Strattera is the only drug for ADHD that is not a stimulant of some sort. Since it is not a narcotic like all the others, refills are easier to get.
Sudan's Narcotic Drugs and Psychotropic Substances Act, passed in 1994, is designed to fulfill that country's treaty obligations under the Single Convention on Narcotic Drugs, Convention on Psychotropic Substances, and United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamines, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February 1971. The Single Convention on Narcotic Drugs of 1961 could not ban the many newly discovered psychotropics, since its scope was limited to drugs with cannabis, coca, and opium-like effects.
During the 1960s such drugs became widely available, and government authorities opposed this for numerous reasons, arguing that along with negative health effects, drug use led to lowered moral standards. The Convention, which contains import and export restrictions and other rules aimed at limiting drug use to scientific and medical purposes, came into force on 16 August 1976. As of 2013, 183 states are Parties to the treaty. Many laws have been passed to implement the Convention, including the U.S. Psychotropic Substances Act, the UK Misuse of Drugs Act 1971, and the Canadian Controlled Drugs and Substances Act. Adolf Lande, under the direction of the United Nations Office of Legal Affairs, prepared the Commentary on the Convention on Psychotropic Substances. The Commentary, published in 1976, is an invaluable aid to interpreting the treaty and constitutes a key part of its legislative history.
Provisions to end the international trafficking of drugs covered by this Convention are contained in the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. This treaty, signed in 1988, regulates precursor chemicals to drugs controlled by the Single Convention and the Convention on Psychotropic Substances. It also strengthens provisions against money laundering and other drug-related crimes.
International drug control began with the 1912 International Opium Convention, a treaty which adopted import and export restrictions on the opium poppy's psychoactive derivatives. Over the next half-century, several additional treaties were adopted under League of Nations auspices, gradually expanding the list of controlled substances to encompass cocaine and other drugs and granting the Permanent Central Opium Board power to monitor compliance. After the United Nations was formed in 1945, those enforcement functions passed to the UN.
In 1961, a conference of plenipotentiaries in New York adopted the Single Convention on Narcotic Drugs, which consolidated the existing drug control treaties into one document and added cannabis to the list of prohibited plants. In order to appease the pharmaceutical interests, the Single Convention's scope was sharply limited to the list of drugs enumerated in the Schedules annexed to the treaty and to those drugs determined to have similar effects.
During the 1960s, drug use increased in Western developed nations. Young people began using hallucinogenic, stimulant, and other drugs on a widespread scale that has continued to the present. In many jurisdictions, police had no laws under which to prosecute users and traffickers of these new drugs; LSD, for instance, was not prohibited federally in the U.S. until 1967.
In 1968, "[d]eeply concerned at reports of serious damage to health being caused by LSD and similar hallucinogenic substances," the United Nations Economic and Social Council (ECOSOC) passed a resolution calling on nations to limit the use of such drugs to scientific and medical purposes and to impose import and export restrictions. Later that year, the UN General Assembly requested that ECOSOC call upon its Commission on Narcotic Drugs to "give urgent attention to the problem of the abuse of the psychotropic substances not yet under international control, including the possibility of placing such substances under international control".
Circa 1969, with use of stimulants growing, ECOSOC noted with considerable consternation that the Commission "was unable to reach agreement on the applicability of the Single Convention on Narcotic Drugs, 1961 to these substances". The language of the Single Convention and its legislative history precluded any interpretation that would allow international regulation of these drugs under that treaty. A new convention, with a broader scope, would be required in order to bring those substances under control. Using the Single Convention as a template, the Commission prepared a draft convention which was forwarded to all UN member states. The Secretary-General of the United Nations scheduled a conference for early 1971 to finalize the treaty.
Meanwhile, countries had already begun passing legislation to implement the draft treaty. In 1969, Canada added Part IV to its Food and Drugs Act, placing a set of "restricted substances," including LSD, DMT, and MDA, under federal control. In 1970, the United States completely revamped its existing drug control laws by enacting the Controlled Substances Act (amended in 1978 by the Psychotropic Substances Act, which allows the U.S. drug control Schedules to be updated as needed to comply with the Convention). In 1971, the United Kingdom passed the Misuse of Drugs Act 1971. A host of other nations followed suit. A common feature shared by most implementing legislation is the establishment of several classes or Schedules of controlled substances, similarly to the Single Convention and the Convention on Psychotropic Substances, so that compliance with international law can be assured simply by placing a drug into the appropriate Schedule.
The conference convened on 11 January 1971. Nations split into two rival factions, based on their interests. According to a Senate of Canada report, "One group included mostly developed nations with powerful pharmaceutical industries and active psychotropics markets . . . The other group consisted of developing states...with few psychotropic manufacturing facilities". The organic drugmaking states that had suffered economically from the Single Convention's restrictions on cannabis, coca, and opium, fought for tough regulations on synthetic drugs. The synthetic drug-producing states opposed those restrictions. Ultimately, the developing states' lobbying power was no match for the powerful pharmaceutical industry's, and the international regulations that emerged at the conference's close on 21 February were considerably weaker than those of the Single Convention.
The Convention's adoption marked a major milestone in the development of the global drug control regime. Over 59 years, the system had evolved from a set of loose controls focused on a single drug into a comprehensive regulatory framework capable of encompassing almost any mind-altering substance imaginable. According to Rufus King, "It covers such a grab-bag of natural and manufactured items that at every stage of its consideration its proponents felt obliged to stress anew that it would not affect alcohol or tobacco abuse."
As of June 2013, there are 183 state parties to the convention. This total includes 182 member states of the United Nations and the Holy See. The 11 UN member states that are not party to the convention are East Timor, Equatorial Guinea, Haiti, Kiribati, Liberia, Nauru, Samoa, Solomon Islands, South Sudan, Tuvalu, and Vanuatu. Liberia has signed the treaty but has not yet ratified it.
The Convention has four Schedules of controlled substances, ranging from Schedule I (most restrictive) to Schedule IV (least restrictive). A list of psychotropic substances, and their corresponding Schedules, was annexed to the 1971 treaty. The text of the Convention does not contain a formal description of the features of the substances fitting in each Schedule, in contrast to the US Controlled Substances Act of 1970, which gave specific criteria for each Schedule in the US system. However, a 2002 European Parliament report informally describes the international Schedules as follows:
A 1999 UNODC report notes that Schedule I is a completely different regime from the other three. According to that report, Schedule I mostly contains hallucinogenic drugs such as LSD that are produced by illicit laboratories, while the other three Schedules are mainly for licitly produced pharmaceuticals. The UNODC report also claims that the Convention's Schedule I controls are stricter than those provided for under the Single Convention, a contention that seems to be contradicted by the 2002 Senate of Canada and 2003 European Parliament reports.
Although estimates and other controls specified by the Single Convention are not present in the Convention on Psychotropic Substances, the International Narcotics Control Board corrected the omission by asking Parties to submit information and statistics not required by the Convention, and using the initial positive responses from various organic drug producing states to convince others to follow. In addition, the Convention does impose tighter restrictions on imports and exports of Schedule I substances. A 1970 Bulletin on Narcotics report notes:
Article 2 sets out a process for adding additional drugs to the Schedules. First, the World Health Organization (WHO) must find that the drug meets the specific criteria set forth in Article 2, Section 4, and thus is eligible for control. Then, the WHO issues an assessment of the substance that includes:
Article 2, Paragraph 4:
If the World Health Organization finds: (a) That the substance has the capacity to produce (i) (1) A state of dependence, and (2) Central nervous system stimulation or depression, resulting in hallucinations or disturbances in motor function or thinking or behaviour or perception or mood, or (ii) Similar abuse and similar ill effects as a substance in Schedule I, II, III or IV, and (b) That there is sufficient evidence that the substance is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of the substance under international control, the World Health Organization shall communicate to the Commission an assessment of the substance, including the extent or likelihood of abuse, the degree of seriousness of the public health and social problem and the degree of usefulness of the substance in medical therapy, together with recommendations on control measures, if any, that would be appropriate in the light of its assessment.
The Commentary gives alcohol and tobacco as examples of psychoactive drugs that were deemed to not fit the above criteria by the 1971 Conference which negotiated the Convention. Alcohol can cause dependence and central nervous depression resulting in disturbances of thinking and behavior, furthermore alcohol causes similar effects as barbiturates, alcohol causes very serious "public health and social problems" in many countries, and also alcohol has minimal use in modern medicine. Nevertheless, according to the Commentary:
Similarly, tobacco can cause dependence and has little medical use, but it was not considered to be a stimulant or depressant or to be similar to other scheduled substances. Most important, according to the Commentary:
The Commission on Narcotic Drugs makes the final decision on whether to add the drug to a Schedule, "taking into account the communication from the World Health Organization, whose assessments shall be determinative as to medical and scientific matters, and bearing in mind the economic, social, legal, administrative and other factors it may consider relevant". A similar process is followed in deleting a drug from the Schedules or transferring a drug between Schedules. For instance, at its 33rd meeting, the WHO Expert Committee on Drug Dependence recommended transferring tetrahydrocannabinol to Schedule IV of the Convention, citing its medical uses and low abuse potential. However, the Commission on Narcotic Drugs has declined to vote on whether to follow the WHO recommendation and re-schedule tetrahydrocannabinol. The UN Economic and Social Council, as a parent body of the Commission on Narcotic Drugs, can alter or reverse the Commission's scheduling decisions.
In the event of a disagreement about a drug's Scheduling, Article 2, Paragraph 7 allows a Party to, within 180 days of the communication of the Commission's decision, give the UN Secretary-General "a written notice that, in view of exceptional circumstances, it is not in a position to give effect with respect to that substance to all of the provisions of the Convention applicable to substances in that Schedule." This allows the nation to comply with a less stringent set of restrictions. The U.S. Controlled Substances Act's 21 U.S.C. § 811(d)(4) implies that placing a drug in Schedule IV or V of the Act is sufficient to "carry out the minimum United States obligations under paragraph 7 of article 2 of the Convention". This provision, which calls for temporarily placing a drug under federal drug control in the event the Convention requires it, was invoked in 1984 with Rohypnol (flunitrazepam). Long before abuse of the drug was sufficiently widespread in the United States to meet the Act's drug control criteria, rohypnol was added to the Schedules of the Convention on Psychotropic Substances, and the U.S. government had to place rohypnol in Schedule IV of the Controlled Substances Act in order to meet its minimum treaty obligations.
As of March 2005, 111 substances were controlled under the Convention.
In 1998, ephedrine was recommended for control under the Convention. The Dietary Supplement Safety and Science Coalition lobbied against control, stressing the drug's history and safety, and arguing that "ephedrine is not a controlled substance in the US today, nor should it be internationally". After a two-year debate, the Expert Committee on Drug Dependence decided against regulating ephedrine. However, the Commission on Narcotics Drugs and the International Narcotics Control Board listed the drug as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, a move that did not require WHO approval.
The Expert Committee on Drug Dependence cautiously began investigating ketamine at its thirty-third meeting, noting, "Its use in veterinary medicine must also be considered in relation to its control". Ketamine remains uncontrolled internationally, although many nations (eg. USA and UK) have enacted restrictions on the drug.
