASs can contribute to suicide in subjects with predisposing risk factors.

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DISCUSSION AND CONCLUSIONS

Cognitive enhancers and AASs can be considered as the two sides of the same coin. Both of them represent the more general desire of “human enhancement” which can be defined as the wish to overcome, temporarily or permanently, the existing limits in the human body with natural or artificial methods. The use of artificial methods (including the use of drugs) in order to choose, vary and improve human features and capabilities beyond those that already exist in human beings, is the heart of this concept [45,  46 ].

In the era of “cosmetic neurology”, the first question that we ought to ask ourselves is, why should methylphenidate, be considered as a cognitive enhancer in the absence of scientific evidence? Many arguments can be provided; first of all, the one we think better suits this answer is “the sociological desire to find a pharmacological solution to social problems” [20]. But is this desire strong enough to support the wide spread of methylphenidate as a cognitive enhancer? And then, is its use among healthy subjects really so diffused?

The first question can be answered in this way, sustaining that “sociological desire” generates numerous expectations regarding what this compound can do, could do or even should do [47, 48]. These expectations have also promoted large speculation about the enhancement of

different cognitive domains such as memory, attention and creativity. The overestimation of these expectations makes feasible what is only potentially hypothetical. Furthermore, another reason that supports the vast abuse of this drug rises from the mental association between the therapeutic use for ADHD treatment and its misuse in order to improve learning skills in healthy subjects. This improper use is based on exceeding the marked borderline between health and disease, which appears in the eyes of abusers increasingly blurred until it disappears. As a consequence, the word “treatment” might become a synonym of enhancement in the cognitive field [20, 48, 49].

Regarding the diffusion of methylphenidate among healthy subjects, no exhaustive conclusion can be formulated. Moreover, it is always necessary to contextualize the data available, not only by comparing its trends of abuse with other smart drugs, but also with several other drugs of abuse, which are constantly changing.

The expected cognitive advantages related to the use of methylphenidate offer an unfair advantage to those who use it. This “unfair advantage” becomes more evident in sport and the use of AASs represents a frank manifestation of this form of “cheating” [50,  51 ]. AASs have been abused over the time either alone or in association to several other prohibited substances especially among bodybuilders, such as gamma-hydroxybutyrate (GHB), which was thought to induce a significant release of growth hormone (GH) [52,53].

We can argue that the thread that joins cognitive enhancers (including methylphenidate) and AASs in academia and in sport are the expected results and the Ovid’s maxim “exitus acta probat” (the result validates the deeds) highlights in fact this concept; the “exitus” is represented by human enhancement (both physical and mental), whereas the “acta” necessary to pursue this goal are represented by the misuse and abuse of these substances not taking into account the numerous established and potential side effects. The latter can represent the same criterion adopted in banning their use in sports, whether the risk is a real or only potential. This strategy has been applied by several organizations, such as: the World Anti-Doping Agency (WADA), Association of Tennis Professionals, Major League Baseball, Fédération Internationale de Football Association, the Olympics, the National Basketball Association, the National Hockey League, and the National Football League and many others [54-56].

The topic of cosmetic neurology is a controversial but emerging field, where medical therapies are used to enhance neurological functions [57]. The discussion above reported and the brief review of the literature in this field allow us almost to speculate: if on the one hand, cognitive enhancers may be intended as potential “steroids of the mind”, on the other hand, AASs can be considered “enhancers of the body”. This dualism may explain why there are the two sides of the same coin.

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CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

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ACKNOWLEDGEMENTS

Declared none.

8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429779/

9. J Pharm Sci. Author manuscript; available in PMC 2015 May 13.

10. Published in final edited form as:

11. J Pharm Sci. 2011 Jul; 100(7): 2966–2978.

12. Published online 2011 Jan 14. doi:  10.1002/jps.22476

13. PMCID: PMC4429779

14. NIHMSID: NIHMS686477

15. Transdermal and Oral dl-Methylphenidate–Ethanol Interactions in C57BL/6J Mice: Transesterification to Ethylphenidate and Elevation of d-Methylphenidate Concentrations

16. GUINEVERE H. BELL ,1 ANDREW J. NOVAK,2 WILLIAM C. GRIFFIN, III,2 and KENNERLY S. PATRICK1

19. Correspondence to: Guinevere H. Bell (Telephone: +843-7928429; Fax: +843-7921712; Email: ude.csum@2bhg)

20. Author information   ▼  Copyright and License information   ►

21. The publisher's final edited version of this article is available at J Pharm Sci

22. See other articles in PMC that cite the published article.

24.Abstract

27. Go to:

28. INTRODUCTION

29. Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed childhood neuropsychiatric condition. The stimulant drug dl-methylphenidate (dl-MPH; Fig. 1,) has remained a first-line pharmacotherapeutic agent to treat ADHD since the 1950s.1–3 Further, the persistence of ADHD into adulthood is increasingly recognized.1,4–8 In the adult ADHD population, dl-MPH is also the most widely prescribed psychotherapeutic agent.7 As a consequence, this controlled substance has become more widely available for abuse and diversion,9–11 especially among high school12 and college students.13,14

30.

31. Figure 1

32. Enantiomers of MPH: d-MPH (left) and l-MPH (right).

33. Appropriate drug therapy for this older ADHD population requires a special consideration of lifestyle and lifespan comorbidities7 such as hypertension.13,15 Optimized adult ADHD pharmacotherapy may be complicated by alcohol consumption, alcohol use disorder (AUD), or other substance use disorder (SUD). Both AUD and SUD are over-represented in adult ADHD,4,16,17 especially in women.18 Not surprisingly, given the clinical nature of adult ADHD,19 and the susceptible population for which MPH is prescribed,4 dl-MPH-related emergency department visits have totaled in the thousands each year, for example, 8000 in 2004.11 Moreover, emergency room presentations for incidents involving alcohol in combination with drugs have risen 63% for persons aged 18–19 years, and have increased 100% for persons age 45–54 years.20Poison center data reveal how extensive dl-MPH abuse has become.11,21–24 In a drug diversion context, ADHD stimulants are often coabused with ethanol, for example, in 53% of those surveyed,25 and dl-MPH in particular has been reported to be coabused with ethanol in 92% of those surveyed.10 Accordingly, prescribing or diverting psychostimulants has generated special concern regarding concomitant ethanol use or abuse.26–28

34. These statistics are consistent with MPH being classified as a Drug Enforcement Agency (DEA) schedule II controlled substance,29 that is, a medication of very high abuse potential.30–32 Accordingly, the prevalence and inherent danger of concomitant dl-MPH and ethanol warrant research into the pharmacology of this drug combination.

35. Coadministration of ethanol and dl-MPH orally to humans33,34 results in a drug–drug interaction, wherein the methyl ester of MPH is transesterified to yield ethylphenidate

(EPH; Fig. 2)33 in addition to being hydrolyzed to the inactive35 metabolite ritalinic acid.36 Both EPH and ritalinic acid formation appear to be primarily mediated by the actions of carboxylesterase 1 (CES1),37–39 which exhibits l-MPH substrate enantioselectivity in both the transesterification and hydrolysis pathways.33,40

36.

37. Figure 2

38. Enantioselective transesterification of dl-MPH to l-EPH following concomitant ethanol.

39. The metabolic transesterification of dl-MPH with ethanol to yield EPH was first reported in vitro using rat microsomes.41 Subsequently, EPH was detected in human tissues from two fatal drug overdoses in which unknown amounts of MPH and ethanol were consumed.42 These findings prompted a normal human volunteer pilot study of the

40. dl-MPH–ethanol interaction43 followed by a larger human study wherein enantiospecific methodology for plasma analysis was utilized.32 In this latter study, it was established that the dl-MPH–ethanol transesterification pathway primarily yields the l-enantiomer of EPH (Fig. 2).

