"The Smart Drug"
Cognitive Enhancer Methylphenidate
If we make a survey asking people who would want to be more intelligent, aplicated, and concentrated, we bet that at least 95% of the people would say: ME! The possibility that a drug can make this possible has been something that continues to fascinate men and investigators. Methylphenidate, or most commonly known as Ritalin, is a widely used drug to treat ADHD and narcolepsy. It's believed that this drug is a potential "cognitive enhancer" and for these reason some people are abusing it. Its capacity to prolongate attention, reduce sleepiness, and enhance retention make it a popular drug for students. In this blog we provide basic information about Methylphenidate taking in account neurological, biological, physiological, and psychological context.
The use of medical stimulants to sustain attention, augment memory
and enhance intellectual capacity is increasing in society. The use of
Methylphenidate for cognitive enhancement is a subject that has received much
attention in the literature and academic circles globally in recent times. Ritalin is the common
name for methylphenidate, classified by the Drug Enforcement Administration as
a Schedule II narcotic—the same classification as cocaine, morphine and
amphetamines (Beyer, C, et al., 2014). Methylphenidate was first synthetized in 1944 by Leandro Pannizon, a chemist working for Ciba. Was indentified as a stimulant ten years laters and called Ritalin, making reference to Pannizon wife, who had low blood pressure and was using it as a stimulat to play tennis (Meiers, R., 1954). Beginning in the 1960's, it was used to treat ADD and ADHD, and in 2000 the extended release version, Concerta, was approved by the FDA.
Methylphenidate is commonly prescribed for treatment of ADHD and narcolepsy. Attention-deficit/hyperactivity disorder (ADHD) is among the most common neurobehavioral disorders presenting for treatment in children. It carries a high rate of comorbid psychiatric problems such as oppositional defiant disorder (ODD), conduct disorder, mood and anxiety disorders, and cigarette and substance use disorders. Across the life span, the social and societal costs of untreated ADHD are considerable, including academic and occupational underachievement, delinquency, motor vehicle safety, and difficulties with personal relationships (Wilens, T., & Spencer, T., 2013). According to recent survey, the number of children diagnosed eith ADHD continues to increase reaching nearly 2 million additional cases in U.S. children and adolescents in 2011 compared to 2003 (Yang, M., et al, 2014).
The extended release form of Methylphenidate is usually prescribed to patients suffering of narcolepsy. Narcolepsy is a chronic brain disorder that involves poor control of sleep-wake cycle. People with this conditions experience periods of extreme daytime sleepines and sudden, irresitible bouts of sleep that can strike at any time. For more information about narcolepsy visit NIH Narcolepsy Fact Sheet
In the other side, the off-label use is increasing in students. Studies by Beyer, C. et al, 2014, show that Medical Students in South Africa are using it as a cognitive enhancer. Other studies made in the University of Pennsylvania, show that at least 25% of the students used at least one time in their life Ritalin. Perhaps desiring similar effects of staying awake, which is seen in people with narcolepsy, and the increase in attention and decrease in restlessness, seen in patients of ADHD, the prevalence of non-medical cognnitive enhancement usage of Methylphenidate is increasing by students and academics in schools and universities worldwide. (Beyer C., et al., 2014)
Methylphenidate also is used for treatment of depression and nicotine and amphetamine replacemente therapy. While the benefits of Methylphenidate in patients suffering from attention defict disorder have been tested and proven, the benefits for a healthy person cannot be assured. Furthermore, in sleep-deprived individuals that are treated with Methylphenidate, tend to overestimate their own performance, and experience a subjective experience. In other word, the perception of Methylphenidate by healthy users may be related to the subjective experience rather than realistic implications (Mommaerts, JL., 2013).
