Introduction to Methylphenidate

methylphenyl(piperidin-2-yl)acetate
C₁₄H₁₉NO₂

Methylphenidate is a synthetic central nervous system stimulant--also well described as a substituted amphetamine, though its mechanism of action is distinct from the classical amphetamines-- which is prescribed worldwide for a variety of diagnoses, such as Attention-Deficit (Hyperactivity) Disorder, Postural Orthostatic Tachycardia Syndrome, Chronic Fatigue Syndrome, narcolepsy, depression, obesity and (rarely) Obsessive-Compulsive Disorder. It has been shown to possess neuroprotective effects. [1] It is sold as a racemic mixture under the brand names Ritalin, Ritilana, Ritaline, Attenta, Penid, Ribufen, Concerta, Metadate, Methylin and Daytrana.

The compound itself is a member of the piperidine class, and despite not being a member of the same family, it bears some structural resemblance to amphetamine but its effects are likened to those of cocaine.

It is most commonly sold as the water-soluble salt, methylphenidate hydrochloride.

Dexmethylphenidate

Dexmethylphenidate is the dextrorotatory enantiomer of methylphenidate. It it sold under the brand name Focalin. This differs from the typically racemic form, which is an equal mixture of dextrorotatory and levorotatory molecules.
[2]

Use of Methylphenidate

Methylphenidate can provide a very satisfying high, However; when repeatedly abused, the user can build a tolerance to this drug very quickly. A high tolerance will reduce both the recreational and medicinal value of the drug.

Commonly prescribed forms of Methylphenidate

Instant-Release

Commonly known as ‘Ritalin’ is the conventional and most commonly prescribed form of methylphenidate, It releases the full dose of methylphenidate into the users system almost immediately after consumption.

Extended-Release

Commonly known as ‘Concerta’ releases a small portion of the methylphenidate immediately and gradually releases the rest over a 9 hour period. Concerta is considered more difficult to abuse, It needs to be altered for Instant-release before consumotion, it also somewhat limits the user to oral administration as it is unsuitable for Intranasal or Intravenous use.

Concerta

Ritalin (Ciba)

Transdermal

Daytrana is a methylphenidate-containing patch which is designed to be placed on the hip so that the drug may be absorbed into the blood through the skin. The slow-release mechanism of transdermal patches intentionally decreases the recreational potential of a drug, but is ideal for treatment.

Routes of Administration for Methylphenidate

Methylphenidate can be taken in a number of ways, some being significantly less dangerous than others.

Orally

This is the most common (and arguably safest)- route of administration. Tablets are available in instant release and extended release forms; the latter is designed to give a continuous effect throughout the whole day without the need for re-dosing, however, the recreational value of unaltered Concerta is very minimal.

The oral bioavailability of methylphenidate ranges between 11-52%

Intranasaly

Methylphenidate can be insufflated through the nose, where it is absorbed into the bloodstream via mucous membranes. Snorting crushed tablets may cause damage to the inside of the nose via vasoconstriction by the drug itself and corrosion by binders used in pill manufacture. As with cocaine, it is reasonable to assume that long-term abuse in this manner may lead to permanent damage, including destruction of the septum, which separates the nostrils. Thus, it is advised that an extraction be performed to obtain a relatively pure methylphenidate hydrochloride before attempting this, though extraction may reduce, but does not eliminate the potential for damage.

Intravenously injected

This can be very hazardous and is highly unrecommended. It can very easily cause an overdose and can cause potentially permanent peripheral and arterial damage (especially in an un-purified form) as well as carrying other risks such as infections.

Effects

The effects and their intensity vary depending on tolerance, dosage, route of administration and how the individual responds to the drug but the effects most commonly consist of:

• Alertness
• Attentiveness
• Concentration
• Decreased hyperactivity
• Enhanced libido
• Euphoria
• Lengthened attention span
• Mild empathy
• Mood lift
• Motivation
• Physical and mental stimulation
• Sociability
• Talkativeness
• Wakefulness

Side-effects

Side-effects commonly include:

• Abdominal pain
• Addiction (psychological)
• Agitation
• Anxiety
• Chest pain
• Heart palpitations
• Hyperactivity
• Hypertension
• Loss of appetite
• Insomnia
• Mydriasis (pupil dilation)
• Paranoia
• Sedation
• Tachycardia
• Tics
• Vasoconstriction
• Vasodilation
• Yawning

Comedown

Methylphenidate has comedown effects similar to those of amphetamines and cocaine, though usually less severe, The comedown effects commonly include