41. Any l-MPH, or the metabolite l-EPH, which reaches the bloodstream, is unlikely to contribute directly to the pharmacodynamics of the dl-MPH–ethanol interaction in view of the findings that only the d-isomers of MPH and EPH possess potent effects on dopaminergic and noradrenergic systems.40,44 In spite of this, ethanol consumed with dl-MPH by normal human volunteers resulted in a significant elevation of maximum plasma d-MPH concentrations (Cmax) and overall d-MPH exposure.33 Elevated plasma d-MPH concentrations increase the potential for adverse cardiovascular events, especially in ADHD patients with comorbid hypertension.45,15

42. In addition to the influence of ethanol on dl-MPH pharmacokinetics, the above-mentioned normal human volunteers reported an increase in pleasurable effects when combining dl-MPH with ethanol.32 Such positive subjective effects may predispose individuals to greater abuse liability.26,27,47 The enhanced likability of this drug combination may be based on interactive effects of these two psychoactive drugs on excitatory neural systems as recently reported using a C57BL/J6 (C57) mouse behavioral model.48 However, the increased likability may also pertain to the elevated rate at which d-MPH reaches the bloodstream.49–51 When dl-MPH is combined with ethanol, the time to maximum concentration (Tmax) occurs at the same time as dl-MPH dosed alone. However, the Cmax is much higher at this time following concomitant dl-MPH and ethanol than when dl-MPH is dosed alone.33

43. In 2006, the US Food and Drug Administration approved the first transdermal patch for the administration ofdl-MPH (Daytrana®, Noven Therapeutics LLC, Miami, FL,

USA).This dl-MPH transdermal delivery system (MTS) relies on a high load of dl-MPH free base incorporated within a uniform blend of acrylic polymers and silicone adhesives to drive drug absorption based on the drug concentration gradient without the need for permeability enhancers (for review, see Ref. 3). Using transdermal delivery, dl-MPH circumvents the extensive and highly enantioselective presystemic metabolism associated with oral dosing.33,52 Accordingly, MTS results in approximately 50 times higher plasma l-MPH concentrations than those that occur following oral dosing.53

44. The present preclinical study investigated aspects of MTS and oral MPH absorption and disposition as influenced by the coadministration of ethanol. Special attention was given to the formation of l-EPH in view of the relatively large amount of l-MPH anticipated to reach the bloodstream following MTS delivery. The C57 mouse strain was chosen based on its frequent use as a reference strain in preclinical psychopharmacology of stimulant agents, including MPH and ethanol.40,44,48,54,55 Further, like human MPH metabolism, the C57 mouse has previously been reported to favor l-MPH as a substrate in the transesterification of ethanol to yield l-EPH after intraperitoneal (i.p.) dosing.40

45. Blood, brain, and urine concentrations of d-MPH, l-MPH, d-EPH, and l-EPH were analyzed. The mean MTS dose delivered from a quarter of a 12.5 cm2 patch (smallest of four sizes available) after a 3.25 h wear was calculated by quantifying the residual MPH content in the used patches. This dose was then administered for oral studies, while clearly recognizing the limitations of any direct drug dispositional comparisons of a bolus oral dl-MPH dose to that of the MTS in mice where prolonged release of drug occurs from the patch. A modification of an established gas chromatographic (GC)–mass spectrometric (MS)–electron impact (EI)-selected ion monitoring (SIM) method was used for these enantiospecific determinations.44,56 MPH and EPH enantiomers were derivatized with (S)-N-trifluoroacetylprolyl chloride (TFP-Cl) to yield GC-resolvable diastereomers. Piperidine-deuterated dl-MPH was incorporated for analytical control.

46. Go to:

47.MATERIALS AND METHODS

48. Materials

49. Ethanol used for oral animal studies was from AAPER Alcohol and Chemical Co. (Shelbyville, Kentucky; 95%). dl-MPH·HCl used for oral animal studies was from Sigma–Aldrich (St. Louis, Missouri; lot #118K1052) and the 12.5 cm2 size MTS was from Shire US (Wayne, Pennsylvania; lot #2616811; smallest of four sizes available). Laboratory tape used to secure MTS or placebo was from VWR International ( Radnor, Pennsylvania; white, 12.7 mm). dl-MPH·HCl in methanol (1 mg/mL

calculated as free base; Cerilliant, Round Rock, Texas) was used as the analytical reference standard. The dl-EPH·HCl standard in ethanol (1 mg/mL calculated as free base) was synthesized in-house.44 TFP-Cl in dichloromethane (1 M; Sigma-Aldrich, St. Louis, Missouri), sodium carbonate (Fischer Scientific, Fair Lawn, New Jersey), n-butyl chloride (Burdick & Jackson, Muskegon, Michigan), and acetonitrile (Sigma-Aldrich, St. Louis, Missouri) were also used. Piperidine-deuterated dl-MPH·HCl was synthesized in-house57 and contained approximately 25% of the D5-isotopolog for SIM and containing no D0–1-MPH. It is noted that piperidine-deuterated D9-MPH·HCl is commercially available (Cerilliant, Round Rock, Texas).

50. Animals

51. Male C57 mice aged 8–10 weeks (25–35 g) were obtained from Jackson Laboratories (Bar Harbor, Maine). They were individually housed in a temperature- and humidity-controlled colony room on a 12-h light/dark cycle (light: 07:00–19:00 h) with free access to food and water for at least 7 days before the start of any tests. All experiments were approved by and conducted within the guidelines of the Institutional Animal Care and Use Committee at the Medical University of South Carolina and followed the guidelines of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publication no. 80-23, revised 1996). Animal studies were conducted in the Institute of Psychiatry at the Medical University of South Carolina.

52. Drug Administration

53. Mice were randomly placed into one of four test groups as shown in Table 1. All mice, regardless of group assignment, were treated similarly. This included the use of active (MTS) or placebo patches and delivery of ethanol or water by gastric intubation (gavage). To this end, mice were lightly anesthetized by placement into a chamber containing 5% isofluorane for 8–10 min. The mice were taken out and their hair was clipped along their abdomen and back, from shoulders to hips.

54.

55. Table 1

56. Dosing Regimens for C57 Mice

57. Immediately after hair clipping, one-fourth of a 12.5 cm2 MPH transdermal patch, or a placebo patch (band-aid adhesive resembling the MTS), was applied to the lower left hip area. The patch was secured by applying tape over the patch and around the

mouse for one full loop to ensure a constant skin interface and to prevent the mice from disturbing the patch. Mice were returned to their home cage for 15 min to recover from anesthesia, then dosed by gavage, according to their assigned group, that is, 3.0 g/kg ethanol and 7.5 mg/kg (calculated as the free base) dl-MPH·HCl, or deionized water (dH2O) using a standard volume of 0.02 mL/g body weight.

58. Sample Collection

59. Following gavage, mice were individually placed for 3 h in single metabolic chambers designed to separate urine from solid waste. Urine was collected and measured to the nearest microliter value. Mice were then deeply anesthetized using isofluorane. Venous blood was collected using cardiac puncture and stored in heparinized tubes. The brain was removed, separated along the sagittal line, weighed, and stored as two separate samples. Used patches were collected and later extracted for residual dl-MPH to calculate the dose delivered to the cutaneous site. Blank urine, blood, and brain used for calibration curves were collected from mice not exposed to any drugs. All matrices were kept on dry ice unti;8l stored in a °70°C freezer.

