Lisdexamfetamine was developed by New River Pharmaceuticals as a longer-lasting and abuse-resistant version of d-amphetamine (dextroamphetamine).
The FDA approved lisdexamfetamine for ADHD treatment in adults on the 23th of April 2008 , followed by an approval for use in treating binge eating disorder in adults in January 2015.
Lisdexamphetamine is a codrug composed of the amino acid L-lysine, covalently bonded to dextroamphetamine. Amphetamine is comprised of a phenethylamine core featuring a phenyl ring bound to an amino (NH2) group through an ethyl chain with an additional methyl substitution at Rα. It can be referred to as a methyl homologue of phenethylamine as it has the same general formula, differing only in the addition of one methyl group.
Lisdexamfetamine was developed with the goal of providing a long duration of effect that remains consistent throughout the day as well as reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine that is released into the bloodstream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. There is, therefore, no way to speed up absorption via alternate routes of administration, such as via insufflation, vaporization, or injection, making the drug theoretically less abusable.
As a prodrug, lisdexamfetamine is inactive in the form administered. Once ingested, it is enzymatically cleaved into two parts: L-lysine, a naturally occurring essential amino acid, and d-amphetamine, a central nervous system stimulant. Thus lisdexamfetamine functions as an extended release version of dexamphetamine. Because d-amphetamine needs to be liberated from lysine via contact with red blood cells, effects are independent of route of administration. Conversion of lisdexamfetamine into active d-amphetamine is enzymatically rate-limited, slowing down the time to achieve peak concentrations and decreasing its magnitude and dampening consequent striatal dopamine release, which is thought to be responsible for the euphoric and compulsive redosing effects of stimulants.
Amphetamine is a full agonist of the trace amine-associated receptor 1 (TAAR1), which is a key regulator of common and trace brain monoamines such as dopamine, serotonin and noradrenaline. The agonism of this set of receptors results in the release of increased concentrations of dopamine, serotonin and noradrenaline in the synaptic cleft. This leads to cognitive and physical stimulation within the user.
d-amphetamine's affinity for the TAAR1 receptor is twice that of l-amphetamine. As a result, d-amphetamine produces three to four times as much central nervous system (CNS) stimulation as l-amphetamine. l-amphetamine, on the other hand, has stronger cardiovascular and peripheral effects.
29.7% of the weight of lisdexamfetamine dimesylate (the usual prescribed form) is dexamphetamine: 30 mg lisdexamfetamine dimesylate is equivalent to 8.9 mg of dexamfetamine.
The subjective experience will differ due to the slower, more steady release of active substance in the prodrug. An equivalent dose of dexamphetamine will have a higher peak plasma concentration and shorter duration.
While the subjective effects are essential identical to that of dextroamphetamine, and thus amphetamine, lisdexamfetamine is significantly longer in duration and more consistent in intensity due to its slow release. Although this drug is rate-limited in its metabolism, sufficiently high doses are comparable to its instant release counterparts once the peak has been reached.
Peripheral effects (such as increased heart rate and higher body temperature) are reported to be less prominent than formulations that partly contain l-amphetamine, such as Adderall or the racemic amphetamine sulphate sold illicitly.
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
It is strongly recommended that one use harm reduction practices when using this drug.
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical long-term medical use at therapeutic doses. Lisdexamfetamine has been posited to have less potential for abuse and addiction than other pharmaceutical amphetamines due to the slower onset and the self-limiting metabolism, which puts a cap on the maximum peak plasma concentration and consequent dopamine release. Caution is nonetheless advised, as with other drugs in the amphetamine class.
Tolerance develops rapidly in amphetamine abuse (i.e. a recreational amphetamine overdose), so periods of extended use often require increasingly larger doses of the drug in order to achieve the same effect. Repeated use of lisdexamfetamine results in a gradual tolerance proportional to the dosage taken. Patients prescribed this drug often must increase their dosage after a time to maintain its efficacy.
Using amphetamines in very high doses can result in stimulant psychosis which may include symptoms such as paranoia, delusions, and hallucinations, including the infamous Shadow people. A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use. The combination of prolonged use of high doses combined with sleep deprivation significantly increases the risk of stimulant psychosis
Lisdexamphetamine is approved for medical use with a doctor's prescription, but in most countries it is illegal to sell or possess without a prescription.
It requires a special certificate while traveling within the Schengen Area, which covers most of Europe, but not the United Kingdom.
Australia: It is a Schedule 8 drug.
Canada: Lisdexamfetamine, as well as other amphetamines, is a Schedule I drug.
Germany: Lisdexamfetamine is controlled under Anlage III BtMG (Narcotics Act, Schedule III) as of July 17, 2013. It can only be prescribed on a narcotic prescription form.
Norway: Lisdexamfetamine is a Class A drug under particularly strict control.
Sweden: Lisdexamfetamine is a Class II narcotic, with strict requirements for prescription. It has been placed under "utökad övervakning" (extended surveillance).
Switzerland: Lisdexamphetamine is a controlled substance as of October 1, 2014 specifically named under Verzeichnis A. Medicinal use is permitted.
United Kingdom: Lisdexamfetamine is a Schedule II, Class B controlled drug.
United States: Lisdexamfetamine is a Schedule II controlled drug.
Responsible use
Stimulants
Amphetamine
Methylphenidate
Lisdexamfetamine (Wikipedia)
Lisdexamfetamine (Isomer Design)
Lisdexamfetamine (DrugBank)
Lisdexamfetamine (Drugs.com)
Dextroamphetamine and Amphetamine (MedicinePlus)
Galli, A., Poulsen, N.W., Sulzer, D., & Sonders, M.S. (2005). Mechanisms of neurotransmitter release by amphetamines: a review. Progress in Neurobiology, 75 6, 406-33. https://doi.org/10.1016/j.pneurobio.2005.04.003
Berman, S. M., Kuczenski, R., McCracken, J. T., & London, E. D. (2009). Potential adverse effects of amphetamine treatment on brain and behavior: a review. Molecular Psychiatry, 14(2), 123. https://doi.org/10.1038/mp.2008.90.