The Expert Committee's evaluation of MDMA, or Ecstasy, during its 22nd meeting was marked by pleas from doctors to allow further research into the drug's therapeutic uses. The UN was under considerable pressure from the United States government to control the drug in the wake of extensive seizures of the drug by American authorities. Paul Grof, chairman of the Expert Committee, argued that international control was not yet warranted, and that scheduling should be delayed pending completion of more studies. The Expert Committee concluded that because there was "insufficient evidence to indicate that the substance has therapeutic usefulness," it should be placed in Schedule I. However, its report did recommend more MDMA research:
MDMA has since been added to the convention as a Schedule I controlled substance.][
MBDB (Methylbenzodioxolylbutanamine) is an entactogen with similar effects to MDMA. The thirty-second meeting of the WHO Expert Committee on Drug Dependence (September 2000) evaluated MBDB and recommended against scheduling.
From the WHO Expert Committee assessment of MBDB:
Circa 1994, the United States government notified the UN Secretary General that it supported controlling methcathinone, an addictive stimulant manufactured with common household products, as a Schedule I drug under the Convention. The FDA report warned of the drug's dangers, even noting that addicts in Russia were observed to often have "potassium permanganate burns on their fingers" and to "tend not to pay attention to their appearance, thus looking ragged with dirty hands and hair". With methcathinone having no medical use, the decision to place the drug in Schedule I was uncontested.
Traditionally, the UN has been reluctant to control nicotine and other drugs traditionally legal in Europe and North America, citing tolerance of a wide range of lifestyles. This contrasts with the regulatory regime for other highly addictive drugs. Gabriel G. Nahas, in a Bulletin on Narcotics report, noted:
Nonetheless, in October 1996, the Expert Committee considered controlling nicotine, especially products such as gum, patches, nasal spray, and inhalers. The UN ultimately left nicotine unregulated. Since then, nicotine products have become even more loosely controlled; Nicorette gum, for instance, is now an over-the-counter drug in the United States.
Tetrahydrocannabinol (THC), the main active ingredient in cannabis, was originally placed in Schedule I when the Convention was enacted in 1971. At its twenty-sixth meeting, in response to a 1987 request from the Government of the United States that THC be transferred from Schedule I to Schedule II, the WHO Expert Committee on Drug Dependence recommended that THC be transferred to Schedule II, citing its low abuse potential and "moderate to high therapeutic usefulness" in relieving nausea in chemotherapy patients. The Commission on Narcotic Drugs rejected the proposal. However, at its twenty-seventh meeting, the WHO Expert Committee again recommended that THC be moved to Schedule II. At its 45th meeting, on 29 April 1991, the Commission on Narcotic Drugs approved the transfer of dronabinol and its stereochemical variants from Schedule I to Schedule II of the Convention, while leaving other tetrahydrocannabinols and their stereochemical variants in Schedule I.
At its thirty-third meeting (September 2002), the WHO Committee issued another evaluation of the drug and recommended that THC be moved to Schedule IV, stating:
No action was taken on this recommendation. And at its thirty-fourth meeting the WHO Committee recommended that THC be moved instead to Schedule III. In 2007 the Commission on Narcotic Drugs decided not to vote on whether to re-schedule THC, and they requested that the WHO make another review when more information is available.
2C-B is a psychedelic phenethylamine, with a similar structure and effects as mescaline. At its thirty-second (September 2000) meeting the WHO Expert Committee on Drug Dependence recommended that 2C-B be placed in Schedule II, rather than with other scheduled psychedelics in Schedule I.
Without citing any actual evidence of harm from 2C-B, the Committee warned, "The altered state of mind induced by hallucinogens such as 2C-B may result in harm to the user and to others."
From the WHO Expert Committee assessment of 2C-B:
Like the Single Convention, the Convention on Psychotropic Substances recognizes scientific and medical use of psychoactive drugs, while banning other uses. Article 7 provides that,
In this sense, the U.S. Controlled Substances Act is stricter than the Convention requires. Both have a tightly restricted category of drugs called Schedule I, but the US Act restricts medical use of Schedule I substances to research studies, while the Convention allows broader, but limited, medical use of Schedule I substances.
Several of the substances originally placed in Schedule I are psychedelic drugs which are contained in natural plants and fungi (such as peyote and psilocybin mushrooms) and which have long been used in religious or healing rituals. The Commentary notes the "Mexican Indian Tribes Mazatecas, Huicholes and Tarahumaras" as well as the "Kariri and Pankararu of eastern Brazil" as examples of societies that use such plants.
Article 32, paragraph 4 allows for States, at the time of signature, ratification or accession, to make a reservation noting an exemption for
However, the official Commentary on the Convention on Psychotropic Substances makes it clear that psychedelic plants (and indeed any plants) were not included in the original Schedules and are not covered at all by the Convention. This includes "infusion of the roots" of Mimosa hostilis (which contains DMT) and "beverages" made from psilocybin mushrooms. The purpose of Paragraph 4 of Article 32 was to allow States to "make a reservation assuring them the right to permit the continuation of the traditional use in question" in the case that plants were in the future added to the Schedule I. Currently, no plants or plant products are included in the Schedules of the 1971 Convention.
Furthermore, in a letter, dated 13 September 2001, to the Dutch Ministry of Health, Herbert Schaepe, Secretary of the UN International Narcotics Control Board, clarified that the UN Conventions do not cover "preparations" of psilocybin mushrooms:
As you are aware, mushrooms containing the above substances are collected and abused for their hallucinogenic effects. As a matter of international law, no plants (natural material) containing psilocine and psilocybin are at present controlled under the Convention on Psychotropic Substances of 1971. Consequently, preparations made of these plants are not under international control and, therefore, not subject of the articles of the 1971 Convention. However, criminal cases are decided with reference to domestic law, which may otherwise provide for controls over mushrooms containing psilocine and psilocybin. As the Board can only speak as to the contours of the international drug conventions, I am unable to provide an opinion on the litigation in question.
Nonetheless, in 2001 the U.S. Government, in Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, argued that ayahuasca, an infusion of Mimosa hostilis and other psychoactive plants that is used in religious rituals, was prohibited in the US because of the 1971 Convention. That case involved a seizure by U.S. Customs and Border Protection of several drums of DMT-containing liquid. Plaintiffs sued to have the drugs returned to them, claiming that they used it as a central part of their religion.
In the discussions on Article 32, paragraph 4, noted in the Official Record of the 1971 Conference, the representative from the United States supported the explicit exemption of sacred psychoactive substances, stating: "Substances used for religious services should be placed under national rather than international control", while the representative of the Holy See observed: "If exemptions were made in favour of certain ethnic groups, there would be nothing to prevent certain organizations of hippies from trying to make out, on religious grounds, that their consumption of psychotropic substances was permissible."
The Commentary on the Convention on Psychotropic Substances notes that while many plant-derived chemicals are controlled by the treaty, the plants themselves are not:
Mexico, in particular, argued that "production" of psychotropic drugs should not apply to wild-growing plants such as peyote cacti or psilocybin mushrooms. The Bulletin on Narcotics noted that "Mexico could not undertake to eradicate or destroy these plants". Compared to the Single Convention on Narcotic Drugs (which calls for "uprooting of all coca bushes which grow wild" and governmental licensing, purchasing, and wholesaling of licit opium, coca, and cannabis crops), the Convention on Psychotropic Substances devotes few words to the subject of psychoactive plants.
On 2 July 1987, the United States Assistant Secretary of Health recommended that the Drug Enforcement Administration initiate scheduling action under the Controlled Substances Act in order to implement restrictions required by cathinone's Schedule I status under the Convention. The 1993 DEA rule placing cathinone in the CSA's Schedule I noted that it was effectively also banning khat:
A 1971 Bulletin on Narcotics notes:
This provision was eventually judged to be inadequate, and was strengthened by the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances's precursor control regime, which established two Tables of controlled precursors. The Commission on Narcotic Drugs and International Narcotics Control Board were put in charge of adding, removing, and transferring substances between the Tables.
Circa 1999, the Government of Spain proposed amending Schedules I and II to include isomers, esters, ethers, salts of isomers, esters and ethers, and any "substance resulting from modification of the chemical structure of a substance already in Schedule I or II and which produced pharmacological effects similar to those produced by the original substances". The WHO opposed this change. The Commission on Narcotic Drugs did amend the Schedules to include stereoisomerisms, however, with the understanding that "specific isomers that did not have hazardous pharmacological activity and that posed no danger to society could be excluded from control, as dextromethorphan had been in the case of Schedule I of the 1961 Convention."
Article 22 provides:
Conspiracy, attempts, preparatory acts, and financial operations related to drug offenses are also called on to be criminalized. Parties are also asked to count convictions handed down by foreign governments in determining recidivism. Article 22 also notes that extradition treaties are "desirable", although a nation retains the right to refuse to grant extradition, including "where the competent authorities consider that the offence is not sufficiently serious."
As with all articles of the Convention on Psychotropic Substances, the provisions of Article 22 are only suggestions which do not override the domestic law of the member countries:
Article 22 allows Parties, in implementing the Convention's penal provisions, to make exceptions for drug abusers by substituting "treatment, education, after-care, rehabilitation and social reintegration" for imprisonment. This reflects a shift in focus in the war on drugs from incarceration to treatment and prevention that had already begun to take hold by 1971. Indeed, in 1972, a parallel provision allowing treatment for drug abusers was added to the Single Convention on Narcotic Drugs by the Protocol Amending the Single Convention on Narcotic Drugs.
Article 20 mandates drug treatment, education, and prevention measures and requires Parties to assist efforts to "gain an understanding of the problems of abuse of psychotropic substances and of its prevention" and to "promote such understanding among the general public if there is a risk that abuse of such substances will become widespread." To comply with these provisions, most Parties financially support organizations and agencies dedicated to these goals. The United States, for instance, established the National Institute on Drug Abuse in 1974 to comply with the research requirement and began sponsoring Drug Abuse Resistance Education in 1983 to help fulfill the educational and prevention requirements.
Control of stimulants has become a major challenge for the UN. In 1997, the World Drug Report warned:
A 1998 UN General Assembly Special Session on the World Drug Problem report noted:
The report mentioned proposals to increase the flexibility of scheduling drugs under the Convention and to amend the drug-control treaties to make them more responsive to the current situation. Neither proposal has gained traction, however. Due to the ease of manufacturing methamphetamine, methcathinone, and certain other stimulants, control measures are focusing less on preventing drugs from crossing borders. Instead, they are centering around increasingly long prison sentences for manufacturers and traffickers as well as regulations on large purchases of precursors such as ephedrine and pseudoephedrine. The International Narcotics Control Board and Commission on Narcotic Drugs help coordinate this fight by adding additional precursors to the Tables of chemicals controlled under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
In 1997, ECOSOC called on nations to help enforce international law by cooperating "with relevant international organizations, such as Interpol and the World Customs Organization . . . in order to promote coordinated international action in the fight against illicit demand for and supply of amphetamine-type stimulants and their precursors." That resolution also called on governments overseeing precursor exports "to inquire with the authorities of importing States about the legitimacy of transactions of concern, and to inform the International Narcotics Control Board of the action taken, particularly when they do not receive any reply to their inquiries".
Pockets of high-intensity clandestine production and trafficking, such as rural southwest Virginia, exist in most industrialized nations. However, the United Nations Office on Drugs and Crime believes that East Asia (particularly Thailand) now has the most serious amphetamine-type stimulant (ATS) problem in the world. A 2002 report by that agency noted:
The Office called on nations to bring more resources to bear in the demand reduction effort, improving treatment and rehabilitation processes, increasing private sector participation in eliminating drugs from the workplace, and expanding the drug information clearing house to share information more effectively.