60. Sample Preparation

61.Urine

62. All urine samples were thawed immediately prior to analysis. Blank mouse urine (150 μ L) was fortified over a range of concentrations with dl-MPH (0, 0.5, 0.75, 1.5, 3, 4.5 μ g/mL) and dl-EPH (0, 0.15, 0.3, 0.45, 0.6, 0.9 μ g/mL). These calibrators were run in parallel with experimental urine samples (150 μ L). The internal standard, piperidine-deuterated dl-MPH, was dissolved in dH2O such that 200 μ L aliquots provided a concentration of 5 μ g D5-dl-MPH per 150 μ L of urine. Sodium carbonate (50 μ L, 1.2 M) was added to each urine sample to adjust the pH to approximately 9.5. Samples were extracted with n-butyl chloride/acetonitrile (2 mL, 4:1) by vortexing for approximately 0.5 min.

63. Blood

64. All blood samples were thawed immediately prior to analysis and used in the freezer-hemolyzed state in view of MPH having previously been reported to distribute nearly equally between serum and the red cell fraction.58 Blank mouse blood (200 μ L) was fortified over a range of concentrations with dl-MPH (0, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0 μ g/mL) and dl-EPH (0, 0.01, 0.025, 0.05, 0.075, 0.1 μ g/mL). These were run in parallel with experimental blood (200 : L) as calibrators. The internal standard, piperidine-deuterated dl-MPH, was dissolved in dH2O such that 200 μ L aliquots provided a concentration of 5 μ g D5-dl-MPH per 200 μ L of blood. Sodium carbonate (2 mL, 1.2 M) was added to each blood sample to adjust the pH to approximately 9.5. Samples were extracted with n-butyl chloride/acetonitrile (2 mL, 4:1) by vortexing for approximately 0.5 min.

65. Brain

66. All brain samples were thawed immediately prior to analysis. Blank mouse brain (1/2, left hemisphere) was fortified over a range of concentrations with dl-MPH (0, 0.025, 0.05, 0.1, 0.2, 0.5, 1.0, 1.5 μ g/g) and dl-EPH (0, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1.0 μ g/g) and run in parallel with experimental brains (left hemisphere). The internal standard, piperidine-deuterated dl-MPH, was dissolved in dH2O such that 200 μ L aliquots provided a concentration of 5 μ g D5-dl-MPH per 150 μ L of urine. The internal standard, piperidine-deuterated dl-MPH, was dissolved in dH2O such that 200 μ L aliquots provided a concentration of 2.5 μ g D5-dl-MPH per brain sample. Sodium carbonate (2 mL, 1.2 M) was added to each brain sample to adjust the pH to approximately 9.5. Samples were homogenized (Polytron PT1200) for 10 s, then 0.5 g sodium chloride was added and the samples were vortexed for 20 s. Samples were extracted with n-butyl chloride/acetonitrile (2 mL, 4:1) by vortexing for 30 s, then centrifuged at 1137 g for 7 min.

67. MPH Extraction from Used Patches

68. Used patches were analyzed for residual content of dl-MPH to establish the cutaneous dose delivered. Before being placed on the animal, whole patches (including the backing) were weighed and then cut into quarters. Each quarter was then weighed and used to determine what percent of the whole patch it represented.

69. In advance of analyzing the used patches for their dl-MPH content, a method for dl-MPH recovery from unused patches was developed. The unused patches were placed in scintillation vials with methanol (1 mL/calculated mg of dl-MPH) and sonicated over a range of times from 1 min to more than 20 min to determine the time required for near-complete extraction/recovery. An unused 12.5 cm2 patch contains 27.5 mg of dl-MPH free base, whereby a quarter patch contains 6.875 mg of dl-MPH. For specific quarter patch cuttings, the exact dl-MPH content was calculated as follows: [(weight of quarter MTS/weight of whole MTS) × 27.5 = mg dl-MPH]. Accordingly, for the used study patches, residual dl-MPH was determined by taking a 100 μ L aliquot after 15 min of sonication and adding D5-dl-MPH (10 μ g) as the internal standard.

70. Chiral Derivatization

71. The organic phases from all matrix extractions were transferred into 4 mL screw-cap silanized vials (Supelco) and the solvent was evaporated to dryness under nitrogen. TFP-Cl (1 M, 250 μ L) was added to each vial, sealed with Teflon® lined caps (Supelco) and heated at 58°C for 45 min. Aliquots of these samples were then transferred to silanized microvial inserts within auto sampler vials for GC–MS analysis.

72. Instrumental Analysis

73. All analyses were conducted using an Agilent Model 6890 GC-5973N MS with ChemStation and a modification of published methods.44,56 GC separations were carried out on a 30 m × 0.32 mm, 0.25 μ m film thickness, 5% phenylmethylpolysiloxane fusedsilica column (DB-5; J & W Scientific, Folsom, California). Pulsed-splitless injections (2 μ L) were used. The injector port was fit with a deactivated glass wool protected sleeve operated at 250°C and the helium carrier gas linear velocity was 50 cm/s. The GC was held at 70°C for 1.5 min, then ramped to 315°C at 10°C/min and held for 4 min for a total run time of 30 min. Detection was carried out by EI ionization (70 eV) and SIM, acquiring the N-TFP-piperidyl fragment ions of d-MPH, l-MPH, d-EPH, and l-EPH (m/z 277) with D5-d-MPH and D5-l-MPH monitored at m/z 282 (Fig. 3).

74.

75. Figure 3

76. Representative GC–MS-SIM chromatogram of d-MPH, l-MPH, and l-EPH from a C57 mouse brain extract (upper ion profile). The sample was collected 3.25 h after dosing with one quarter of a 12.5 cm2 MTS and 3 h after dosing with 3.0 g/kg ethanol by ...

77. The lower limit of quantitation was based on a signal-to-noise ratio of at least 10 for all analytes. The signal-to-noise ratios for the lowest calibrators were at least 25. It is noted that calibrator concentrations are indicated as racemic (dl-) MPH and EPH, whereas analyte concentrations are reported for each enantiomer. All calibration plots provided a linearity of r2 above 0.99.

78. Statistical Methods

79. A two-way analysis of variance followed by pairwise comparisons using the Student’s t-test method was used in the analysis of all data. Samples were analyzed as independent samples and were assumed to have equal variances. Statistical analysis was conducted using SPSS 12.0 (SPSS Inc., Chicago, Illinois).

80. Go to:

81.RESULTS

82. MPH Dose Delivered from MTS

83. The dl-MPH dose received by the MTS test animals over the 3.25 h wear time was determined by extracting the remaining dl-MPH from used patches and back calculating from the initial dl-MPH content in a quarter of a 12.5 cm2 MTS. Sonication for 15 min was necessary to extract a mean no less than 95% of the

labeled dl-MPH content of unused quarter patches and, accordingly, 15 min of sonication was used to calculate the 3.25 h dose delivered by difference. Shorter sonication times did not allow for complete dl-MPH extraction, whereas using later time points caused the MTS matrix to significantly degrade. This resulted in the extractant becoming cloudy, and GC–MS of such aliquots were found to foul the injector port and resulted in unacceptable chemical noise in the chromatograms. The mean dl-MPH dose delivered using the MTS over 3.25 h was 0.23 mg or 7.5 mg/kg. This dose was used for oral dosing (gastric intubation) in a parallel study of oral dl-MPH–ethanol interactions. The 7.5 mg/kg oral dose is likely to over-represent the bioavailable fraction of the mean dl-MPH MTS dose calculated as above in view of the likelihood of some residual dl-MPH remaining in the skin prior to circulatory absorption, for example, in humans dosed with MTS, residualdl-MPH results in a biphasic decay of the drug from plasma following patch removal.59