Methylphenidate is a central nervous system stimulat derived from piperdine which is structurally similar to amphetamine, and acts as a norepinephrine - dopamine reuptake inhibitor. It increases dopaminergic neurotransmission by inhibiting presynaptic dopamine transporters. By blocking the reuptake of noradrenaline and dopamine at the level of the presynaptic neuron, it increases the release of these monoamines at the level of the presynaptic neuron, it increases the release of these monoamines at the level of the synaptic cleft. The effects are mediated by blocking Dopamin Transporter, known as DAT, wich increases the concentration of dopamine, known to be a key neuromodulating agent (Trenque, T., et al, 2014)
In humans, Methylphenidate is metabolized predominantly by hydrolysis to the pharmacologically inactive ritalinic acid. Human carboxylesterase 1A1 has shown to be the major enzyme responsible for the stereoselective hydrolysis of Methylphenidate. Other minor metabolites are produced through oxidation and subsequent conjugation or hydrolysis, including the pharmacologically active para-hydroxymethylphenidate. In healthy adult humans, only 22±8% and 55±3% of the d- and 1-MPH, respectively, reach the systemic ciculation. The majority of Methylphenidate administered orally, the commonly used route of administration, has a bioavailability of 11-52% with a duration peak from 2-8 hours depending on the dose. Is excreted in urine, accounting for 80% and 78 - 97% of the administered dose withing 48h and 96h respectively (Yang, X., et al, 2014).
Ritalin is available in both immediate and sustained release forms in varying in the form of tablets, capsules, patches, or oral suspension syrup. The inmediate release form is also prescribed for adults with narcolepsy. For all forms of methylphenidate, it is recommended not to exceed 60mg per day. An animal model study showed that 20mg methylphenidate might decrease the function of the DAT by 50% in the prefrontal cortex. For ADHD, methylphenidate is estimated to ameliorate symptoms by 75-80% (Wiguna, T., et al., 2014). For more information about doses you can visit this Mayo Clinic link: Doses for Methylphenidate.
Physiological Effects
The ultimate desire anf result of using Methylphenidate is increased attention, motor function, and memory. Even when ritalin is used as a prescription drug, it may have sever side effects including nervousness, insomnia, anorexia, loss of apetite, pulse changes, health problems, and weight loss. The manufacterer says it is a drug of dependecy.
In June 2005, the US food and Drug Administration issued a series of public health advisories warning that Ritalin and similar drugs may cause visual hallucinations, suicidal thoughts and psychotic behavior, as well as aggression and violent behavior. All this information and more about secondary effects and Ritalin related conditions is available in FDA Medication Guide for Ritalin. Despite being in the market for almost 60 years, the tolerance and long term safety of methylphenidate use is poorly documented and has never been studied in detail. In a pedriatic study to evaluate diurnal changes in salivary hormones of children taking psychotropic medications, those taking Methylphenidate tablets exhibited disminished rhythms of testosterone, while children taking extended release MP had significantly higher testosterone levels. Through its amphetamine-like properties, methylphenidate also exherts anorecigenic effects, being anorexia the most frequently reported side effect in children treated for ADHD in UK (Trenque, T., 2014).
A study supported by the National Institute on Drug Abuse found that users of Ritalin and similar drugs showed the highest percentage of cocaine abuse. Because a tolerance builds up, abuse of Ritalin can lead users to consume stronger drugs to achieve the same high. When the effects start to wear off, the person may turn to more potent drugs to rid himself of the unwanted conditions that prompted him to abuse the drug in the first place.Ritalin itself does not lead the person to other drugs: people take drugs to get rid of unwanted situations or feelings. The drug masks the problem for a time. When the high fades, the problem, unwanted condition or situation returns more intensely than before. The user may then turn to stronger drugs since Ritalin no longer works. (Trudeau, M., 2005)
According to a 2005 study, teens who abuse prescription drugs are twelve times likelier to use heroin, fifteen times likelier to use Ecstasy and twenty times likelier to use cocaine, compared to teens who do not abuse such drugs (Trudeau, M., 2005)
Rock
legend Kurt Cobain, Nirvana singer, started on Ritalin at age 7. Cobain’s widow, Courtney Love,
believed that this drug led to his later abuse of stronger drugs. He committed
suicide with a shotgun in 1994. Love was also prescribed Ritalin as a child.