In 2000, the International Narcotics Control Board chastised Canada for refusing to comply with the Convention's requirement that international transactions in controlled psychotropics be reported to the Board. INCB Secretary Herbert Schaepe said:
In an unusual departure from its normally pro-industry leanings, the INCB issued a press release in 2001 warning of excessive use of licit psychotropics:
The Board also warned that the Internet provides "easy access to information on drug production and drug-taking," calling it "a growing source of on-line drug trafficking." The Board pointed out that some Internet suppliers sell controlled drugs without regard to the Convention's medical prescription requirements.
Source: INCB Green List (24th Edition, May 2010, DOC version)
All Schedules consist of 116 positions and common generalization clause for salts. Schedule I also contains generalization clause for stereoisomers. There are also 2 specific generalizations, both for tetrahydrocannabinol stereochemical variants. There are no exclusions.
Contains 62 positions (including 1 position for six tetrahydrocannabinol isomers), generalization clause for stereoisomers, specific generalization for tetrahydrocannabinol stereochemical variants and common generalization clause for salts.
Isomers of natural tetrahydrocannabinol:
The stereoisomers of substances in Schedule I are also controlled, unless specifically excepted, whenever the existence of such stereoisomers is possible within the specific chemical designation.
Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.
Contains 17 positions, specific generalization for tetrahydrocannabinol stereochemical variants and common generalization clause for salts.
Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.
Contains 9 positions and common generalization clause for salts.
Semisynthetic agonist–antagonist opioids:
Synthetic agonist–antagonist opioids – benzomorphans:
Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.
Contains 62 positions and common generalization clause for salts.
Schedule IV (62):
Drugs with both stimulant and opioid effects:
Salts of all the substances covered by the four schedules, whenever the existence of such salts is possible, are also under international control.
The following are scheduled by Single Convention on Narcotic Drugs.
Coca leaf, cocaine and ecgonine:
All other drugs scheduled by the narcotic convention are agonist-only opioids (and natural sources of them).
Plants being the source of substances scheduled by this convention are not scheduled (see Psychedelic plants and fungi and Organic plants sections).
Partial list of psychotropic substances currently or formerly used in medicine, but not scheduled:
Of course there are also many designer drugs, not used in medicine.
(INN) ) is a psychostimulant drug typically used for the treatment of attention deficit-hyperactivity disorder (ADHD) and narcolepsy.
Dextroamphetamine is the dextrorotatory, or "right-handed"
, enantiomer of the amphetamine molecule. The amphetamine molecule has two stereoisomers; levoamphetamine and dextroamphetamine. Names for dextroamphetamine include d-amphetamine
, and (S)-(+)-amphetamine
. Dextroamphetamine is available as a generic drug or under several brand names, including Dexedrine
Dextroamphetamine is also an active metabolite of the prodrug lisdexamfetamine (Vyvanse), as well as of several older N-substituted amphetamine prodrugs used as anorectics, such as clobenzorex (Asenlix), benzphetamine (Didrex), and amphetaminil (Aponeuron).
Common side effects include dry mouth, insomnia and headache. A study has found temporary reduction in growth rate in pediatric use.]
Dextroamphetamine is used for the treatment of ADHD and narcolepsy.
Side effects of amphetamine salts include dry mouth, insomnia, drowsiness, dizziness, nervousness, headache and weight loss, diarrhea, as well as faster heartbeat combined with lower blood pressure.
A study on comparative effects between amphetamine mixed salts (commonly known as adderall) and methylphenidate in children who have been treated for a year or more have shown a temporary decrease in growth rate that does not affect final adult height. Change in weight was reported as slightly greater for amphetamine mixed salts and authors concluded that the result may be clinically insignificant.
Studies on rats show long-term neurological and behavioral changes resulting from prenatal and early postnatal exposure to amphetamines. Warnings from the Patient Medication Guide for Adderall include serious cardiovascular events, sudden deaths, stroke, emergence of new psychotic or manic symptoms, aggression and blurred vision.
Prolonged high doses of amphetamines followed by an abrupt cessation can result in extreme fatigue, insomnia, irritability, weight gain, mental depression, urination problems (sometimes mistaken for a urinary tract infection), and bloody stools. Chronic abuse of amphetamines can result in the manifestation of amphetamine psychosis; occasionally this psychosis can occur at therapeutic doses during chronic therapy as a treatment emergent side effect.
The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil are being investigated and sometimes issued for this reason.
Though such use remains out of the mainstream, dextroamphetamine has been successfully applied in the treatment of certain categories of depression as well as other psychiatric syndromes. Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue, and early-stage physiotherapy for severe stroke victims. If physical therapy patients take dextroamphetamine while they practice their movements for rehabilitation, they may learn to move much faster than without dextroamphetamine, and in practice sessions with shorter lengths.
Physical effects can include anorexia, dilated pupils, vasoconstriction or vasodilation, tachycardia or bradycardia, hypertension or hypotension, blood shot eyes, flushing, erectile dysfunction, restlessness, dry mouth, bruxism, headache, tachypnea, fever, diaphoresis, diarrhea, constipation, blurred vision, dizziness, reduced seizure threshold, insomnia, numbness, palpitations, arrhythmias, tics, dry and/or itchy skin, acne, and pallor. Effects of extremely high doses can include coma, rhabdomyolysis, adrenergic storm, and stereotypy. Dangerous physical side effects are exceedingly rare in typical pharmaceutical doses.
Recent studies by the FDA indicate that, in children, young adults, and adults, there is no association
between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the use of dextroamphetamine or other ADHD stimulants.
Psychological effects can include euphoria, anxiety, increased libido, alertness, concentration, increased energy, increased self-esteem and self-confidence, sociability, irritability, aggressiveness, grandiosity, hallucinations, repetitive and obsessive behaviors, paranoia, and with chronic and/or high doses, amphetamine psychosis can occur; occasionally this psychosis can occur at therapeutic doses during chronic therapy as a treatment emergent side effect.
Although withdrawal symptoms of Dextroamphetamine are rare, Withdrawal symptoms of dextroamphetamine primarily consist of fatigue, depression and an increased appetite. Symptoms may last for days with occasional use and weeks or months with chronic use, with severity dependent on the length of time and the amount of dextroamphetamine used. Withdrawal symptoms may also include anxiety, irritability, headaches, agitation, seizures, vomiting, akathisia, hypersomnia (excessive sleeping), vivid or lucid dreams, deep REM sleep and suicidal ideation.
The Physician's 1991 Drug Handbook
reports: "Symptoms of overdose include restlessness, tremor, hyperreflexia, tachypnea, confusion, aggressiveness, hallucinations, and panic." Dilated pupils are common with high doses. Repeated high doses may lead to manifestations of acute psychosis. Additionally at least one case report identifies rhabdomyolysis as an associated side effect of dextroamphetamine in the presence of other risk factors.
The fatal dose in humans is not precisely known, but in various species of rat generally ranges between 50 and 100 mg/kg, or a factor of 100 over what is required to produce noticeable psychological effects. Although the symptoms seen in a fatal overdose are similar to those of methamphetamine, their mechanisms are not identical, as some substances which inhibit dextroamphetamine toxicity do not do so for methamphetamine.
An extreme symptom of overdose is amphetamine psychosis, characterized by vivid visual, auditory, and sometimes tactile hallucinations. Many of its symptoms are identical to the psychosis-like state which follows long-term sleep deprivation, so it remains unclear whether these are solely the effects of the drug, or due to the long periods of sleep deprivation which are often undergone by the chronic user. Amphetamine psychosis, however, is extremely rare in individuals taking oral amphetamines at therapeutic doses; it is usually seen in cases of prolonged or high-dose intravenous (IV) for non-medicinal uses.
Dextroamphetamine is the dextrorotatory stereoisomer of the amphetamine molecule, which can take two different forms. It is a slightly polar, weak base and is lipophilic.
In the United States, an instant-release (IR) tablet preparation of the salt dextroamphetamine sulfate is available]
[ under the brand names Dexedrine
, in 5 mg and 10 mg strengths]
[, and generic formulations from Teva Pharmaceutical Industries and recently Wilshire Pharmaceuticals. It is also available as a capsule preparation of controlled-release (CR) dextroamphetamine sulfate, under the brand names Dexedrine SR
and Dexedrine Spansule
, in the strengths of 5 mg, 10 mg, and 15 mg. A bubblegum flavored oral solution is available under the brand name ProCentra
, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine.
In Australia, dextroamphetamine is available in bottles of 100 under the generic name dexamphetamine
] as 5 mg instant release sulfate tablets., or slow release dexamphetamine preparations may be compounded by individual chemists. Similarly, in the United Kingdom it is only available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulphate
] having had been available under the brand name Dexedrine
prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).
Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-d-amphetamine), available by the trademark name Vyvanse. Lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic. Lisdexamfetamine is therefore an inactive compound until it is converted into an active compound by the digestive system. Although still rated as a Schedule II drug by the U.S. Drug Enforcement Administration, lisdexamfetamine has a slower onset and its route of administration is limited to being taken orally, unlike dextroamphetamine, Adderall, and methylphenidate, which can be insufflated to achieve a faster onset with a higher bioavailability]
[. Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and in six strengths; 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate of lisdexamfetamine to dextroamphetamine base is 0.2948, thus a 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.844 mg dextroamphetamine base.
Another pharmaceutical that contains dextroamphetamine is Adderall. The drug formulation of Adderall (both controlled and instant release forms) is:
Adderall is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine).
An experiment with rats suggested Adderall's inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine. One study has shown that although the human brain usually has a preference for dextroamphetamine over levoamphetamine, certain children have a better clinical response to levoamphetamine.
Amphetamine exists as two stereoisomers that differ in effects. The l- enantiomer (levoamphetamine) produces more cardiovascular and peripheral effects than the d- enantiomer (dextroamphetamine). At low doses, levoamphetamine produces greater arousal than dextroamphetamine, acting primarily on norepinephrine. At higher doses, dextroamphetamine has stimulant properties that are three to four times as potent as those of levoamphetamine, and acts primarily on dopamine, although few clinical studies of ADHD have documented differences among d-, l- and racemic amphetamine.
Just as dextroamphetamine has greater central effects and fewer peripheral effects than levoamphetamine, methamphetamine, which is equipotent to dextroamphetamine in producing behavioral stimulant effects, has even fewer peripheral effects and greater central effects than dextroamphetamine.
In relation to other over-the-counter ADD/ADHD pharmaceuticals, the d- isomer of racemic amphetamine is superior in bioavailibility and CNS stimulation.
Scientific findings have established that dextroamphetamine administration increases the activity of the phosphoinositol cycle via an indirect release of dopamine and Norepinephrine. These results are the first time that this has been confirmed in humans. Because dextroamphetamine is a substrate analog at monoamine transporters, at all doses, dextroamphetamine prevents the re-uptake of these neurotransmitters by competing with endogenous monoamines for uptake. Transporter inhibition causes monoamines to remain in the synaptic cleft for a prolonged period (amphetamine inhibits monoamine reuptake in rats with a norepinephrine to dopamine ratio (NE:DA) of 1:1 and a norepinephrine to 5-hydroxytryptamine ratio (NE:5-HT) of about 100:1).