• Anxiety
• Chill
• Craving for more of the drug
• Depression
• Dry mouth/Seemingly unquenchable thirst
• Excessive sweating
• Fever
• Headache
• Hoarse voice
• Insomnia
• Irritability
• Jaw clenching/Teeth grinding
• Muscle pain
• Restlessness
• Sore throat
• Sedation
• Shakiness/Tremor
• Vasoconstriction

Dosage

Strength	Oral	Insufflated	IM	IV
Therapeutic	5mg - 20mg
Moderate	15mg - 40mg
Strong	35mg - 60mg
Dangerous	>60mg

Chronic abuse or very high doses can lead to auditory hallucinations and stimulant psychosis. [3] The long-term effects of methylphenidate use are unknown. [4]

Methylphenidate Compared to Amphetamine

Amphetamine is a drug with similar effects as methylphenidate; it has the same indications, especially ADD/ADHD. However, methylphenidate is not an amphetamine, despite structural resemblances. Amphetamine's action slightly differs from methylphenidate's insofar as it also promotes the release of neurotransmitters into the synapse and significantly affects serotonin. [5]

A Drugs-Forum poll shows a significant majority of users preferring the effects of Adderall (mixed amphetamine salts) over methylphenidate.

Combinations

Alcohol

Combining methylphenidate with alcohol (ethanol) can enhance euphoria, libido and sociability as well as counteracting alcohol's drowsiness. It also often makes the user feel less drunk than they really are, and can be dangerous for this reason.

​

Ethylphenidate is a homologue of methylphenidate, which has an ethyl - instead of a methyl - group attached to the single-bonded oxygen of the acetate.

Ethylphenidate is created in the human body when ethanol and methylphenidate are ingested at the same time, by a process called transesterification. Methanol may be a byproduct of this reaction. The same process results in the formation of cocaethylene when cocaine and alcohol are co-ingested. [6][7]

Stimulants

Methylphenidate is a powerful stimulant in its own right but can be combined with others to enhance its efficacy or recreational value. This practice carries overdose dangers as dosage does not directly translate from methylphenidate to other substances, as well as potentially increased risks to the cardiovascular system and of psychosis.

SSRIs

selective serotonin reuptake inhibitor are prescribed for the treatment of depression, anxiety and Obsessive-Compulsive Disorder. There are no serious dangers inherent to combining methylphenidate with an SSRI. Some antidepressants, such as venlafaxine (Effexor), also inhibit the reuptake of noradrenaline, which can cause feelings of agitation and panic attacks when combined with methylphenidate.

MAOIs

Monoamine oxidase inhibitors are last resort antidepressants which inhibit the action of an enzyme called monoamine oxidase (MAO). MAO's function involves deanimation through the oxidation of monoamine compounds (such as neurotransmitters serotonin, dopamine and noradrenaline), which renders them inactive. By inhibiting this enzyme, the levels of these monoamines increase.

Methylphenidate should never be taken with an MAOI, and up to two to six weeks or more after taking any MAOI, since the rise in dopamine, norepinephrine, and serotonin levels associated with methylphenidate usage could provoke hypertensive crisis, serotonin syndrome, stroke, heart attack and death. The clinical use of combinations of stimulants, such as methylphenidate, and MAOIs is exclusively done in a hospital setting under very close medical supervision.

Pharmacology of Methylphenidate

LD₅₀ : 190 mg/kg orally in mice (as the hydrochloride salt)

Methylphenidate is a dopamine and noradrenaline/norepinephrine reuptake inhibitor (DNRI). It competitively binds to the transporter proteins which remove these neurotransmitters from the synaptic cleft, thereby allowing them to agonise receptors for longer. This is similar to the mechanism by which SSRI antidepressants inhibit the reuptake of serotonin. [2]

Dopamine and Noradrenaline
Endogenous phenethylamine neurotransmitters.​

It's primary metabolic path is hepatic by the cytochrome P450 as a substrate inhibitor of enzyme CYP2D6.[8]

Chemistry of Methylphenidate

Column 1	Column 2
Systematic (IUPAC) name:	α-Phenyl-2-piperidine-acetic acid methyl ester
Synonyms:	Mehtyl phenidylacetate, methyl α-phenyl-α-(2-piperidyl)acetate, methylphenidan; Ciba 4311b, Concerta, Equasym, Metadate, Ritalin (hydrochloride)
Molecular Formula:	C14H19NO2, C14H19NO2.HCl (hydrochloride)
Molar mass:	233.31 g/mol, 269.77 g/mol (hydrochloride) [1]
CAS Registry Number:	113-45-1, 298-59-9 (hydrochloride)
Melting Point:	74-75 °C [3], 224-226°C (hydrochloride)[2][3]
Boiling Point:	135-137°C @ 0.6 mmHg[2]
Flash Point:	no data
Solubility:	Freebase soluble in alcohol, ethyl acetate, ether[2], acetone[3]; Practically insoluble in water, petroleum ether[2]. Hydrochloride freely soluble in water, methanol[2]; Soluble in alcohol[2]; Slightly soluble in acetone, chloroform[2].
Additionnal data:	pKa 8.9[2]
Notes:	Hydrochloride aspect : white to off white powder[2]