She described the experience this way: “When you’re a kid and you get this drug
that makes you feel that euphoric feeling, where else are you going to turn
when you’re an adult?”(Drug Free World, 2014)
Prefrontal
and limbic systems - in particular, the amygdala - have important roles in the
pathophysiology of ADHD. Children with ADHD showed an
alteration of amygdala function compared to healthy controls, along with more
hyperactivity and inattention, fear learning, negative emotions, and negative
perceptions of emotional stimuli. Other studies found that emotional ability
and impulsive behavior in children correlated with dysfunction in the amygdala (Wiguna, T., et al., 2014).
Studies
using magnetic resonance imaging (MRI) showed a volume reduction in the
prefrontal cortex, which is connected to the limbic system. The studies
suggested that disrupted connectivity between the prefrontal cortex and the hippocampus
and amygdala might adversely impact attention, memory, and emotional control in
children with ADHD. Plessen et al., demonstrated significant reductions
in volume in the lateral and basal nuclei of the amygdala, and these reductions
might be associated with poor emotional control and affective drive, related to
the behavioral reward system in children with ADHD (Wiguna, T., et al., 2014).
Previous studies have indicated that low, therapeutic doses of MPH enhance levels of dopamine and norepinephrine only in the PFC. Because the PFC continues to undergo development until young adulthood, it is interesting to know whether early life perturbation of the dopamine and norepinephrine systems with MPH treatment would alter the developmental course of the PFC. We have previously reported that treatment with 1 mg/kg. MPH resulted in a dose-dependent depression of pyramidal neuron excitability and spontaneous release of glutamate in the PFC, an effect opposite to that seen at the same dosage in adult rats, and that these effects were not fully reversible at dosages above 1mg/kg. However, how this cellular depression occurs, and what effects it may have on circuitry level function remained unclear (Wiguna, T., et al., 2014).
Resperidone and Methylphenidate were given to patients with MA addiction as a replacement therapy. Both drugs were useful for
lowering drug craving in patients; however resperidone was more effective
(6.31 ± 8.31 vs.19.6 ± 12.45 cravings per week,
respectively). T Both drugs were useful for lowering drug craving in patients; however resperidone was more effective; however
methylphenidate was effective too; though with a lower potency (Solhi, H., et al, 2014). The present study confirmed that
both methylphenidate and resperidone can successfully be used for treatment of
MA dependence, in order to reduce drug craving and psychological, neurologic,
and somatic problems in patients. However, the efficacy of methylphenidate was
estimated to be less than that of resperidone for this purpose (Solhi, H., et al, 2014).
For more information about NIH on Methylphenidate Drug abuse please follow this link: DrugFacts: Stimulant ADHD Medications - Methylphenidate and Amphetamines
Maier LJ1, Liechti ME, Herzig F, Schaub MP. (2013). “To dope or not to dope: neuroenhancement with prescription drugs and drugs of abuse among Swiss university students”. PLoS One. 8(11):e77967
Santoni de Sio F, Faulmüller N, Vincent NA. (2014). “How cognitive enhancement can change our duties”. Frontier in System Neuroscience. 8:131
Solhi H, Jamilian HR, Kazemifar AM, Javaheri J, Rasti Barzaki A. (2014). “Methylphenidate vs. resperidone in treatment of methamphetamine dependence: A clinical trial”. Saudi Pharmaceutical Journey. 22(3):191-4
Thierry Trenque, Emmanuelle Herlem, Malak Abou Taam, Moustapha Drame. (2014). “Methylphenidate off-label use and safety”. Springerplus. 3:286
Urban KR, Li YC, Gao WJ. (2013). “Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex”. Neurobiology of Learning Memory. 101:65-74
Wiguna T, Guerrero AP, Wibisono S, Sastroasmoro S. (2014). “The Amygdala's Neurochemical Ratios after 12 Weeks Administration of 20 mg Long-acting Methylphenidate in Children with Attention Deficit and Hyperactivity Disorder: A Pilot Study Using (1)H Magnetic Resonance Spectroscopy”. Clinical Psychopharmacology and Neuroscience. 12(2):137-41
Yang X, Morris SM, Gearhart JM, Ruark CD, Paule MG, Slikker W Jr, Mattison DR, Vitiello B, Twaddle NC, Doerge DR, Young JF, Fisher JW. (2014). “Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates”. PLoS One. 9(9):e106101
Trudeau M. (2009). "More Students Turning Illegally To 'Smart' Drugs". NPR.