At higher doses, when the concentration of dextroamphetamine is sufficient, the drug can trigger direct release of norepinephrine and dopamine from the cytoplasmic transmitter pool, that is, dextroamphetamine will cause norepinephrine and dopamine efflux via transporter proteins, functionally reversing transporter action, which triggers a cascading release of catecholamines. This inversion leads to a release of large amounts of these neurotransmitters from the cytoplasm of the presynaptic neuron into the synapse, causing increased stimulation of post-synaptic receptors, inducing euphoria. Dextroamphetamine releases monoamines in rats with selectivity ratios of about NE:DA = 1:3.5 and NE:5-HT = 1:250, meaning that NE and DA are readily released, but release of 5-HT occurs at a 1/4 ration than of NE:DA.
Dextroamphetamine increases dopamine release in the prefrontal cortex; activation of the dopamine-2 receptors inhibits glutamate release in the prefrontal cortex. Activation of the dopamine-1 receptors in the prefrontal cortex, however, results in elevated glutamate levels in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens is the reason that dextroamphetamine has an ability to increase locomotor activity in rats. Serotonin also plays a role in dextroamphetamine's effect on glutamate levels; however, at therapeutic doses, dextroamphetamine has minuscule effect on the serotonin transporter (SERT).
On average, about one half of a given dose is eliminated unchanged in the urine, while the other half is broken down into various metabolites (mostly benzoic acid). However, the drug's half-life is highly variable because the rate of excretion is very sensitive to urinary pH. Under alkaline conditions, direct excretion is negligible and 95%+ of the dose is metabolized. Having an alkaline stomach will cause the drug to be absorbed faster through the stomach resulting in a higher blood level concentration of amphetamine. Having an alkaline bladder causes dextroamphetamine to be excreted more slowly from the blood and into the urine. Alkalinization of the urine can decrease the renal elimination of amphetamines, both potentiating the strength and prolonging the mechanism of action, especially when ingested with sodium bicarbonate.
The main metabolic pathway is:
Another pathway, mediated by enzyme CYP2D6, is:
Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may have significant physiological effects as a norepinephrine analogue.
Subjective effects are increased by larger doses, however, over the course of a given dose there is a noticeable divergence between such effects and drug concentration in the blood. In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase. This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use. The long-term effects of amphetamines use on neural development in children has not been well established.
Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base, not a chloride or sulfate salt.
Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine. In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, depression, and obesity. In Canada, epilepsy and parkinsonism were also approved indications. Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").
It quickly became apparent that dextroamphetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use. Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).
In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
Zombie dust is a drug cocktail composed of Triazolam and Cocaine. Snorting is the typical method of ingestion. It gets its name from the perceived effects that your body is awake but your head is asleep, as well as the feeling of euphoria.
is a drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is a selective norepinephrine reuptake inhibitor (NRI), not to be confused with serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants. This compound is manufactured, marketed and sold in the United States under the brand name Strattera
by Eli Lilly and Company as a hydrochloride salt (atomoxetine HCl), the original patent filing company, and current U.S. patent owner. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals using the label Tomoxetin
, Ranbaxy Laboratories (through its Division: Solus) using the label Attentin
, Sun Pharmaceuticals (through its Division: Milmet Pharmaceuticals), and Intas Biopharmaceuticals. There is currently no generic manufactured directly in the United States since it is under patent until 2017. On August 12, 2010, Lilly lost a lawsuit that challenged Lilly's patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. In a July 29, 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]’s deferred."
Classified as a norepinephrine (noradrenaline) reuptake inhibitor, atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants, is not scheduled as a controlled substance, and has shown in clinical trials to offer 24-hour coverage of symptoms associated with ADHD in adults and children.
Initial therapeutic effects of atomoxetine may take at least a week to be felt. Atomoxetine should be taken for 6–8 weeks before deciding whether it is effective or not. Many people respond to atomoxetine who don't respond to stimulants (for ADHD). Atomoxetine may be preferred over amphetamine-based stimulants in patients with psychiatric disorders, those who cannot tolerate stimulants, and those with a substance misuse recurring history. Stimulant drugs are not recommended for ADHD patients who suffer from nervous disorders like facial tics, spasms, etc. In such cases Atomoxetine is the better choice. Therapy is usually initiated by gradually increasing the dose to minimize typically minor side effects. As well, some individuals are sensitive to lower doses. If the individual is on stimulants, a gradual titration down of the stimulant dose may be prescribed to minimize side effects.
Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested – and subsequently approved – as an ADHD treatment.
Atomoxetine was originally known as "tomoxetine". However, the U.S. Food and Drug Administration (FDA) requested the name be changed because, in their opinion, the similarity of "tomoxetine" to "tamoxifen" (a breast cancer drug) could lead to dispensing errors at pharmacies.
Atomoxetine inhibits NET, SERT and DAT with respective Ki values of 5, 77 and 1451 nM. In microdialysis studies it increased NE and DA levels by 3 fold in the prefrontal cortices but did not alter DA levels in the striatum or nucleus accumbens. Atomoxetine also acts as an NMDA-receptor antagonist at clinically relevant doses. The role of NMDA-receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated; however recent literature has further implicated glutaminergic dysfunction as central in ADHD pathophysiology and etiology]
[. Atomoxetine has little affinity for serotonergic, cholinergic, and adrenergic receptors.
Atomoxetine is designated chemically as (-)-N
-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82. It has a solubility of 27.8 mg/mL in water. Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pre-gelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.
Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several placebo-controlled trials. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound.
The side effects include alopecia, dry mouth, tiredness, irritability, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, decreased libido, urinary retention or hesitancy, increased obsessive behavior, weight changes, slowed growth in children, palpitations, increases in heart rate and blood pressure.
Confirmed cases of severe liver damage have been reported by Eli Lilly and Company. A black box warning was issued by the FDA in 2004.
Other side effects can include psychosis, mood swings, mood disorders, depression, abnormal thought patterns, suicidal thoughts or tendencies, and self injury.
Strattera can be discontinued without being tapered. Side effects are usually counter-reactions to usage effects: increased appetite and irregularity are common, as well as mood swings and depression.
Strattera is included on the Black Triangle List for drugs under intensive surveillance, maintained by the British Medicines and Healthcare Products Regulatory Agency (MHRA). It has had this listing since 2004.]
[ "The MHRA assesses the Black Triangle status of a product usually two years after marketing. However, there is no standard time for a product to retain Black Triangle status. The symbol is not removed until the safety of the drug is well established."
In a further release by the MHRA of the Strattera (Atomoxetine) Risk Benefit Assessment, under the Freedom of Information act, on 9 December 2005, it was noted:
In the March 2009 issue of its Drug Safety Update, the MHRA declared that, after "continued case reports of possible nervous-system and psychiatric adverse effects prompted a review of data from all sources", it advised, "Atomoxetine is associated with treatment-emergent psychotic or manic symptoms in children and adolescents without a history of such disorders."
On 1 August 2006, an article was published by Janne Larsson, in which he states an MHRA document was ordered made public by a court in Sweden. In it is revealed, according to Larsson, that Eli Lilly received 10,998 reports of adverse psychiatric reactions in a period of three years.
To date, atomoxetine's misuse potential has not been researched extensively. The two studies that have been performed suggest that atomoxetine has a low to moderate risk for abuse, since it has a long titration time (meaning that it may have no effect on the user unless they've been taking it regularly for days) and does not produce strong stimulating effects like most other ADHD medications. Monkeys will not self-administer atomoxetine at the doses tested. However, rats, pigeons and monkeys trained to distinguish cocaine or methamphetamine from saline indicate that atomoxetine produces effects indistinguishable from low doses of cocaine or methamphetamine, but not at all like high doses of cocaine.
Atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression, but did not show a favorable benefit-to-risk ratio in trials. Failed clinical trials are not submitted to drug regulatory agencies and are considered trade secrets. Subsequently, Lilly then chose to pursue an ADHD treatment route for atomoxetine. Many patients have seen a pronounced anti-depressive effect in conjunction with other antidepressants. More study is needed to understand the full pharmacodynamics.
In 2007, 40-participant, 10-week, double-blind clinical trial was reported in the Journal of Clinical Psychiatry
on the effectiveness of atomoxetine for treating binge eating disorder. The average daily dose given was 106 mg/day. At the conclusion of the trial, it was reported that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, [and] body mass index." The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder.
A preliminary 12-week, randomized, double-blind, placebo-controlled trial was conducted at Duke University Medical Center which studied the effectiveness of atomoxetine on adult obese women. The study included 30 obese women with an average body mass index of 36.1. Fifteen women were given atomoxetine therapy starting at 25 mg/day with a gradual increase to 100 mg/day over 1 week. Fifteen women were given a placebo with identical dosing. By the end of the trial, the atomoxetine group lost an average of 3.6 kg (3.7% of their body mass) vs a 0.1 kg gain in the placebo group (0.2% gain). Three participants in the atomoxetine group and none in the placebo group lost greater than 5% of their mass.
Somnolence is the most common symptom of acute or chronic overdose. Other signs may include agitation, hyperactivity, abnormal behavior and gastrointestinal symptoms. Mydriasis causing blurred vision, tachycardia and dry mouth occasionally occurs as a result of overdose. Treatment of atomoxetine overdose may include gastric emptying and repeated doses of activated charcoal. However, lavage or "stomach pumping", is no longer an accepted procedure in emergency departments for overdose. Atomoxetine is highly protein bound so dialysis is unlikely to be of benefit.
Atomoxetine may be quantitated in plasma, serum or whole blood in order to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.
First step appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although not formally written in the scheme.
Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, .
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
(ex.Ritalin) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as hyperactivity. Prescribed from 1960 it became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted.
ADHD and some other conditions are believed to be linked to sub-performance of the dopamine, norepinephrine, and glutamate processes in the brain, primarily in the prefrontal cortex and peripheral cortex, responsible for self-regulation functions, leading to self-regulation disorders compromising the sufferer's attention, self-control, behaviour, motivation, and executive function.
Methylphenidate acts primarily to inhibit the reuptake of dopamine and to a lesser extent norepinephrine thereby retaining these hormones longer which increases the levels of these neurotransmitters in the brain.
Methylphenidate possesses some structural and pharmacological similarities to cocaine, though methylphenidate is less potent and longer in duration.
Methylphenidate is produced in the United States, Mexico, Spain and Pakistan. Ritalin is also sold in Canada, Australia, the United Kingdom, Spain, Germany and other European countries (although in much lower volumes than in the United States). Other brands include Concerta
, and Daytrana
, and generic forms, including Methylin
are produced by numerous pharmaceutical companies throughout the world. In Belgium the product is sold under the name Rilatine
and in Brazil, Portugal and Argentina as Ritalina
. In Thailand, it is found under the name Hynidate
The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin
Methylphenidate was first synthesized in 1944, and was identified as a stimulant in 1954.
Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. His wife, Marguerite, had low blood pressure and would take the drug as a stimulant before playing tennis. He named the substance Ritaline, after his wife's nickname, Rita.
Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer.
Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.
In 2000 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of Ritalin. See the "Extended-release" section of this article, below, for more information about Concerta.
Methylphenidate primarily acts as a dopamine-norepinephrine reuptake inhibitor. It is a benzylpiperidine derivative which also shares part of its basic structure with catecholamines and phenethylamines.
Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine. Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.
While both amphetamine and methylphenidate are dopaminergic, it should be noted that their methods of action are distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is a dopamine releasing agent. Each of these drugs has a corresponding effect on norepinephrine which is weaker than its effect on dopamine. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters. Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamine.
Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A
subtypes, though direct binding to the serotonin transporter was not observed.