84. Influence of Ethanol on Urinary Analytes

85.Transdermal Dl-MPH

86. The total urinary elimination of d-MPH following the 3.25 h MTS wear time was significantly greater in the animals dosed with ethanol compared with those given dH2O [Fig. 4a; t = 5.52, degree of freedom (df) = 10, p < 0.001]; rising from 0.48 to 1.39 μ g to account for 0.04% of the total dose of d-MPH calculated to be cutaneously delivered. Further, in animals dosed with MTS, total urinary excretion of l-MPH was significantly increased, rising from 0.43 μ g for animals dosed with dH2O to 0.96 μ g for animals dosed with ethanol (Fig. 5a; t = 4.07, df = 10, p < 0.01). There was not a significant difference between the urinary excretion of d-MPH compared with l-MPH in animals dosed with dH2O; however, in animals dosed with ethanol, the urinary excretion of d-MPH was significantly greater than l-MPH (t = 2.13, df = 10, p < 0.05). Both enantiomers of EPH were detectable in animals gavaged with ethanol; however, l-EPH was enantioselectively formed with a significantly greater total elimination found relative to d-EPH (Fig. 6a; t = 5.74, df = 10, p < 0.001). The total urinary elimination of l-EPH was 0.2 μ g, which represents 0.01% of the total dose of l-MPH calculated to be cutaneously delivered, whereas the total urinary elimination of d-EPH was 0.05 μ g. The total urine volume excreted following ethanol treatment was significantly greater than following dH2O treatment (t = 4.81, df = 10, p < 0.001) as consistent with the diuretic effect of ethanol.

87.

88. Figure 4

89. (a) In mice treated with one quarter of a 12.5 cm2 MTS for 3.25 h, ethanol (3.0 g/kg, gavaged at 0.25 h) increased total excretion of d-MPH in urine and increased d-MPH concentrations in blood and brain relative to dH2O. (b) In mice gavaged with dl-MPH ...

90.

91. Figure 5

92. (a) In mice treated with one quarter of a 12.5 cm2 MTS for 3.25 h, ethanol (3.0 g/kg, gavage at 0.25 h) increased total excretion of l-MPH in urine and increased l-MPH concentrations in blood and brain relative to dH2O gavage. (b) In mice gavaged with ...

93.

94. Figure 6

95. (a) Ethanol (3.0 g/kg, gavage at 0.25 h) and one quarter of a 12.5 cm2MTS resulted in enantioselective l-EPH formation as quantified in 3.25 h urine, blood, and brain. (b) Concomitant gavage of ethanol (3.0 g/kg) and dl-MPH (7.5 mg/kg) resulted in greater ...

96. Oral Dl-MPH

97. The total urinary elimination of d-MPH following oral dl-MPH over the 3 h collection period was significantly greater in the animals dosed with ethanol compared with those given dH2O (Fig. 4b; t = 7.56, df = 10, p < 0.001); rising from 0.09 to 0.46 μ g and accounting for 0.012% of the total dose of d-MPH gavaged. Further, in animals dosed with oral dl-MPH, the total urinary excretion of l-MPH was significantly increased, rising from 0.07 μ g for animals dosed with dH2O to 0.31 μ g for animals dosed with ethanol (Fig. 5b; t = 5.45, df = 10, p < 0.001). There was not a significant difference between the urinary excretion ofd-MPH compared with l-MPH in animals dosed with dH2O; however, in animals dosed with ethanol, the urinary excretion of d-MPH was significantly greater than l-MPH (t = 2.23, df = 10, p < 0.05). Both isomers of EPH were detectable in animals gavaged with ethanol; however, l-EPH was enantioselectively formed with a significantly greater total urinary elimination of l-

EPH relative to d-EPH (Fig. 6b; t = 3.71, df = 10, p < 0.01). The total urinary elimination of l-EPH was 0.02 μ g, whereas the total urinary elimination of d-EPH was 0.005 μ g. Again, the total urine volume excreted followed ethanol (a diuretic) treatment was significantly greater than following dH2O treatment (t = 4.39, df = 10, p < 0.001).

98. Influence of Ethanol on Blood Analytes

99.Transdermal Dl-MPH

100. The blood concentration of d-MPH after MTS dosing was significantly greater in animals dosed with ethanol compared with dH2O; increasing 72% from 0.36 to 0.61 μ g/mL (Fig 4a; t = 4.22, df = 10, p < 0.01). Further, in animals dosed with MTS, concentrations of l-MPH significantly increased from 0.29 μ g/mL for animals dosed with dH2O to 0.51 μ g/mL for animals dosed with ethanol (Fig. 5a; t = 2.82, df = 10, p < 0.05). There was no significant difference between the blood concentration ofd-MPH and l-MPH in animals dosed with dH2O or in animals dosed with ethanol. Both enantiomers of EPH were formed in animals gavaged with ethanol; however, l-EPH was enantioselectively formed with a significantly greater concentration found relative to d-EPH (Fig. 6a; t = 2.99, df = 10, p < 0.05). The blood concentration of l-EPH was 0.04 μ g/mL, whereas the concentration of d-EPH was 0.03 μ g/mL.

101. Oral Dl-MPH

102. The blood concentration of d-MPH following oral dl-MPH was significantly greater in the animals dosed with ethanol compared with those given dH2O; increasing 59% from 0.018 to 0.03 μ g/mL (Fig. 4b; t = 2.95, df = 10, p < 0.05). Further, in animals dosed with oral dl-MPH, concentrations of l-MPH were significantly increased from 0.015 μ g/mL for animals dosed with dH2O to 0.05 μ g/mL for animals dosed with ethanol (Fig. 5b; t = 4.56, df = 10, p < 0.001). There were no significant differences between the blood concentration of d-MPH and l-MPH in animals dosed with dH2O or in animals dosed with ethanol. Neither isomer of EPH was detectable in animals gavaged with oral dl-MPH and ethanol.

103. Effect of Ethanol on Brain Analytes

104. Transdermal Dl-MPH

105. The brain concentration of d-MPH after MTS dosing was significantly greater in animals dosed with ethanol compared with the dH2O group; increasing 65.3% from 0.81 to 1.34 μ g/g (Fig. 4a; t = 2.89, df = 10, p < 0.05). Further, in animals dosed with MTS, concentrations of l-MPH were significantly increased by ethanol, rising from 0.84 μ g/g for animals dosed with dH2O to 1.33 μ g/g for animals dosed with ethanol (Fig. 5a; t = 2.18, df = 10, p < 0.05). There were no significant differences between the brain concentration of d-MPH and l-MPH in animals dosed with dH2O or in animals dosed with ethanol. Both isomers of EPH were formed in animals gavaged

with ethanol; however, l-EPH was enantioselectively formed with a significantly greater concentration found relative to d-EPH (Fig. 6a; t = 8.57, df = 10, p < 0.001). The brain concentration of l-EPH was 0.14 μ g/g, whereas that of d-EPH was 0.005 μ g/g.

106. Oral Dl-MPH

107. The brain concentration of d-MPH following oral dl-MPH was significantly greater in the animals dosed with ethanol compared with those given dH2O; increasing 40.6% from 0.03 to 0.05 μ g/g (Fig. 4b; t = 3.67, df = 10, p < 0.01). Further, in animals dosed with oral dl-MPH, concentrations of l-MPH were significantly increased from 0.02 μ g/g for animals dosed with dH2O to 0.06 μ g/g for animals dosed with ethanol (Fig. 5b; t = 3.83, df = 10, p < 0.01). There were no significant differences between the brain concentration of d-MPH and l-MPH in animals dosed with dH2O or in animals dosed with ethanol. Both isomers of EPH were formed in animals gavaged with ethanol; however, l-EPH appeared to have been enantioselectively formed, although the mean concentration was not significantly different from that of d-EPH (Fig. 6b).