Medication Guide. Ritalin. Retrieved from
http://www.fda.gov/downloads/drugs/drugsafety/089090.pdf
Drug Facts Stimulant ADHD Medications - Methylphenidate and Amphetamines. (2014). NIH.
Retrieved from http://www.drugabuse.gov/publications/drugfacts/stimulant-adhd-medications-methylphenidate-amphetamines
Background
The use of medical stimulants to sustain attention, augment memory
and enhance intellectual capacity is increasing in society. The use of
Methylphenidate for cognitive enhancement is a subject that has received much
attention in the literature and academic circles globally in recent times. Ritalin is the common
name for methylphenidate, classified by the Drug Enforcement Administration as
a Schedule II narcotic—the same classification as cocaine, morphine and
amphetamines (Beyer, C, et al., 2014). Methylphenidate was first synthetized in 1944 by Leandro Pannizon, a chemist working for Ciba. Was indentified as a stimulant ten years laters and called Ritalin, making reference to Pannizon wife, who had low blood pressure and was using it as a stimulat to play tennis (Meiers, R., 1954). Beginning in the 1960's, it was used to treat ADD and ADHD, and in 2000 the extended release version, Concerta, was approved by the FDA.Names
- Methylphenidate brand names are (Drugs.com, 2014):
- Concerta
- Ritalin
- Ritalin-LA
- Ritalin-SR
- Methylin
- Quillivant XR
- Metadate
- Daytrana
- The Street Names are (Drug Free World, 2014):
- Kiddie Coke
- Diet Coke
- Smarties
- Rids
- Poor's man cocaine
- R-ball
- Skittles
- Vitamin R
Prescripted and "Off-label" use
Methylphenidate is commonly prescribed for treatment of ADHD and narcolepsy. Attention-deficit/hyperactivity disorder (ADHD) is among the most common neurobehavioral disorders presenting for treatment in children. It carries a high rate of comorbid psychiatric problems such as oppositional defiant disorder (ODD), conduct disorder, mood and anxiety disorders, and cigarette and substance use disorders. Across the life span, the social and societal costs of untreated ADHD are considerable, including academic and occupational underachievement, delinquency, motor vehicle safety, and difficulties with personal relationships (Wilens, T., & Spencer, T., 2013). According to recent survey, the number of children diagnosed eith ADHD continues to increase reaching nearly 2 million additional cases in U.S. children and adolescents in 2011 compared to 2003 (Yang, M., et al, 2014). 
The extended release form of Methylphenidate is usually prescribed to patients suffering of narcolepsy. Narcolepsy is a chronic brain disorder that involves poor control of sleep-wake cycle. People with this conditions experience periods of extreme daytime sleepines and sudden, irresitible bouts of sleep that can strike at any time. For more information about narcolepsy visit NIH Narcolepsy Fact SheetIn the other side, the off-label use is increasing in students. Studies by Beyer, C. et al, 2014, show that Medical Students in South Africa are using it as a cognitive enhancer. Other studies made in the University of Pennsylvania, show that at least 25% of the students used at least one time in their life Ritalin. Perhaps desiring similar effects of staying awake, which is seen in people with narcolepsy, and the increase in attention and decrease in restlessness, seen in patients of ADHD, the prevalence of non-medical cognnitive enhancement usage of Methylphenidate is increasing by students and academics in schools and universities worldwide. (Beyer C., et al., 2014)
Methylphenidate also is used for treatment of depression and nicotine and amphetamine replacemente therapy. While the benefits of Methylphenidate in patients suffering from attention defict disorder have been tested and proven, the benefits for a healthy person cannot be assured. Furthermore, in sleep-deprived individuals that are treated with Methylphenidate, tend to overestimate their own performance, and experience a subjective experience. In other word, the perception of Methylphenidate by healthy users may be related to the subjective experience rather than realistic implications (Mommaerts, JL., 2013).
How does Methylphenidate acts on the brain?