Methylphenidate may also exert a neuroprotective action against the neurotoxic effects of Parkinson's disease and methamphetamine abuse.
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.]
Studies confirm that biological and genetic differences of the kinds predicted by low arousal theory are clearly visible in ADHD sufferers, and have been confirmed both genetically and by in vivo
scans of ADHD affected brains. MRI scans have revealed that people with ADHD show differences from non-ADHD individuals in brain regions important for attention regulation and control of impulsive behavior. Methylphenidate's cognitive enhancement effects have been investigated using fMRI scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increases activity in the prefrontal cortex and attention-related areas of the parietal cortex during challenging mental tasks; these are the same areas that the above study demonstrated to be shrunken in ADHD brains. Methylphenidate also increased deactivation of default network regions during the task.
Methylphenidate taken orally has a bioavailability of 11-52% with a duration of peak action around 2–4 hours for instant release, 3–8 hours for sustained release, and 8–12 hours for extended release (Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours. Contrary to the expectation, taking methylphenidate with a meal speeds absorption.
The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.
MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system. It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown. The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of lethargy, Bipolar depression, Major Depressive Disorder, and obesity.
Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome. While stimulants such as methylphenidate increase attention and concentration, they do not improve learning and academic performance. People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk. A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature.
There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD have also been noted. A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed. The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects. This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day. Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.
The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses. This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain. However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific neurotransmitters is unsupported and unproven by the evidence and remains a speculative hypothesis.
Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test, but performance does not improve to levels comparable to healthy controls.
While side-effects and misuse of methylphenidate have been associated with an increased risk of aggression and psychosis, newer studies indicate that it could be useful in the treatment of ADHD in adults with a history of aggressive and criminal behavior. A large clinical study conducted in Sweden found a significant reduction of the criminality rate in males (32%) and females (42%) as compared with the rate for the same patients while not receiving medication. Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.
Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial. In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function. Methylphenidate may be used in addition to an antidepressant for refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.
Although possible, substance dependence is rare with Methylphenidate. Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine. Cocaine and methamphetamine block the protein DAT, over time causing DAT upregulation and lower cytoplasmic dopamine levels in their absence. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.
Early research began in 2007–2008 by Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, in University of Maryland, Baltimore, Maryland, first published, 19 September 2007 in the United States on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence, owing to methylphenidate's longer half life, and reduced vasoconstrictive effects. This replacement therapy is used in other classes of drugs such as opiates for maintenance and gradual withdrawal such as methadone, suboxone, etc. A second generation of N-substituted 3α-[bis(4′-fluorophenyl)methoxy]-tropanes (GA 1–69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1
). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague–Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69–34.3 vs. 0.9 L/kg) along with longer elimination (t1/2: 4.1–5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3–2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain dopamine levels ranged from minimal effects (GA 1–69) to several fold elevation (∼850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure–response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit dopamine reuptake (0.1–0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 1993–2007, 2008
Animal studies using rats with ADHD-like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of follow-up study whether this occurs in ADHD like animals and whether it occurs in humans. However, long lasting benefits of stimulant drugs have not been found in humans.
Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended. Some adverse effects of stimulant therapy may emerge during long-term therapy, but there is very little research of the long-term effects of stimulants. The most common side effects of methylphenidate are nervousness, drowsiness and insomnia. Other adverse reactions include:
On March 22, 2006, the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need black box warnings about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk." Previously, 19 possible cases had been reported of cardiac arrest linked to children taking methylphenidate and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a "black-box" warning in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.
Historical concerns related to child growth and cancer risk have existed, and these are still monitored and studied, however current scientific consensus is that the evidence of studies suggests these are either dubious or low-significance risks. (See : Previous health concerns now considered doubtful or largely minor
On occasion, treatment emergent psychosis can occur during long-term therapy with methylphenidate. Regular psychiatric monitoring of people who are taking methylphenidate for adverse effects such as psychotic symptomatology has been recommended. In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under six years of age. Normally any reaction will show within three hours. However, injection (particularly arterial) has sometimes led to toxic necrosis and amputation at the point of injection. Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using monoamine oxidase inhibitors (MAOIs).
It was documented in 2000, by Zito et al. "that at least 1.5% of children between the ages of two and four are medicated with stimulants, anti-depressants and anti-psychotic drugs, despite the paucity of controlled scientific trials confirming safety and long-term effects with preschool children."
The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate. Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. There are no well defined withdrawal schedules for discontinuing long-term use of stimulants. There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks. Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%. A small study of just under 100 children that assessed long-term outcome of stimulant use found that 6% of children became psychotic after months or years of stimulant therapy. Typically, psychosis would abate soon after stopping stimulant therapy. As the study size was small, larger studies have been recommended. The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown. Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants. Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoid delusions, confusion, increased aggression and irritability. Methylphenidate psychosis is unpredictable in whom it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in children with ADHD. High rates of childhood stimulant use is found in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder. Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.
Juvenile rhesus monkeys chronically administered twice daily methylphenidate doses that cause plasma levels similar to those of higher pharmalogical doses in humans show no apparent lasting effects. Measures tested included -like dopamine receptor2
D density, dopamine transporter density, amphetamine-induced dopamine release responsiveness, cognitive performance, and growth.
Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity. When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylyphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible. Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%. Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound, but has significantly less activity on the norepinephrine transporter (NET).
Methylphenidate should not be prescribed concomitantly with tricyclic antidepressants, such as desipramine, or monoamine oxidase inhibitors, such as phenelzine or tranylcypromine, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).]
[ Methylphenidate should not be prescribed to patients who suffer from severe arrhythmia, hypertension or liver damage. It should not be prescribed to patients who demonstrate drug-seeking behaviour, pronounced agitation or nervousness. Care should be taken while prescribing methylphenidate to children with a family history of Paroxysmal Supraventricular Tachycardia (PSVT).
Special precaution is recommended in individuals with epilepsy with additional caution in individuals with uncontrolled epilepsy due to the potential for methylphenidate to lower the seizure threshold. There is no published evidence to suggest that either the short or long term treatment with methylphenidate increases the risk of developing seizures in children with ADHD. A number of small trials suggest that it is safe for use in children with epilepsy. Further randomised control trials are needed.
The U.S. FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks. Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies. One of these studies (N = 11) demonstrated no significant increases in malformations. A second (N = 13) demonstrated one major malformation in newborns with early exposure to methylphenidate, which was in the expected range of malformations. However, this was a cardiac malformation, which was not within the statistically expected range. Finally, in a retrospective analysis of patients' medical charts (N = 38), researchers examined the relationship between abuse
of intravenous methylphenidate and pentazocine in pregnant women. Twenty-one percent of these children were born prematurely, and several had stunted growth and withdrawal symptoms (31% and 28%, respectively). Intravenous methylphenidate abuse was confounded with the concurrent use of other substances (e.g., cigarettes, alcohol) during pregnancy.
In the majority of unremarkable isolated cases MPH overdose is asymptomatic (symptomless) or only incurs minor symptoms even in children under age 6. In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia. LD50 in mice is 190 mg/kg.
Studies of reported incidents tend to show that most overdoses are unintentional and generally conclude that severe or major toxicity are comparatively rare events (none in the Michigan study of 289 incidents, 0.9% in the 2004 US national analysis with n=8336, and 0.2% in the same analysis for 2010 with n=6503).
Death rates are also comparatively low (none in the Michigan study, 0.36 per 1000 with n=3 for the 2004 US national analysis, 0.15 per 1000 with n=1 for the 2010 analysis; the US national guideline approved 2007 also notes only 2 deaths reported as primarily to MPH overdose from 2000-05).
A 2008 review generally agreed these findings but noted recreation or study use was "fairly common" in US university studies and that the risk could only be said to be low "in the short term" since there was little certainty about long term effects of overdose and abuse. A 2011 Swiss study also agreed the general findings, adding a cautionary note that serious or severe outcomes such as necrosis, abscess and amputation had occurred as a result of severe toxicity at the injection site in 3 cases of abuse via injection, especially when arterial.
Key recommendations in US guidelines for overdose handling include:
A study in 2000 looked in detail at all 289 overdoses of MPH reported to the Children's Hospital of Michigan regional poison control center during 1993 and 1994 (excluded: 105 extended-release formulations or co-ingestants, to ensure MPH overdose effects were not confounded by other effects). The case histories were: Age:
251 aged under 18, 38 adult; Reason:
68 (23%) intentional/unknown/error. In 163 cases (56%) the dose was known and in 41% the patient's own MPH was involved. Variation in overdose ranged from <1 mg/kg (30%) to >3 mg/kg (7.5%) mean 1.7 mg/kg. Findings:
In 2004, the American Association of Poison Control Centers Toxic Exposure Surveillance System annual report showed about 8300 methylphenidate ingestions reported in US poison center data, of which 72% were accidental or unintended, and 19% involved children age 0-6. The most common reasons for intentional exposure were drug abuse and suicide attempts. The 2010 report showed 6500 single reported exposures in the US for the year. 2010 incidents:
A Swiss study in 2011 also concurred, noting similar findings in several studies and national analyses in that country, but noted that these findings were potentially inapplicable to the few cases of abuse via crushed MPH injection, which was the sole situation where "serious" or "severe" local toxicity was observed, leading in their study to pain, necrosis and partial limb or digit amputation in two of 14 adult cases over 8 years (14%) who mistakenly injected arterially, and inguinal abscess and fever in one who injected intravenously.
Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate. There is also cross tolerance with other stimulants such as amphetamine and cocaine. Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, e.g. via a gradual tapering off of medication over a period of weeks or months. A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless, withdrawal reactions may still occur in susceptible individuals. The withdrawal or rebound symptoms of methylphenidate can include psychosis, depression, irritability and a temporary worsening of the original ADHD symptoms. Methylphenidate, due to its very short elimination half life, may be more prone to rebound effects than d-amphetamine. Up to a third of children with ADHD experience a rebound effect when methylphenidate dose wears off.
However, there have also been studies that show that chronic administration of methylphenidate increases
sensitivity. This phenomenon, known as sensitization, is known to occur with chronic administration of amphetamine.
Methylphenidate has some potential for abuse due to its action on dopamine transporters, although individuals with ADHD are unable to get any recreational use. Methylphenidate, like other stimulants, increases dopamine levels in the brain, but at therapeutic doses this increase is slow, and thus euphoria only rarely occurs even when it is administered intravenously. The abuse and addiction potential of methylphenidate is therefore significantly lower than that of cocaine. The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or when it is injected, producing effects somewhat similar to cocaine. Cocaine-like effects can also occur with very large doses taken orally.]
[ However, the dose that produces euphoric effects varies among individuals. Methylphenidate has less abuse potential than cocaine and amphetamine.
The primary source of methylphenidate for abuse is diversion from legitimate prescriptions, rather than illicit synthesis. Those who use methylphenidate medicinally generally take it orally, while intranasal and intravenous are the preferred means for recreational use. IV users tend to be adults whose use may cause panlobular pulmonary emphysema.
Abuse of prescription stimulants is higher amongst college students than non-college attending young adults. College students use methylphenidate either as a study aid or to stay awake longer. Increased alcohol consumption due to stimulant misuse has additional negative effects on health.
Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally. In the USA it is one of the top ten stolen prescription drugs.]