[1]

Reagent test results of Methylphenidate

Reagent	color produced
Liebermann's	Orange

[3]

Dangers

Immediate dangers

• Panic attack

Toxicity

Toxicity studies in rats indicate:[9]

Column 1	Column 2	Column 3
ROA	Value	Dose
ORL-RAT	LD50	367mg/kg-1
SCU-RAT	LD50	170mg/kg-1
IVN-RAT	LD50	50mg/kg-1
ORL-MUS	LD50	60mg/kg-1
IVN-MUS	LDLO	40mg/kg-1
ORL-CHD	TDLO	32mg/kg-1 6w-i

Overdose

Overdose symptoms include:

• Anxiety
• Chest pain
• Feeling faint/Unconsciousness
• Hallucinations/Delusions
• Irregular or pounding heartbeat/Heart palpitations
• Nausea
• Paranoia/Panic attack
• Seizures
• Tremor/Ticks/Muscle Spasms
• Vomiting

Long-term dangers

• Dependence
• Depression
• Malnutrition
• Psychosis
• Stunted growth

Investigated as a carcinogen, mutagen and teratogen. No evidence of such activity found. (expand + source)

Producing Methylphenidate

https://drugs-forum.com/forum/sho...d.php?t=120977

History

Methylphenidate was first synthesised 1944 in Basel, Switzerland, by Ciba (Chemische Industrie Basel). [10]

Legal Status of Methylphenidate

United Nations

Africa

Asia

Europe

Ireland

Controlled as a schedule 2 drug as per the Misuse of Drug Regulations, 1988. Possession is only legal on prescription from a licensed medical practitioner, or on permission from the Minister for Health (An tAire Sláinte). Prescriptions cannot be repeated. Illegal possession can result in an unlimited fine and/or a prison sentence of up to seven years. (Misuse of Drugs Act 1984, section 8, subsection 1b)

Central / South America

North America

Oceania

References

1. ^T.J. Volz "Neuropharmacological Mechanisms Underlying the Neuroprotective Effects of Methylphenidate" Current Neuropharmacology, 2008, 6, 379-385 https://drugs-forum.com/forum/loc...59&linkid=8982
2. ^ a bHeal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system." CNS Drugs 20 (9): 713–38.
3. ^Randal G. Ross, M.D. "Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder" American Journal of Psychiatry 163:1149-1152, July 2006 https://drugs-forum.com/forum/loc...59&linkid=9237
4. ^Kimko HC, Cross JT, Abernethy DR. (1999) "Pharmacokinetics and clinical effectiveness of methylphenidate." Clinical Pharmacokinetics. 1999 Dec; 37 (6): 457-70. http://www.ncbi.nlm.nih.gov/pubmed/10628897
5. ^Kuczenski R, Segal DS. "Effects of Methylphenidate on Dopamine, Serotonin and Norepinephrine: A Comparison With Amphetamine (1997)" Journal of Neurochemistry 1997 May; 68 (5): 2032-7
6. ^Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS. "Ethylphenidate Formation In Human Subjects After The Administration of a Single Dose of Methylphenidate and Alcohol" Drug Metabolism and Disposition 2000 Jun; 28 (6): 620-4 https://drugs-forum.com/forum/loc...59&linkid=4061
7. ^Evgenia V. Pindel, Natalia Y. Kedishvili, et al. "Purification and Cloning of a Broad Substrate Specificity Human Liver Carboxylesterase That Catalyzes the Hydrolysis of Cocaine and Heroin" The Journal of Biological Chemistry Vol. 272, No. 23, Issue of June 6, pp. 14769–14775, 1997 https://drugs-forum.com/forum/loc...42&linkid=9457
8. ^Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue) 237-43. Epub 2009 Nov 24. http://www.ncbi.nlm.nih.gov/pubmed/19934256
9. ^http://msds.chem.ox.ac.uk/ME/methylp...ochloride.html
10. ^Panizzon, L. (1944). "La preparazione di piridil- e piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia)". Helvetica Chimica Acta 27: 1748–1756. Digital object identifier: 10.1002/hlca.194402701222 Last accessed: 22/06/2010

[1] Calculated from Atomic Weights of the Elements, 2007
[2] Merck Index, fifteenth edition (2013)
[3] Methylphenidate monograph