Methylphenidate is a central nervous system stimulat derived from piperdine which is structurally similar to amphetamine, and acts as a norepinephrine - dopamine reuptake inhibitor. It increases dopaminergic neurotransmission by inhibiting presynaptic dopamine transporters. By blocking the reuptake of noradrenaline and dopamine at the level of the presynaptic neuron, it increases the release of these monoamines at the level of the presynaptic neuron, it increases the release of these monoamines at the level of the synaptic cleft. The effects are mediated by blocking Dopamin Transporter, known as DAT, wich increases the concentration of dopamine, known to be a key neuromodulating agent (Trenque, T., et al, 2014)Metabolism, Pharmacokinetics, and Dosage
In humans, Methylphenidate is metabolized predominantly by hydrolysis to the pharmacologically inactive ritalinic acid. Human carboxylesterase 1A1 has shown to be the major enzyme responsible for the stereoselective hydrolysis of Methylphenidate. Other minor metabolites are produced through oxidation and subsequent conjugation or hydrolysis, including the pharmacologically active para-hydroxymethylphenidate. In healthy adult humans, only 22±8% and 55±3% of the d- and 1-MPH, respectively, reach the systemic ciculation. The majority of Methylphenidate administered orally, the commonly used route of administration, has a bioavailability of 11-52% with a duration peak from 2-8 hours depending on the dose. Is excreted in urine, accounting for 80% and 78 - 97% of the administered dose withing 48h and 96h respectively (Yang, X., et al, 2014). Ritalin is available in both immediate and sustained release forms in varying in the form of tablets, capsules, patches, or oral suspension syrup. The inmediate release form is also prescribed for adults with narcolepsy. For all forms of methylphenidate, it is recommended not to exceed 60mg per day. An animal model study showed that 20mg methylphenidate might decrease the function of the DAT by 50% in the prefrontal cortex. For ADHD, methylphenidate is estimated to ameliorate symptoms by 75-80% (Wiguna, T., et al., 2014). For more information about doses you can visit this Mayo Clinic link: Doses for Methylphenidate.
Physiological Effects
The ultimate desire anf result of using Methylphenidate is increased attention, motor function, and memory. Even when ritalin is used as a prescription drug, it may have sever side effects including nervousness, insomnia, anorexia, loss of apetite, pulse changes, health problems, and weight loss. The manufacterer says it is a drug of dependecy.
Usage, Abuse and Dependence
Healthy, partially sleep-deprived young students who assume they have received 20 mg of MPH experience a substantial placebo effect that improves consolidation of information into long term memory. This is independent of any pharmacological effects of MPH, which had no significant effects on verbal memory in this study. This information may be used to dissuade students from taking stimulants such as MPH during examination periods thus, thus avoiding subsequent abuse and addiction. No significant differences were found between those subjects who received MPH and those who received a placebo. However, significant differences were found between subjects who assumed they had received MPH or had no opinion, and those who assumed they had received a placebo (Mommaerts, JL., 2013).
Although Adderall and Ritalin might seem like wonder drugs that can help students study for hours, the drugs are amphetamine-based. That means that they can be habit-forming, according to Martha J. Farah, director at the Center for Cognitive Neuroscience at the University of Pennsylvania. She says she understands the drugs' appeal because they do measurably increase concentration and motivation. This is what makes studying for hours on end, or any kind of intellectual work, more engrossing and more rewarding. But she cautions: "It's also a little worrisome, because basically that extra
motivation that you feel when you're using these drugs is the result of the
drugs' effects on the brain's reward system." and as they target the
brain's reward center, Farah says, there can be trouble. "These are
serious drugs with serious side effects," such as severe sleep deprivation
and rare heart problems, she says. But most importantly, she says, the drugs
can be addictive (Trudeau, M., 2005)How does abuse of the drug begin and why is it so common?