[ Recreational users may crush the tablets and either snort the powder, or dissolve the powder in water, filter it through cotton wool into a syringe to remove the inactive ingredients and other particles and inject the drug intravenously. Both of these methods increase bioavailability and produce a much more rapid onset of effects than when taken orally (within c. 5–10 minutes through insufflation and within just 10–15 seconds through intravenous injection); however the overall duration of action tends to be decreased by any non-oral use of drug preparations made for oral use.
Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor John Harris, an expert in bioethics, has said that it would be unethical to stop healthy people taking the drug. He also argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities. Professor Anjan Chatterjee however has warned that there is a high potential for abuse and may cause serious adverse effects on the heart, meaning that only people with an illness should take the drug. In the British Medical Journal
he wrote that it was premature to endorse the use of Ritalin in this way as the effects of the drug on healthy people have not been studied. Professor Barbara Sahakian has argued that the use of Ritalin in this way may give students an unfair advantage in examinations and that as a result universities may want to discuss making students give urine samples to be tested for the drug.
The dosage forms of methylphenidate are tablets, capsules, patches, and liquid.
A formulation by the Novartis trademark name Ritalin, is an immediate-release racemic mixture, although a variety of formulations and generic brand names exist. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, and Rubifen. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations.
Extended-release tablets or capsules include:
A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for nicotine replacement therapy.
Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the dose is immediate release, and the remaining 78% of the dose is released over 10–12 hours post ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.
Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Both Ritalin LA and Equasym XL provide two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours.
Metadate CD capsules contain two types of beads; 30% of the beads are immediate release, and the other 70% of the beads are evenly sustained release.
Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. One such criticism is prescribing psychostimulants medication to children to reduce ADHD symptoms. The pharmacological effects of methylphenidate resemble closely those of cocaine and amphetamine, which is the desired effect in the treatment of ADHD, and how methylphenidate works. However, while particular effects of Methylphenidate may resemble closely those of cocaine, individuals with ADHD have no recreational use of Methylphenidate.
Shortages of Ritalin in 2011 have been blamed on overmedication, itself ironically due to inattention to alternative therapies or measurement of long-term efficacy. Attempts have been made to rebut these charges, primarily by questioning the assumptions of studies conducted long after the treatment period has ended.
A 2002 study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine. The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life".
Another controversial idea surrounding ADHD is whether to call it a disorder when patients, in general, have healthy appearing brains with no gross neurological deficits.
Treatment of ADHD by way of Methylphenidate has led to legal actions including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems. In the U.S. and the United Kingdom, it is approved for use in children and adolescents. In the U.S., the Food and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD. Methylphenidate has been approved for adult use in the treatment of narcolepsy.
Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects. When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo diastereomers. The erythro diastereomers are also pressor
amines. "TMP" is referring only to the threo product that does not contain any erythro diastereomers. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure (2R
-methylphenidate hydrochloride has been published.
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
Attention deficit hyperactivity disorder management are the treatment options available to people with attention-deficit/hyperactivity disorder (ADHD).
There are several effective and evidence-based options to treat people with ADHD. Multimodal treatment, that is combined pharmacological and behavioral treatment, is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment. However, these results have been questioned because the study from the multimodal treatment group phased out the behavioral procedure 3 months prior to the last evaluation point but continued the medication group. Indeed, after 14 months the medication group lost its advantage to the long discontinued behavior modification group. By year eight socioeconomic status and family structure were the only predictive variables for ADHD treatment A separate study highlighted the influence that nonclinical factors such as family size may have in mediating the use of pharmacologic therapies for children with ADHD.
The most common stimulant medications are methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall). Atomoxetine (Strattera), guanfacine (Intuniv) and clonidine (Kapvay) are non-stimulant drugs approved for the treatment of ADHD. Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs. The presence of comorbid (co-occurring) disorders make finding the right treatment and diagnosis much more costly and time consuming. Having a comorbid disorder makes the treatment and diagnosis of ADHD more complicated, so it is recommended to assess and treat any comorbid disorders simultaneously.
A variety of psychotherapeutic and behavior modification approaches to managing ADHD including psychotherapy and working memory training may be used. Improving the surrounding home and school environment with Parent Management Training and classroom management can improve the behavior of children with ADHD. Specialized ADHD coaches provide services and strategies to improve functioning, like time management or organizational suggestions. Self-control training programs have shown to have limited effectiveness. Behaviorally based self-control does better than cognitive self-control training A meta-analysis found that the use of behavior modification for ADHD are effective.
As of 2006 there was a shortage of data regarding ADHD drugs' potential adverse effects, with very few studies assessing the safety or efficacy of treatments beyond four months, and no randomized controlled trials assessing for periods of usage longer than two years. Treatment of preschool children is not recommended. The U.S. Food and Drug Administration (FDA) found that a large number of the controlled trials required subjects who were known to respond to stimulants or who had no history of intolerance to stimulants, and this limits assumed generalizability of the trials' results.
There are a variety of psychotherapeutic approaches employed by psychologists and psychiatrists; the one used depends on the patient and the patient's symptoms. The approaches include psychotherapy, cognitive-behavior therapy, support groups, parent training, meditation, and social skills training. If psychotherapy fails to bring improvement, medications can be considered as an add-on or alternative.
Psychotherapy is another option, with or without medication, that has been shown to be effective.
Improving the surrounding home and school environment can improve the behavior of children with ADHD. Parents of children with ADHD often show similar deficits themselves, and thus may not be able to sufficiently help the child with his or her difficulties. Improving the parents' understanding of the child's behavior and teaching them strategies to improve functioning and communication and discourage unwanted behavior has measurable effect on the children with ADHD. The different educational interventions for the parents are jointly called Parent Management Training. Techniques include operant conditioning: a consistent application of rewards for meeting goals and good behavior (positive reinforcement) and punishments such as time-outs or revocation or privileges for failing to meet goals or poor behavior. Classroom management is similar to parent management training; educators learn about ADHD and techniques to improve behavior applied to a classroom setting. Strategies utilized include increased structuring of classroom activities, daily feedback, and token economy.
Many of the problems shown by children with ADHD can be traced back to deficits in working memory (or short-term memory). By training and improving this memory some of the other symptoms may diminish as well. In a study by Klingberg et al., a computerized training program has shown good results in working memory, even if the generalized effect to behavioural symptoms was not as clear.
ADHD coaching is a specialized type of life coaching that uses specific techniques geared toward working with the unique brain wiring of individuals with attention-deficit/hyperactivity disorder. Professional coaching is not considered a substitute for traditional treatment such as medication and therapy.
Timers have been found to be effective for allowing people with ADHD to concentrate more effectively on the task at hand. When a target is set, one method is to only turn the timer on whilst working on the given task. A physical stopwatch or an online timer may be used.
Stimulants are the most commonly prescribed medications for ADHD. The most common stimulant medications are the chain subsitituted amphetamine methylphenidate (Ritalin, Metadate, Concerta), dexmethylphenidate (Focalin), dextroamphetamine (Dexedrine), mixed amphetamine salts (Adderall), dextromethamphetamine(Desoxyn) and lisdexamfetamine (Vyvanse). According to several studies, use of stimulants (e.g. methylphenidate) can lead to development of drug tolerance to therapeutic doses; tolerance also occurs among high dose abusers of methylphenidate.
Stimulants used to treat ADHD raise the extracellular concentrations of the neurotransmitters dopamine and norepinephrine which causes an increase in neurotransmission. The therapeutic benefits are due to noradrenergic effects at the locus coeruleus and the prefrontal cortex and dopaminergic effects at the nucleus accumbens.
A meta analysis of clinical trials found that about 70 percent of children improve after being treated with stimulants in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature. There have been no randomized placebo controlled clinical trials investigating the long term effectiveness of methylphenidate (Ritalin) beyond 4 weeks. Thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD has also been noted.
On occasion, treatment emergent psychosis can emerge during long-term therapy with methylphenidate. Stimulants such methylphenidate should be avoided in people who have a vulnerability to schizophrenia or addiction; however, psychotic symptoms may emerge during therapy with methylphenidate in individuals without these risk factors; regular psychiatric monitoring of people who are taking methylphenidate for adverse effects such as psychotic symptomatology (with regard to the need for dose adjustment or discontinuation of medication) has been recommended. Higher rates of schizophrenia and bipolar disorder as well as increased severity of these disorders occur in individuals with a past history of stimulant use for ADHD in childhood.
Both children with and without ADHD abuse stimulants, with ADHD individuals being at the highest risk of abusing or diverting their stimulant prescriptions. Between 16 and 29 percent of students who are prescribed stimulants report diverting their prescriptions. The National Survey on Drug Use and Health reported that 15% of college students admitted to having used a psychotherapeutic drug for a purpose other than that for which it was prescribed. It also reported that 7% of the 15% said they used Adderall to party or to improve their attention span or grades.
One review indicates that long-term use of methylphenidate has potential for abuse and addiction due to its similarity pharmacologically to cocaine and amphetamines. However, other doctors argue that use of stimulant therapy for ADHD does not increase the risk of subsequent substance abuse and may be protective against it when treatment is started in childhood.][ However, when stimulant therapy is started during adolescence or adulthood, there is an increased risk of subsequent substance abuse.
Although "under medical supervision, stimulant medications are considered safe", the use of stimulant medications for the treatment of ADHD has generated controversy because of undesirable side effects, uncertain long term effects and social and ethical issues regarding their use and dispensation. The U.S. FDA has added black-box warnings to some ADHD medications, while the American Heart Association and the American Academy of Pediatrics feel that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications.
A novel stimulant drug that has been used to treat ADHD is modafinil. There have been double-blind randomized controlled trials that have demonstrated the efficacy and tolerability of modafinil, however there are risks of serious side effects such as skin reactions and modafinil is not recommended for use in children.
Stimulants are the most effective medications available for the treatment of ADHD. Five different formulations of stimulants have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD: three derived from amphetamine and two derived from methylphenidate. Atomoxetine, guanfacine and clonidine are the only non-controlled, non-stimulant FDA-approved drugs for the treatment of ADHD. There are no differences in effectiveness between medications used for ADHD.
Short term clinical trials have shown medications to be effective for treating ADHD, but the trials usually use exclusion criteria, meaning knowledge on medications for ADHD is based on a small subset of the typical patients seen in clinical practice. They have not been found to improve school performance and data is lacking on long term effectiveness and the severity of side effects. This class of medicines is generally regarded as one unit; however, they affect the brain differently. Some investigations are dedicated to finding the similarities of children who respond to a specific medicine. The behavioural response to stimulants in children is similar regardless of whether they have ADHD or not.
Stimulant medication is an effective treatment for Adult Attention-deficit hyperactivity disorder although the response rate may be lower for adults than children. Some physicians may recommend antidepressant drugs as the first line treatment instead of stimulants although antidepressants have lower treatment effect sizes than stimulant medication.
A study showed that children taking stimulant medications tend to be lighter in weight and shorter than their peers. A 2012 study found that among patients (adults and in teenagers over age 15) with a diagnosis of ADHD, their criminality rate during periods of receiving ADHD medication was significantly reduced, compared with nonmedication periods. Criminality consisted of mainly burglary and theft, as opposed to truly violent crimes, like murder.
Three different medicines derived from amphetamine are used in ADHD treatment. Their trade names are Adderall (a mixture of 72% dextroamphetamine and 28% levoamphetamine), Dexedrine (pure dextroamphetamine), and Desoxyn (pure dextromethamphetamine). The differences in these three amphetamine-based medications' active compounds and mixture ratios results in each medications' slightly different activities.