108. Go to:

109. DISCUSSION

110. Oral dl-MPH in humans is subject to pronounced enantioselective first-pass metabolism that limits l-isomer systemic exposure to approximately 1% that of d-MPH.52 The mean absolute bioavailability of dl-MPH has been reported to be 30%, but ranges from 11% to 51%.60,61 In effect, first-pass metabolism biocatalytically “resolves” oral dl-MPH,62 resulting in only the d-isomer appreciably reaching the blood-stream. The d-isomer component of dl-MPH is generally regarded as the pharmacologically active isomer, responsible for efficacy in the treatment of ADHD.63,64 The low oral bioavailability of dl-MPH is largely due to the facile hydrolysis of the constituent methyl ester to yield the inactive35 metabolite dl-ritalinic acid and catalyzed primarily through the actions of CES1.37,38,39,65 This facile pathway limits the half-life of dl-MPH to only 2–3 h.66 Approximately 1% of MPH is excreted in urine unchanged in humans over 24 h, and excreted predominantly as the d-isomer.56

111. Our studies with mice dosed with oral dl-MPH (7.5 mg/kg) and dH2O, while being limited to a single 3-h time point for blood and brain sampling, suggest a lower degree of metabolic enantioselectivity relative to humans, whereby the d-MPH-to-l-MPH ratio for blood and brain were 1.22 and 1.36, respectively. This apparent greater oral bioavailability of l-MPH in the C57 mouse than in man is in general agreement with plasma results using CD1 mice dosed at 5.0 mg/kg67 or pregnant rats dosed at 7.0 mg/kg.68 Further, the extent of accumulation in brain relative to blood is expected to

be less dramatic at 3 h than at earlier time points, especially after oral administration if the decay time course resembles that of the Sprague–Dawley rat.58

112. A primary aim of the present study was to model transdermal MPH–ethanol metabolic interactions. A quarter of the smallest commercially available MTS patch was used and this delivered a mean dose of approximately 7.5 mg/kg of dl-MPH over the 3.25 h wear period based on the difference between drug content before and after application. Although the MTS is not designed to be cut into portions for clinical applications, the dl-MPH content in each patch is evenly distributed throughout the patch3 and required apportioning when using such a small species as the mouse. dl-MPH delivery has been reported to occur in a manner directly proportional to the patch surface area in humans.3,69 Accordingly, the drug content in the quarter 12.5 cm2patches used in the present study was 25% of 27.5 mg, that is, 6.88 mg. The mean dose of 0.23 mg of dl-MPH delivered to the mice (n = 12) over the 3.25 h wear period represents 3.3% of the quarter patch content of dl-MPH and ranged from 1.9% to 5.1%. In humans, the uncut 12.5 cm2 patch size is designed to deliver a mean dl-MPH dose of 10 mg over the recommended 9 h wear period. This dose represents 36% of the patchdl-MPH content, although ranging between subjects from 15% to 72%.70

113. These apparent transdermal dl-MPH absorption differences reflect many factors including: (1) the shorter wear time of 3.25 h for the mouse, (2) the faster rate of ester substrate metabolism expected with rodents relative to humans,71 (3) the hair follicle-rich shaved skin of the mice opposed to the skin surface of the recommended hip placement in clinical applications, and (4) the potential for a greater relative absorption lag time for the 3.25 h wear period in mice versus 9 h in humans. In this latter context, the average lag time for detectable d-MPH in plasma after applying MTS to humans is 3.1 h (ranging from 1 to 6 h).72 The above factors notwithstanding, it is recognized that the percutaneous absorption rate for a range of drugs in mice and other rodents has generally been found to be more rapid than in humans or pigs.73

114. Although the present investigation appears to represent the first MTS study to use mice, previous preclinical studies have shown that shaved mice serve to model transdermal drug delivery.74 Hairless or nude mice are more typically used for transdermal delivery studies across the range of patch technologies75; however, the neuropharmacological reference strain status of the C57 mouse provided the justification for its use in investigating dl-MPH–ethanol interactions (see Introduction section). Maintaining the mice in the metabolic chambers for a total of 3 h allowed for the collection of adequate urine volume for analysis, while still permitting quantification of analytes from blood and brain. In this context, the mean elimination half-life ofdl-MPH in mice (B6C3F1 strain; 3 mg/kg orally) has been reported to be 1.1 h,76 whereas that of ethanol (2 g/kg i.p.) in C57 mice appears to be approximately 1.3 h.77

115. Enantioselective l-EPH Transesterification

116. As with oral dosing in humans,33 coadministration of ethanol and transdermal or oral dl-MPH in C57 mice resulted in the enantioselective transesterification of dl-MPH, favoring l-MPH over d-MPH as a substrate. EPH was detectable in the brain, blood, and urine of these mice. Selection of an appropriate species to model esterase-mediated metabolism of dl-MPH was an important consideration in our study design. For instance, beagle dogs have been used in pioneering dl-MPH metabolism studies,78 and in subsequent toxicokinetic studies.79 However, esterase-mediated hydrolysis of dl-MPH in beagle dogs exhibit the opposite enantioselectivity, preferentially deesterifying d-MPH over l-MPH.80 Further, on the basis of both human investigations33 and the present findings with C57 mice, the enantioselective formation of l-EPH with coadministration of dl-MPH and ethanol is accompanied by an elevation in d-MPH concentrations relative to dosing with dl-MPH alone. Although l-EPH formation was found to be enantioselective, this metabolic pathway was not enantiospecific, that is, l-EPH concentrations significantly exceeded d-EPH values, although d-EPH was readily detectable and quantifiable in C57 mouse samples following MTS and ethanol, as well as in the urine of animals dosed orally with dl-MPH. In humans dosed orally with dl-MPH and ethanol, d-EPH rarely exceeded 10% of the concentration of l-EPH.33

117. In potential forensic medicine applications,42 detection of EPH from biological samples could serve as a biomarker to demonstrate combined consumption of dl-MPH and ethanol, analogous to the detection of cocaethylene as evidence of cocaine–ethanol coabuse.81

118. The high degree of hepatic localization of CES1 compared with its low level of intestinal expression implicates hepatic transesterification as the primary site of EPH formation after oral dosing of dl-MPH.38However, when dosing dl-MPH by the transdermal route, presystemic esterase metabolism may also occur, as has been reported during percutaneous disposition of ester-containing drugs. Transdermal presystemic hydrolysis has been especially associated with the cutaneous fat layer, where methyl ester- and ethyl ester-containing drugs are reported to be readily deesterified in skin during transdermal transport.73,82–85 Some degree of presystemic transesterification of dl-MPH to EPH may also occur. In the presence of ethanol, transesterification of methyl esters to ethyl esters has been reported in skin.86 For instance, the methyl ester methylparaben is rapidly hydrolyzed in skin,83 although in the presence of ethanol, hydrolysis of methylparaben is inhibited by competitive esterase-mediated transesterification of methylparaben to ethylparaben in pig87 or human88 skin.