A study supported by the National Institute on Drug Abuse found that users of Ritalin and similar drugs showed the highest percentage of cocaine abuse. Because a tolerance builds up, abuse of Ritalin can lead users to consume stronger drugs to achieve the same high. When the effects start to wear off, the person may turn to more potent drugs to rid himself of the unwanted conditions that prompted him to abuse the drug in the first place.Ritalin itself does not lead the person to other drugs: people take drugs to get rid of unwanted situations or feelings. The drug masks the problem for a time. When the high fades, the problem, unwanted condition or situation returns more intensely than before. The user may then turn to stronger drugs since Ritalin no longer works. (Trudeau, M., 2005)
According to a 2005 study, teens who abuse prescription drugs are twelve times likelier to use heroin, fifteen times likelier to use Ecstasy and twenty times likelier to use cocaine, compared to teens who do not abuse such drugs (Trudeau, M., 2005)
Ritalin leads to usage of other drugs: Kurt Cobain's Story
Research
Previous studies have indicated that low, therapeutic doses of MPH enhance levels of dopamine and norepinephrine only in the PFC. Because the PFC continues to undergo development until young adulthood, it is interesting to know whether early life perturbation of the dopamine and norepinephrine systems with MPH treatment would alter the developmental course of the PFC. We have previously reported that treatment with 1 mg/kg. MPH resulted in a dose-dependent depression of pyramidal neuron excitability and spontaneous release of glutamate in the PFC, an effect opposite to that seen at the same dosage in adult rats, and that these effects were not fully reversible at dosages above 1mg/kg. However, how this cellular depression occurs, and what effects it may have on circuitry level function remained unclear (Wiguna, T., et al., 2014).
Findings
NIH about Cognitive Enhacers
Conclusion
The purpose of this project is to acquire a clearer vision of how Methylphenidate and similar drugs act on the brain in order to cause morphological changes to it and therefore, changes on the human being's behavior. We also elucidate the effects these drugs have as cognitive enhancers and the potential for abuse that they bring about, since this information leads to a better understanding of the toxic effects that could come about when using the drug in a non appropriate way. Finally, the subject of use and abuse of Methylphenidate and similar drugs is one of great significance due to the fact that the consumption of these drugs by adolescents and college students has increased throughout the years because of its ease in finding it and because of the cognitive effects it or they may have. References
Beyer C, Staunton C, Moodley K. (2014). “The implication of Methylphenidate use by healthy medical students and doctors in South Africa”. BMC Med Ethics. 4:15-20Maier LJ1, Liechti ME, Herzig F, Schaub MP. (2013). “To dope or not to dope: neuroenhancement with prescription drugs and drugs of abuse among Swiss university students”. PLoS One. 8(11):e77967
Santoni de Sio F, Faulmüller N, Vincent NA. (2014). “How cognitive enhancement can change our duties”. Frontier in System Neuroscience. 8:131
Solhi H, Jamilian HR, Kazemifar AM, Javaheri J, Rasti Barzaki A. (2014). “Methylphenidate vs. resperidone in treatment of methamphetamine dependence: A clinical trial”. Saudi Pharmaceutical Journey. 22(3):191-4
Thierry Trenque, Emmanuelle Herlem, Malak Abou Taam, Moustapha Drame. (2014). “Methylphenidate off-label use and safety”. Springerplus. 3:286
Urban KR, Li YC, Gao WJ. (2013). “Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex”. Neurobiology of Learning Memory. 101:65-74
Wiguna T, Guerrero AP, Wibisono S, Sastroasmoro S. (2014). “The Amygdala's Neurochemical Ratios after 12 Weeks Administration of 20 mg Long-acting Methylphenidate in Children with Attention Deficit and Hyperactivity Disorder: A Pilot Study Using (1)H Magnetic Resonance Spectroscopy”. Clinical Psychopharmacology and Neuroscience. 12(2):137-41
Yang X, Morris SM, Gearhart JM, Ruark CD, Paule MG, Slikker W Jr, Mattison DR, Vitiello B, Twaddle NC, Doerge DR, Young JF, Fisher JW. (2014). “Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates”. PLoS One. 9(9):e106101
Trudeau M. (2009). "More Students Turning Illegally To 'Smart' Drugs". NPR.
Medication Guide. Ritalin. Retrieved from
http://www.fda.gov/downloads/drugs/drugsafety/089090.pdf
Drug Facts Stimulant ADHD Medications - Methylphenidate and Amphetamines. (2014). NIH.
Retrieved from http://www.drugabuse.gov/publications/drugfacts/stimulant-adhd-medications-methylphenidate-amphetamines