Levoamphetamine and dextroamphetamine have the same chemical formula but are mirror images of each other, the same way that a person's hands are the same but are mirror images of each other. This mirror difference is enough to cause the two compounds to be metabolized differently. Adderall begins to work before dextroamphetamine because of levoamphetamine. Levoamphetamine also provides Adderall with a longer clinical effect than dextroamphetamine. However, the brain’s preference for dextroamphetamine over levoamphetamine shows that the clinical value of Adderall is, for the most part, due to dextroamphetamine. A few children with ADHD and comorbid disorders have helpful responses to levoamphetamine.
The body metabolizes dextromethamphetamine into dextroamphetamine (in addition to less active metabolites). A quarter of dextromethamphetamine will ultimately become dextroamphetamine. After comparing only the common ground between dextroamphetamine and dextromethamphetamine, the latter is said to be the stronger stimulant. In theory — and in practice — a larger dose of dextroamphetamine is needed to achieve dextromethamphetamine's clinical potency. In fact, when dextroamphetamine and methylphenidate are unhelpful, some doctors may prescribe dextromethamphetamine. Although more rarely prescribed, anecdotal reports suggest dextromethamphetamine is very helpful in cases where the other two are ineffective, or cause limiting side effects.
There are two different medicines derived from methylphenidate: Ritalin, which is half dextrothreomethylphenidate and half levothreomethylphenidate, that is, a mixture of the "chemical mirror images" of methylphenidate, and Focalin, which is pure dextrothreomethylphenidate. Dextrothreomethylphenidate has a higher pharmacological activity than its mirror levo-form or enantiomer. Levothreomethylphenidate has much weaker activity than the dextro isomer, and so for instance if Daytrana (methylphenidate in transdermal patch form) is used, then the levothreomethylphenidate comprising half of the administered dose, accounts for only around one thirteenth of the total clinical effect. Methylphenidate has high potential for abuse and addiction due to its pharmacological similarity to cocaine and amphetamines.
Controlled-release pharmaceuticals may allow once or twice daily administration of medication in the morning. This is especially helpful for children who do not like taking their medication in the middle of the school day. Several controlled-release methods are used.
Atomoxetine (Strattera), guanfacine (Intuniv) and clonidine (Kapvay) are non-stimulant drugs approved for the treatment of ADHD. Other medications which may be prescribed off-label include certain antidepressants such as tricyclic antidepressants, SNRIs, SSRIs or MAOIs.
Atomoxetine (Strattera) is less effective than stimulants for ADHD, is associated with individual cases of liver damage, carries a U.S. FDA black box warning regarding suicidal idealization. Controlled studies show increases in heart rate, decreases of body weight, decreased appetite and treatment-emergent nausea.
Intuniv is an extended release form of guanfacine. Intuniv has been approved by the FDA for the treatment of attention-deficit hyperactivity disorder (ADHD) in children as an alternative to stimulant medications. Its beneficial actions are likely due to its ability to strengthen prefrontal cortical regulation of attention and behavior.
Clonidine (Kapvay), an α2A adrenergic receptor agonist has also been approved in the US. Clonidine, initially developed as a treatment for high blood pressure, low doses in evenings and/or afternoons are sometimes used in conjunction with stimulants to help with sleep and because clonidine sometimes helps moderate impulsive and oppositional behavior and may reduce tics. It may be more useful for comorbid Tourette syndrome.
Certain antidepressants such as tricyclic antidepressants, SNRIs or MAOIs are sometimes prescribed and are also effective in the treatment of ADHD.
Some medications used to treat ADHD are prescribed off-label, outside the scope of their FDA-approved indications for various reasons. The U.S. FDA requires two clinical trials to prove a potential drug's safety and efficacy in treating ADHD. The drugs below have not been through these tests, so the efficacy is unproven (however these drugs have been licensed for other indications, so have been proven to be safe in those populations), however proper dosage and usage instructions are not as well characterized.
The use of atypical antipsychotic medication as an off-label treatment has been rising. Antipsychotics work by blocking dopamine, whereas stimulants trigger its release. Atypical antipsychotics have been approved for use in children and teenagers with schizophrenia spectrum disorders and autistic spectrum disorders by the U.S. FDA.
Non-ADHD children do not respond differently than ADHD children when prescribed antipsychotic drugs, which are also increasingly prescribed off-label for children with aggression or defiant behavior. Social pressure to control a child's difficult and disruptive behavior, both at home and at school, may inadvertently change focus from what is in the best interest of the child's wellbeing; to how to render the child more compliant and easier to manage.
Careful approach needs to be taken when blocking dopamine function, which is responsible for the psychological reward system. Excessive blocking of this neurotransmitter can causedysphoria. This may in turn cause suicidal ideation, or lead some teenagers to compensate for their dopamine deficiency with illicit drugs or alcohol. Atypical antipsychotics are preferred for this reason, because they are less likely to cause movement disorders, dysphoria, and increased drug cravings that have been associated with older typical antipsychotics. Weight gain, diabetes, lactation, gynecomastia, drooling, dysphoria, anhedonia (inability to experience pleasure), fatigue, sexual dysfunction, heart rhythm problems and the possibility of tardive dyskinesia, an irreversible][ movement disorder, are among the adverse events associated with antipsychotic drugs.
The National Institute of Mental Health states that, "stimulant drugs, when used with medical supervision, are usually considered quite safe." Still, some parents and professionals have raised questions about the side effects of drugs and their long term use. A recent review states that ADHD studies "have major methodological deficiencies which are compounded by their restriction to school-age children, relatively short follow-up, and few data on adverse effects."
The American Heart Association feel that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications. Several studies have found growth and weight suppression for stimulants. Compared to the behavior modification group at 8 years of the government-funded MTA study, the stimulant group had higher level of reported substance abuse.
Outpatient treatment rates have held steady in the US recently. Prior to this, outpatient treatment for ADHD in the US grew from 0.9 children per 100 in 1987 to 3.4 per 100 in 1997. A survey conducted by the Centers of Disease Control and Prevention in 2011-2012 found 6.4 million children between the ages of 4 and 17 have been diagnosed with ADHD at some point, a 16% increase since 2007 and a 41% increase over the last decade. There is concern about the rising use of methylphenidate (Ritalin), mainly to treat ADHD and similar disorders, in the UK. The incidence of ADHD is estimated at three to five percent of the population, while the number of children in the United States taking Ritalin is estimated at one to two percent.
There is non-medical prescription stimulant use. A 2003 study found that non prescription use by college students in the US was 6.9% with 4.1% using them within the last year. A 2006 study with teens in Grades 7 to Grade 12 found that 2% reported non-medical use of prescription stimulant medication in the past 12 months, with 2% also reporting non-medical use of prescribed sedatives/and or anxiety medications, 3% using sleeping medications, and 12% reporting non-medical use of prescribed pain medications.
Parents of children with ADHD note that they usually display their symptoms at an early age. There have been few longitudinal studies on the long-term effects psychostimulants have on children. The use of stimulant medication has not been approved by the FDA for children under the age of six. A growing trend is the diagnosis of younger children with ADHD. Prescriptions for children under the age of 5 rose nearly 50 percent from 2000 to 2003. Research on this issue has indicated that stimulant medication can help younger children with "severe ADHD symptoms" but typically at a lower dose then older children. It was also found that children at this age are more sensitive to side effects and should be closely monitored. It has been stated that "it is prudent for physicians to be cautious," with medications. Evidence suggests that careful assessment and highly individualized behavioural interventions significantly improve both social and academic skills while medication only treats the symptoms of the disorder. The same expert indicated that "one of the primary reasons cited for the growing use of psychotropic interventions was that many physicians realize that psychological interventions are costly and difficult to sustain."
The stunting of growth in children has been a concern. Past studies suggested that "long-term use of the drugs could stunt children's growth." A considerable amount of growth hormones (20-40%) are released during the 60-90 minute period after falling asleep. This part of the sleep cycle is suppressed by stimulants, causing a deficit of growth hormones in the body. However, more recent studies suggest that children eventually do reach normal height and weight. According to Wilens (2004), treated children with ADHD tend to grow at a slower rate but catch up during adolescence and adulthood. One notion is that psychostimulant medication can decrease appetite which may result in loss of weight and may be a factor in stunted growth.
Psychostimulants have negative effects on both the gross and biochemical functions of the brain, including the frontal lobes and basal ganglia, which are involved in motor control, learning routine behaviors, motivation, and cognitive and emotional functions. Psychostimulants have also been indicated to disrupt growth hormones, which could affect brain development. A study found that amphetamines such Adderall can have long term effects on the mind. In the study, rhesus monkeys were given escalating injected doses of amphetamine over either six or twelve weeks. Compared to monkeys given inactive saline, the monkeys who received the drug displayed deficits in short term memory. This lasted for at least three years after they were given the drug. The researchers in this study connected this deficiency to a significantly lower level of dopamine activity in the frontal cortex. In another study amphetamine was administered to monkeys by mouth and given twice a day to resemble the way the dose is taken by humans. Two to four weeks after they had begun taking the amphetamines, the researchers on the team detected evidence of brain damage. They found lower levels of dopamine and fewer dopamine transporters on the nerve endings in the striatum, in the animals given the amphetamines compared to those who were not.
There is concern that stimulants and Atomoxetine, which increase the heart rate and blood pressure, might cause serious cardiovascular problems.
In 2007 the FDA requires all ADHD drug manufacturers to notify patients about serious cardiovascular side effects. This was due to reports of sudden death in children taking these medications who had underlying heart problems and of high risk adults who suffered heart attacks and strokes.
Studies indicated that, "the rate of sudden death of children taking ADHD medications do not appear to exceed the base rate of sudden death in the general population". Matthew Smith is purported to have died at age 14 after long-term use of Ritalin. The medical examiner determined that Smith died from Ritalin usage, but medical experts dispute this. The examiner also argued that it was likely that diabetic children were at higher risk for cardiac problems.
In 2006 the FDA examined the occurrence of psychiatric side effects in ADHD medication. They found increased rates of psychosis and or mania with all drug treatments examined, including: Concerta, Ritalin LA, d-MPH, Atomoxetine, Adderall XR, Modafinil, MTS, and Metadate.
Sleep problems may occur, but can also be an extremely common side-effect of ADHD itself.
Many of these drugs are associated with physical and psychological dependence.
The short term use of stimulant medication has been shown to be effective yet its long term effects are yet to be determined. The Multimodal Treatment Study of Children with ADHD concluded that while drugs such as Ritalin and Concerta (a delayed release form of Ritalin) worked in the short term, there was no demonstrable improvement in children's behavior after three years of medication." A long-term study by Swanson et al. treated nearly 600 children in the 1990s for fourteen months to compare methylphenidate (the active ingredient in Ritalin) verses behavioral treatment. The study consisted of three groups: medication only, behavioral treatment only, and a combination of both. Although it was found that medication was more effective in reducing symptoms, 54% of the medication-alone group required a dose increase of on average 19% per unit of body weight. In a follow-up to the study, the children in the medication-only group reported having lost half of the benefit of medication by the end of two-years, and all of it by the end of three years. Similar results were found in a two-year study in 2005 of 200 children taking Concerta, a delay-release form of methylphenidate. Medication was effective through the second year, but only if the dosage was increased 15% on averaged per unit of body weight.
While ADHD is associated with an increased risk of substance abuse, stimulant medications have been shown to reduce the risk of subsequent development of substance abuse.
Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. The long term effects of methylphenidate in drug addiction, withdrawal reactions, psychosis, depression, and pregnancy has received very little research and thus the long term effects of using stimulants for ADHD are largely unknown. There are no well defined withdrawal schedules for discontinuing long term use of stimulants.
Short term clinical trials have shown an incidence of psychosis of 0.1%. One small-sample study found that 6% of children on long-term stimulant medication experienced had experienced some kind of psychotic symptom. The long term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.
Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, i.e. via a gradual tapering off of medication over a period of weeks or months. A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless withdrawal reactions may still occur in susceptible individuals. The withdrawal or rebound symptoms of methylphenidate can include psychosis, irritability and depression and a return of ADHD symptoms in an exaggerated form. Methylphenidate may be worse for causing rebound and withdrawal effects due to its very short half life. Amphetamine may cause less severe rebound or withdrawal effects due to its somewhat longer half life. Up to a third of ADHD children experience a rebound effect in ADHD symptoms when the methylphenidate dose wears off.
Concerns about chromosomal aberrations and possible cancer later in life was raised by a small-scale study on the use of methylphenidate, though a review by the Food and Drug Administration (FDA) found significant methodological problems with the study. A follow-up study performed with improved methodology found no evidence that methylphenidate might cause cancer, stating "the concern regarding a potential increase in the risk of developing cancer later in life after long-term MPH treatment is not supported."
Combined medical management and behavioral treatment is the most effective ADHD management strategy, followed by medication alone, and then behavioral treatment. In terms of cost-effectiveness, management with medication has been shown to be the most cost-effective, followed by behavioral treatment, and combined treatment. The individually most effective and cost efficient way is with stimulant medication. Additionally, long-acting medications for ADHD, in comparison to short-acting varieties, generally seem to be cost effective.Comorbid (relating to two diseases that occur together, e.g. depression and ADHD) disorders make finding the right treatment and diagnosis much more costly than when comorbid disorders are absent.
The first reported evidence of stimulant medication used to treat children with concentration and hyperactivity problems came in 1937. Dr. Charles Bradley in Providence, Rhode Island reported that a group of children with behavioral problems improved after being treated with the stimulant Benzedrine. In 1957, the stimulant methylphenidate (Ritalin, which was first produced in 1950) became available; it remains one of the most widely prescribed medications for ADHD. Initially the drug was used to treat narcolepsy, chronic fatigue, depression, and to counter the sedating effects of other medications. The drug began to be used for ADHD in the 1960s and steadily rose in use.][
In 1975, pemoline (Cylert) was approved by the U.S. FDA for use in the treatment of ADHD. While an effective agent for managing the symptoms, the development of liver failure in 14 cases over the next 27 years would result in the manufacturer withdrawing this medication from the market. New delivery systems for medications were invented in 1999 that eliminated the need for multiple doses across the day or taking medication at school. These new systems include pellets of medication coated with various time-release substances to permit medications to dissolve hourly across an 8–12 hour period (Metadate CD, Adderall XR, Focalin XR) and an osmotic pump that extrudes a liquid methylphenidate sludge across an 8–12 hour period after ingestion (Concerta).][
In 2003, atomoxetine (Strattera) received the first FDA approval for a nonstimulant drug to be used specifically for ADHD. In 2007, lisdexamfetamine (Vyvanse) becomes the first prodrug to receive FDA approval for ADHD.
In 1999 the largest study of treatment for ADHD was published in the American Journal of Psychiatry. Known as the Multimodal Treatment Study of ADHD (MTA Study), it involved more than 570 children with ADHD at 6 sites in the United States and Canada randomly assigned to 4 treatment groups. All 4 treatment groups showed marked improvement from the time of baseline measurements to completion of the study 14 months later. Behavioral treatment was as effective as medication alone on 16 of 19 outcome measures. This was especially good for the behavior modification group, since the behavioral protocols were faded 3 months prior to the last evaluation and the stimulant group continued to receive medication right up to the last evaluation point.
Some proponents of alternative medicine advocate that alternative therapies may be tried before ADHD medications, although not all ADHD children will have any effective response.
Neurofeedback (NF) or EEG biofeedback is a treatment strategy used for children, adolescents and adults with ADHD. The human brain emits electrical energy which is measured with electrodes. Neurofeedback alerts the patient when beta waves are present. This theory believes that those with ADHD can train themselves to decrease ADHD symptoms.][
No serious adverse side effects from neurofeedback have been reported. Research into neurofeedback has been limited and of low quality. While there is some indication on the effectiveness of biofeedback it is not conclusive: several studies have yielded positive results, however the best designed ones have either shown reduced effects or non-existing ones.
Aerobic fitness may improve cognitive functioning and neural organization related to executive control during pre-adolescent development, though more studies are needed in this area. One study suggests that athletic performance in boys with ADHD may increase peer acceptance when accompanied by fewer negative behaviors.
For children and adolescents with ADHD, pediatric massage therapy has been found to improve mood and increase on-task behaviors, while reducing anxiety and hyperactivity.
Art is thought by some to be an effective therapy for some of the symptoms of ADHD.][
Preliminary studies have supported the idea that playing video games is a form of neurofeedback, which helps those with ADHD self-regulate and improve learning. On the other hand ADHD may experience great difficulty disengaging from the game, which may in turn negate any benefits gained from these activities, and time management skills may be negatively impacted as well.
Children who spend time outdoors in natural settings, such as parks, seem to display fewer symptoms of ADHD, which has been dubbed "Green Therapy".
Dietary supplements and specialized diets are sometimes used by people with ADHD with the intent to mitigate some or all of the symptoms. For example, Omega-3 supplementation (seal, fish or krill oil) may reduce ADHD symptoms for a subgroup of children and adolescents with ADHD "characterized by inattention and associated neurodevelopmental disorders." Although vitamin or mineral supplements (micronutrients) may help children diagnosed with particular deficiencies, there is no evidence that they are helpful for all children with ADHD. Furthermore, megadoses of vitamins, which can be toxic, must be avoided. In the United States, no dietary supplement has been approved for the treatment for ADHD by the FDA. There is however a pilot study done which shows that phosphatidyl serine (PS) can help against ADHD.
Some popular supplements used to manage ADHD symptoms:
Perhaps the best known of the dietary alternatives is the Feingold diet which involves removing salicylates, artificial colors and flavors, and certain synthetic preservatives from children's diets. However, studies have shown little if any effect of the Feingold diet on the behavior of children with ADHD.
Results of studies regarding the effect of eliminating artificial food coloring from the diet of children with ADHD have been very varied. It has been found that it might be effective in some children but as the published studies have been of low quality results can be more related to research problems such as publication bias. The UK Food Standards Agency (FSA) has called for a ban on the use of six artificial food colorings and the European Union (EU) has ruled that some food dyes must be labeled with the relevant E number as well as this warning: "may have an adverse effect on activity and attention in children." Nevertheless existing evidence neither refutes nor supports the association between ADHD and food colouring.
Because ADHD comorbidities are diverse and the rate of comorbidity is high, special care must dedicated to certain comorbidities. The FDA is not set up to address this issue, and does not approve medications for comorbidities, nonetheless certain such topics have been extensively researched.
Patients with Tourette syndrome who are referred to specialty clinics have a high rate of comorbid ADHD. Patients who have ADHD along with tics or tic disorders may also have problems with disruptive behaviors, overall functioning, and cognitive function, accounted for by the comorbid ADHD.
The treatment of ADHD in the presence of tic disorders has long been a controversial topic. Past medical practice held that stimulants (such as Ritalin) could not be used in the presence of tics, due to concern that their use might worsen tics; however, multiple lines of research have shown that stimulants can be cautiously used in the presence of tic disorders. Several studies have shown that stimulants do not exacerbate tics any more than placebo does, and suggest that stimulants may even reduce tic severity. Controversy remains, and the PDR continues to carry a warning that stimulants should not be used in the presence of tic disorders, so physicians may be reluctant to use them. Others are comfortable using them and even advocate for a stimulant trial when ADHD co-occurs with tics, because the symptoms of ADHD can be more impairing than tics.
The stimulants are the first line of treatment for ADHD, with proven efficacy, but they do fail in up to 20% of cases, even in patients without tic disorders. Current prescribed stimulant medications include: methylphenidate (brand names Ritalin, Metadate, Concerta), dextroamphetamine (Dexedrine), and mixed amphetamine salts (Adderall). Other medications can be used when stimulants are not an option. These include the alpha-2 agonists (clonidine and guanfacine), tricyclic antidepressants (desipramine and nortriptyline), and newer antidepressants (bupropion and venlafaxine. There have been case reports of tics worsening with bupropion (brand name Wellbutrin). There is good empirical evidence for short-term safety and efficacy for the use of desipramine, bupropion and atomoxetine (Strattera).
Stimulants legal status was recently reviewed by several international organizations:
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
Eli Lilly and Company is an American global pharmaceutical company with headquarters located in Indianapolis, Indiana, in the United States. The company also has offices in Puerto Rico and 17 other countries. Their products are sold in approximately 125 countries. The company was founded in 1876 by Col. Eli Lilly, a pharmaceutical chemist and veteran of the American Civil War, after whom the company was named.
Among other specialties, Lilly was the first company to mass-produce penicillin, the Salk polio vaccine, and insulin, including one of the first pharmaceutical companies to produce human insulin using recombinant DNA. Lilly is also the world's largest manufacturer and distributor of psychiatric medications. Nootropics
Attention deficit hyperactivity disorder (ADHD, similar to hyperkinetic disorder in the ICD-10) is a psychiatric disorder of the neurodevelopmental type in which there are significant problems of attention and/or hyperactivity and acting impulsively that are not appropriate for a person's age. These symptoms must begin by age six to twelve and be present for more than six months for a diagnosis to be made. In school-aged individuals the lack of focus may result in poor school performance.
Despite being the most commonly studied and diagnosed psychiatric disorder in children and adolescents, the cause in the majority of cases is unknown. It affects about 6 to 7 percent of children when diagnosed via the DSM-IV criteria and 1 to 2 percent when diagnosed via the ICD-10 criteria. Rates are similar between countries and depend mostly on how it is diagnosed. ADHD is approximately three times more frequent in boys than in girls. About 30 to 50 percent of people diagnosed in childhood continue to have symptoms into adulthood and between 2 and 5 percent of adults have the condition. The condition can be difficult to tell apart from other disorders as well as that of high normal activity. Stimulant
Attention deficit hyperactivity disorder (ADHD, similar to hyperkinetic disorder in the ICD-10) is a psychiatric disorder of the neurodevelopmental type in which there are significant problems of attention and/or hyperactivity and acting impulsively that are not appropriate for a person's age. These symptoms must begin by age six to twelve and be present for more than six months for a diagnosis to be made. In school-aged individuals the lack of focus may result in poor school performance.
Despite being the most commonly studied and diagnosed psychiatric disorder in children and adolescents, the cause in the majority of cases is unknown. It affects about 6 to 7 percent of children when diagnosed via the DSM-IV criteria and 1 to 2 percent when diagnosed via the ICD-10 criteria. Rates are similar between countries and depend mostly on how it is diagnosed. ADHD is approximately three times more frequent in boys than in girls. About 30 to 50 percent of people diagnosed in childhood continue to have symptoms into adulthood and between 2 and 5 percent of adults have the condition. The condition can be difficult to tell apart from other disorders as well as that of high normal activity.
Disorders that are usually first present during childhood.
This category has the following 2 subcategories, out of 2 total.
Health Medical Pharma