119. As with hepatic esterase substrates, skin esterase activity has also been reported to exhibit enantioselectively, for example, during prodrug ester activation by hydrolysis.89 The possibility of cutaneous esterase-mediated biotransformation resulting in transesterification of transdermal dl-MPH with ethanol may be favored by

the mildly basic cutaneous pH expected at the MTS application site considering the high concentration of dl-MPH free base found in MTS.3 Mild cutaneous basicity has been reported to accelerate the rate of ester xenobiotic hydrolysis. For instance, esterase activity toward transdermal drug substrates was accelerated at a pH of 8, but was inhibited at the lower pH of 5.88 dl-MPH is an especially weak organic base even though it contains a secondary aliphatic amine; it exhibits a pKa of 8.4 versus the pKa of 9.6 for the stimulant methamphetamine.90 This relatively low basicity of dl-MPH has been theorized to be a consequence of an intramolecular hydrogen bonding interaction between the amine and the methyl ester carbonyl within the MPH structure.91

120. Still considering the potential for some degree of cutaneous EPH formation, in addition to subsequent hepatic metabolism, oral ethanol is rapidly distributed throughout mammalian tissue, and a portion of the nonmetabolized dose is excreted cutaneously (sweat), in addition to ethanol excretion by the lungs and kidney.92 Finally, even oral MPH reaches skin, as demonstrated using commercial sweat patches placed on the back.93

121. Significant Increases In d-MPH Concentrations by Ethanol

122. The concentrations of d-MPH in blood, brain, and urine were significantly greater in mice dosed with ethanol than those dosed with dH2O. These findings occurred when dosing either transdermally or orally. d-MPH elevation following concomitant MPH–ethanol administration was especially pronounced under the conditions used when dosing dl-MPH by the transdermal route. However, any direct comparisons between the extent to which ethanol influences either d-MPH concentrations or EPH formation as a function of dosing route cannot be reasonably made due to the inherent disparities of comparing an oral bolus dose of dl-MPH with that of the ongoing release of dl-MPH from the MTS. It is possible that the elevated l-MPH levels associated with transdermal dosing in C57 mice relative to oral dosing could be relevant to the extent to which ethanol elevates d-MPH in the course of ethanol interacting with CES1 to form l-EPH.

123. Approximately 50 times more of l-MPH reaches the systemic circulation in humans when dl-MPH is dosed transdermally than when dosed orally,53 and l-MPH is the isomer that enantioselectively serves as a CES1 substrate in the presence of ethanol.33,38,39,94,95 If ethanol facilitates d-MPH absorption from the MTS through esterase inhibition at the level of the skin and/or liver, the resulting higher drug concentrations, and potentially more rapid rate of absorption of MPH, may influence pleasurable effects33 of this drug combination, and contribute to additional abuse liability.49–51 Further, elevated d-MPH plasma concentrations pose the potential for adverse or lethal42 cardiovascular effects.45,15 In view of the significant influence of ethanol on d-MPH concentrations in the C57 mouse model reported here, transdermal dl-MPH used to treat adult ADHD may be associated with clinical

considerations unique to this route of administration. Should drug interaction findings from of this animal model hold for humans?

124. Go to:

125. ACKNOWLEDGMENTS

126. This study was supported by the NIH RO1 AA016707 (K.S.P.).

9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490317/

Int Neurourol J. 2015 Jun; 19(2): 67–73.

Published online 2015 Jun 29. doi:  10.5213/inj.2015.19.2.67

PMCID: PMC4490317

Does Methylphenidate Affect Cystometric Parameters in Spontaneously Hypertensive Rats?Khae Hawn Kim,1 Ha Bum Jung,2 Don Kyoung Choi,2 Geun Ho Park,3 and Sung Tae Cho2

Corresponding author: Sung Tae Cho http://orcid.org/0000-0002-4691-6159 E-mail:  Department of Urology, Hallym

University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 1 Singil-ro, Yeongdeungpo-gu, Seoul 150-

950, Korea ,  moc.narap@623tsc / Tel: +82-2-829-5198 / Fax: +82-2-846-5198

Author information   ▼  Article notes   ▼  Copyright and License information   ▼

Received 2015 May 24; Accepted 2015 May 31.

Copyright © 2015 Korean Continence Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License

(http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction

in any medium, provided the original work is properly cited.

AbstractGo to:

INTRODUCTION

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated neurological behavior disorders in children and adolescents [1]. The prevalence of ADHD among children and adolescents is estimated to be 3%–5%, depending on the classification system used, with boys affected 3–10 times more frequently than girls [2,3].

ADHD is characterized by inattention, hyperactivity, impulsivity, or a combination of these symptoms, which compromise everyday, basic functions [1]. Although ADHD is the most commonly studied and diagnosed psychiatric disorder in children and adolescents, its cause remains unknown.

Methylphenidate (MPH) is a central nervous system (CNS) stimulant that has been widely prescribed for the treatment of ADHD, and has been used for treating ADHD since more than 50 years [2]. It is presumed that the effects of MPH on ADHD symptoms are related to its role on dopaminergic and noradrenergic neurotransmission in the CNS [4].

Several studies have revealed co-occurrence of lower urinary tract (LUT) symptoms with enuresis and symptoms of ADHD [5,6]. Notably, the co-occurrence of enuresis and ADHD is approximately 30% [6]. However, little is known about the precise effects of MPH on the LUT. Only a limited number of studies have reported therapeutic effects of MPH in the treatment of giggle incontinence [7,8]. We recently performed a cystometric study about the effects of MPH in conscious mice that showed dose-dependent effects on the function of the LUT [9]. However, animal disease models are needed to establish the various effects of MPH on the LUT, particularly in patients with ADHD.

The spontaneously hypertensive rat (SHR) is the most extensively investigated genetic model and the only animal model that has been used to demonstrate all the behavioral characteristics of ADHD [10]. The aim of this study was to investigate whether intragastric injection of MPH affects cystometric parameters in conscious SHRs, an animal model for ADHD.

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MATERIALS AND METHODS

Animals

Fourteen- to 16-week-old male SHRs (n =10), weighing between 280 and 315 g, were purchased from Orient Bio Inc. (Seongnam, Korea). The animals were kept in standard housing facilities with a 12-hour light/dark cycle. The rats were given food and water were ad libitum. All experimental animals were handled according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

Surgical Procedures

Each SHR was intraperitoneally anesthetized using xylazine (15 mg/kg) and ketamine (75 mg/kg). A suprapubic midline incision was made to expose the bladder and the urethra. Three days before the cystometric investigations, a surgery was performed for catheter placement to record intra-abdominal pressure (IAP) and intravesical pressure (IVP), and the procedure was based on a previously used method [11].

A polyethylene PE-50 catheter (Clay-Adams, Parsippany, NJ, USA) with a cuff was introduced into the bladder dome. A purse-string suture was applied to attach the catheter. A balloon was placed around the cuff proximal to the bladder for recording the IAP.

Another PE-50 catheter (Clay-Adams) with a cuff was introduced into the body of the stomach in a similar manner. All catheters were tunneled subcutaneously and transported percutaneously to the backs of the animals.

Materials

MPH (Ritalin, Novartis Pharmaceuticals, Basel, Switzerland) was dissolved in 0.9% saline solution. To evaluate the effects of two different doses of MPH (3 mg/kg and 6 mg/kg), a 0.39- to 0.94-mL solution was administered intragastrically using the catheter.

Cystometric Investigations

Three days after the surgery, awake cystometry was performed. The catheter from the bladder was connected to a pressure transducer and an injection pump by using a T-tube. The other catheter to the balloon was connected to an extra pressure transducer for recording the IAP. A thin polyester sealing film prevented leakage through the connectors. These leakages can introduce errors while recording the IAP.

Micturition volumes (MVs) were measured using a collecting funnel connected to a force displacement transducer. Saline was continuously infused intravesically at a rate of 10 mL/hr. A cystometrogram was recorded using the AcqKnowledge software (Biopac Systems, Goleta, CA, USA) and an MP150 system (Biopac Systems) at a recording speed of 10 mm/min.

Three representative MVs were recorded consecutively to analyze the baseline data. One hour after each intragastric injection of MPH, cystometrograms were obtained consecutively using the same method. The results were compared with the corresponding baseline values.

The cystometric parameters were analyzed using the mean values of three consecutive micturition cycles. The parameters analyzed are listed as follows:

Basal pressure (BP): the lowest bladder pressure during filling Maximal pressure (MP): the maximum bladder pressure during micturition

Threshold pressure (TP): the bladder pressure immediately before micturition

Residual volume (RV): the volume of urine remaining after micturition

Micturition volume (MV): the volume of urine passed

Bladder capacity (BC: RV + MV)

Micturition interval (MI): the intercontraction interval

IAP was defined as the recorded balloon pressure corrected by subtracting the lowest balloon pressure in each micturition cycle.

After the procedure, the animals were sacrificed by cervical dislocation. The bladder and urethra were excised and weighed.

Statistical Analyses

Data were analyzed using paired Student t-tests. GraphPad Prism (GraphPad Software Inc., La Jolla, CA, USA) was used for the same. The results were expressed as mean±standard error. The level of significance was set at P<0.05.

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RESULTS

Five SHRs were each administered a low dose of MPH (3 mg/kg), and the other five received a higher dose of MPH (6 mg/kg). Body and bladder weights did not differ significantly between the two groups (Fig. 1).

Fig. 1.

Body weight (A) and bladder weight (B) in spontaneous hypertensive rats treated with 3- or 6-mg/kg MPH. There was no difference in body and bladder weights between the two groups. MPH, methylphenidate; NS, not significant.

The representative baseline cystometrograms and the cystometrograms obtained 1 hour after intragastric injections of MPH in the two groups are shown in Fig. 2. The different pressure parameters were compared on the basis of detrusor pressure, which is derived by subtracting IAP from IVP.

Fig. 2.

Representative baseline cystometrograms and cystometrograms obtained 1 hour after intragastric injection of methylphenidate in the low-dose, 3-mg/kg group (A and B, respectively) and in the high-dose, 6-mg/kg group (C and D, respectively). Pves, vesical ...

The BP and MP increased significantly after the 3-mg/kg MPH injection (BP: 13.9±6.9 cm H2O before the injection vs. 23.2±6.9 cm H2O after the injection, P<0.01; MP: 47.0±9.8 cm

H2O before vs. 57.9±8.2 cm H2O after the injection, P<0.05). However, BP and MP did not show any significant changes after the 6-mg/kg MPH injection. There were no significant changes in TP after either injection (Fig. 3).

Fig. 3.

Effects of each dose MPH on cystometric parameters. (A) Basal pressure. (B) Micturition pressure. (C) Threshold pressure. MPH, methylphenidate; NS, not significant. *P<0.05. **P<0.01.

Volume parameters, including BC, MV, and MI increased significantly after the 6-mg/kg MPH injection (BC: 0.47±0.07 mL before the injection vs. 0.60±0.05 mL after the injection, P<0.01; MV: 0.47±0.07 mL before vs. 0.60±0.05 mL after the injection, P<0.01; MI: 4.68±0.21 minutes before vs. 5.75±0.26 minutes after the injection, P<0.01). However, there were no significant changes in these parameters after the 3-mg/kg MPH injection (Fig. 4). There was no RV at any time, either before or after the MPH injection, in any group.

Fig. 4.

Effects of each dose MPH on cystometric parameters. (A) Bladder capacity. (B) Micturition volume. (C) Micturition interval. MPH, methylphenidate; NS, not significant. **P<0.01.

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DISCUSSION

This study investigated dose-dependent changes in cystometric parameters after intragastric administration of MPH in SHRs, an animal model of ADHD, and determined whether the CNS stimulant MPH could influence LUT function in this animal disease model.

The SHR is a well validated and frequently used animal model of ADHD [10,11]. It has been reported that although other strains and species may present hyperactivity and attention deficits in accordance with the genetic, environmental, and pharmacological interventions, the SHR is the only strain to have the main behavioral appearances of ADHD [11,12]. In addition, because of their multiple, coexisting phenotypic characteristics, SHRs have also been used as models of other diseases, such as hypertension, stroke, anxiety, and detrusor

overactivity [13,14]. Therefore, in this study, we evaluated the cystometric response to MPH by using conscious SHRs.

Previous studies reported increased afferent sensitivity in SHRs that may contribute to their bladder hyperactivity [15]. SHRs show increased voiding frequency, and conversely, decreased BC and MV compared to Wistar rats [13]. The results of our study, using the animal model of ADHD, are similar to those of previous studies on SHRs.

MPH is a CNS stimulant that has been used as the first choice in the treatment of ADHD in children [2,4]. MPH blocks the reuptake of dopamine and noradrenaline, but its precise mechanisms of action on symptoms of ADHD are not clear [12]. MPH has also been used in the treatment of narcolepsy, mild depression, brain injury, cancer, cognitive disorders, and in combination with other drugs, in the treatment of chronic pain [16]. Side effects are usually mild and are generally well tolerated by patients. The most common side effects are insomnia, stomachache, headache, and anorexia [17]. Usually, these side effects either diminish in severity over time to tolerable levels or can be managed effectively during the course of the treatment [16,17].

In this study, we used two different doses of MPH: 3 mg/kg and 6 mg/kg. Most of the previous studies have used significantly higher doses (2–15 mg/kg, intravenously or 10–50 mg/kg, intraperitoneally) than those used clinically in humans (0.3–1 mg/kg) [18]. In SHRs, the effects of MPH over a wide range of doses (0.1–20 mg/kg, intraperitoneally) have been evaluated [19,20]. Intraperitoneal MPH (5 mg/kg and 10 mg/kg) was approximately twice as potent as intragastric MPH regarding the increase of extracellular dopamine levels and locomotion stimulation [18]. MPH doses used in this present study were selected based on a previous study.

In our previous study, we administered a low dose of MPH (1.25 mg/kg) as well as high doses of MPH (2.5 mg/kg and 5.0 mg/kg) in mice by using a gastric catheter. We observed typical micturition cycles of mice using awake cystometry. MP decreased and BC increased without any elevation in RV in the low-dose group. However, in the high-dose groups, we could not find any typical configurations of micturition cycles, except urine leakage [9].

Unlike our previous mice study, this study showed typical micturition cycles, regardless of the dose of MPH for all SHRs. With high doses of MPH (6 mg/kg), the SHRs showed increased MV, MI, and BC with no increase in RV. However, with low doses of MPH (3 mg/kg), the SHRs showed no significant changes in MV, MI, or BC. These findings suggest that despite being a CNS stimulant, MPH may play a pivotal role in the peripheral nervous system (PNS) of the LUT in patients receiving treatment for ADHD with high doses of MPH (6 mg/kg). To date, the exact oral dose of MPH to regulate LUT has not been established, especially for SHRs. However, our results provide knowledge on the doses of MPH to regulate LUT involving PNS action while maintaining CNS effects.

One of the limitations of this study was the absence of a control group to compare the effects of MPH on the LUT. A control group consisting of normal Sprague-Dawley or Wistar rats

should have been included to compare the results of the effects of MPH on a rat model without ADHD. Another limitation is the lack of morphological assessment using molecular assays. We only evaluated the functional role of MPH in the LUT by using awake rat cystometry. However, the combined use of functional and molecular assays would have elucidated the precise effects of MPH on the LUT of SHRs. Despite these limitations, this study provides important information on the effects of MPH on the LUT.

In conclusion, intragastric injection of MPH (6 mg/kg) in SHRs showed significant increases in BC, MV, and MI. This suggests that the PNS, as well as the CNS, may have important roles in LUT function when treating ADHD with MPH.

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Footnotes

Grant Support

This study was supported by Hallym University Research Fund 2013 (HURF-2013-23).

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

10. http://ijnp.oxfordjournals.org/content/ijnp/15/1/41.full.pdf >> Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies

11. http://ijnp.oxfordjournals.org/content/ijnp/early/2015/07/17/ijnp.pyv074.full.pdf >> Waiting Impulsivity: The Influence of Acute Methylphenidate and Feedback

12

Atomoxetine (Strattera (R)) adalah selektif norepinefrin (noradrenalin) reuptake inhibitor yang tidak diklasifikasikan sebagai stimulan, dan diindikasikan untuk digunakan pada pasien dengan gangguan attention-deficit hyperactivity disorder (ADHD). Atomoxetine efektif dan umumnya ditoleransi dengan baik. Hal ini secara signifikan lebih efektif daripada terapi plasebo dan standar saat ini dan tidak berbeda secara signifikan dari atau noninferior untuk segera-release methylphenidate; Namun, hal itu secara signifikan lebih efektif daripada formulasi extended-release methylphenidate Oros (R) methylphenidate (selanjutnya disebut sebagai osmotik dirilis methylphenidate) dan extended-release garam dicampur amfetamin. Atomoxetine dapat diberikan baik sebagai dosis harian tunggal atau dibagi menjadi dua dosis terbagi, memiliki risiko diabaikan penyalahgunaan atau penyalahgunaan, dan bukan merupakan zat yang dikendalikan di Amerika Serikat. Atomoxetine sangat berguna untuk pasien berisiko penyalahgunaan zat, serta mereka yang memiliki kecemasan co-morbid atau tics, atau yang tidak ingin mengambil zat yang dikendalikan. Dengan demikian, atomoxetine adalah pilihan yang berguna dalam pengobatan ADHD pada anak-anak dan remaja. Mekanisme kerja dari atomoxetine tidak jelas, namun diduga terkait dengan penghambatan selektif dari presinaptik norepinephrine reuptake di korteks prefrontal. Atomoxetine memiliki afinitas tinggi dan selektivitas untuk transporter norepinefrin, tapi sedikit atau tidak ada afinitas untuk berbagai reseptor neurotransmitter. Atomoxetine memiliki kemampuan yang ditunjukkan untuk selektif menghambat penyerapan norepinefrin pada manusia dan hewan, dan penelitian menunjukkan bahwa secara istimewa mengikat ke daerah distribusi yang tinggi diketahui neuron noradrenergik, seperti subsistem fronto-kortikal. Atomoxetine yang umumnya terkait dengan statistik, tetapi tidak secara klinis, peningkatan yang signifikan di kedua denyut jantung dan tekanan darah pada pasien anak dengan ADHD. Sementara ada kerugian awal tinggi diharapkan dan berat antara penerima atomoxetine, ini akhirnya kembali normal dalam jangka panjang. Data menunjukkan bahwa atomoxetine tidak mungkin untuk memiliki potensi penyalahgunaan. Atomoxetine muncul kurang mungkin dibandingkan methylphenidate memperburuk tidur teratur pada pasien anak dengan ADHD. Atomoxetine adalah diserap dengan cepat, dan menunjukkan peningkatan dosis-proporsional dalam paparan plasma. Itu mengalami biotransformasi luas, yang dipengaruhi oleh metabolisme yang buruk oleh sitokrom P450 (CYP) 2D6 dalam persentase kecil dari populasi; pasien ini memiliki eksposur yang lebih besar untuk dan penghapusan lebih lambat dari atomoxetine dari metabolisme luas. Pasien dengan insufisiensi hati menunjukkan peningkatan eksposur atomoxetine. Inhibitor CYP2D6, seperti paroxetine, yang berhubungan dengan perubahan farmakokinetik atomoxetine serupa dengan yang diamati antara metabolisme CYP2D6 miskin. Sekali-dua kali sehari atomoxetine efektif dalam pengobatan jangka pendek ADHD pada anak-anak dan remaja, seperti yang diamati di beberapa dirancang dengan baik uji coba terkontrol plasebo. Atomoxetine juga menunjukkan keberhasilan dalam pengobatan jangka panjang dari pasien-pasien ini. Dosis pagi tunggal terbukti efektif ke dalam malam, dan penghentian atomoxetine tidak berhubungan dengan gejala rebound yang. Khasiat atomoxetine tampaknya tidak berbeda antara anak-anak dan remaja. Pasien stimulan-naif juga merespon dengan baik terhadap pengobatan atomoxetine. Atomoxetine tidak berbeda secara signifikan dari atau adalah noninferior untuk segera-release methylphenidate pada anak-anak dan remaja dengan ADHD berkaitan dengan keberhasilan, dan secara signifikan lebih efektif daripada terapi standar saat ini (kombinasi obat-obatan [tidak termasuk atomoxetine] dan / atau konseling

perilaku, atau tidak ada perawatan). Namun, atomoxetine secara signifikan kurang efektif daripada osmotik dirilis methylphenidate dan diperpanjang-release garam dicampur amfetamin. Khasiat atomoxetine tampaknya tidak terpengaruh oleh adanya gangguan co-morbid, dan gejala gangguan co-morbid tidak terpengaruh atau ditingkatkan dengan pemberian atomoxetine. Kualitas kesehatan yang berhubungan-hidup (HR-QOL) tampaknya positif terkena atomoxetine dalam kedua studi jangka pendek dan jangka panjang; atomoxetine juga ditingkatkan SDM-QOL untuk sebagian besar dari terapi standar saat ini. Atomoxetine pada umumnya ditoleransi dengan baik pada anak-anak dan remaja dengan ADHD. Efek samping yang umum sakit kepala termasuk, sakit perut, nafsu makan menurun, muntah, mengantuk, dan mual. Mayoritas efek samping yang ringan atau sedang; ada kejadian yang sangat rendah dari efek samping yang serius. Beberapa pasien menghentikan pengobatan atomoxetine karena efek samping. Atomoxetine penghentian tampaknya ditoleransi dengan baik, dengan insiden rendah efek samping penghentian-muncul. Atomoxetine muncul ditoleransi lebih baik antara metabolisme CYP2D6 yang luas dari kalangan metabolisme miskin. Sedikit perbedaan yang jelas dalam profil efek samping dari atomoxetine dan stimulan, baik immediate- dan extended-release. Mengantuk muncul lebih umum di antara penerima atomoxetine dan insomnia muncul lebih umum di antara penerima stimulan. Sebuah kotak hitam peringatan untuk ide bunuh diri telah diterbitkan dalam informasi resep AS, berdasarkan temuan dari meta-analisis menunjukkan atomoxetine yang berhubungan dengan kejadian secara signifikan lebih tinggi dari keinginan bunuh diri dibandingkan plasebo. Jarang, atomoxetine juga dapat dikaitkan dengan kerusakan hati yang serius; Data postmarketing menunjukkan bahwa tiga pasien memiliki efek samping terkait hati dianggap mungkin terkait dengan pengobatan atomoxetine. Algoritma pengobatan yang melibatkan penggunaan awal atomoxetine muncul biaya yang efektif terhadap algoritma yang melibatkan methylphenidate awal (immediate- atau diperpanjang-release), dexamfetamine, antidepresan trisiklik, atau tanpa pengobatan dalam stimulan-naif, -failed, dan anak-anak -contraindicated dan remaja dengan ADHD. Biaya tambahan per berkualitas disesuaikan hidup tahun ini di bawah umum diterima ambang efektivitas biaya, seperti yang ditunjukkan pada beberapa model yang Markov analisis dilakukan dari sudut pandang berbagai negara Eropa, dengan horizon waktu 1 tahun.