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Lisdexamfetamine: Difference between revisions
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{{SubstanceBox/Lisdexamfetamine}} | {{SubstanceBox/Lisdexamfetamine}} | ||
'''Lisdexamfetamine''' (also known as '''lisdextroamphetamine''', '''L-lysine-dextroamphetamine''', or '''lisdexamfetamine dimesylate''' when under the brand names '''Elvanse''', '''Tyvense''', and '''Vyvanse''') is a [[psychoactive class::stimulant]] substance of the [[chemical class::amphetamine]] class. It is a "mutual [[prodrug]]" ([https://en.wikipedia.org/wiki/Codrug codrug]) for [[ | '''Lisdexamfetamine''' (also known as '''lisdextroamphetamine''', '''L-lysine-dextroamphetamine''', or '''lisdexamfetamine dimesylate''' when under the brand names '''Elvanse''', '''Tyvense''', and '''Vyvanse''') is a [[psychoactive class::stimulant]] substance of the [[chemical class::amphetamine]] class. It is a "mutual [[prodrug]]" ([https://en.wikipedia.org/wiki/Codrug codrug]) for [[Amphetamine#Enantiomers|<small>d</small>-amphetamine]] (dextroamphetamine) that is approved for the treatment of attention deficit hyperactivity disorder (ADHD) and moderate to severe binge-eating disorder.<ref>https://www.drugs.com/pro/vyvanse.html</ref> Like amphetamine, lisdexamfetamine produces its effects by promoting the release of [[neurotransmitters]] [[dopamine]] and [[norepinephrine]] in the brain. | ||
[[Subjective effects]] are essentially identical to that of | [[Subjective effects]] are essentially identical to that of dextroamphetamine except with a slower onset and a longer duration. These include [[stimulation]], [[focus enhancement]], [[motivation enhancement]], [[euphoria]], as well as paradoxical sedation in a small percentage of the population. However, unlike dextroamphetamine, lisdexamfetamine was specifically designed to prevent non-oral forms of administration (marketed as an anti-abuse design). This means that [[insufflation]], [[Route of administration#Smoked|smoking]] or [[Route of administration#Injection|injection]] do not provide faster absorption or onset. It is sometimes sold and used illicitly as a "study drug" as well as a recreational substance. | ||
Despite the marketed anti-abuse design, | Despite the marketed anti-abuse design, lisdexamfetamine is capable of producing dependence and addiction like other [[euphoric]] stimulants, particularly when it is taken above the recommended dosage. As a result, it is highly advised to use [[harm reduction practices]] if using this substance. | ||
==History and culture== | ==History and culture== | ||
{{historyStub}} | {{historyStub}} | ||
Lisdexamfetamine was developed by New River Pharmaceuticals as a longer-lasting and | Lisdexamfetamine was developed by New River Pharmaceuticals as a longer-lasting and abuse-resistant version of [[Amphetamine#Enantiomers|<small>d</small>-amphetamine]] (dextroamphetamine). <ref name="CNS Spectrums">{{cite journal | vauthors = Mattingly G | title = Lisdexamfetamine dimesylate: a prodrug stimulant for the treatment of ADHD in children and adults | journal = CNS Spectrums | volume = 15 | issue = 5 | pages = 315–325 | date = May 2010 | pmid = 20448522 | doi = 10.1017/S1092852900027541 | s2cid = 46435024 | url = https://digitalcommons.wustl.edu/open_access_pubs/3506 }}</ref> | ||
The FDA approved lisdexamfetamine for ADHD treatment in adults on the 23th of April 2008 <ref name="FDAAdultApproval">{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/021977s001ltr.pdf|title=FDA Adult Approval of Vyvanse – FDA Label and Approval History|website=Accessdate.fda.gov|access-date=12 March 2022}}</ref>, followed by an approval binge eating disorder in adults in January 2015. <ref>{{cite press release | title=FDA expands uses of Vyvanse to treat binge-eating disorder | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 January 2015 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-url=https://web.archive.org/web/20180126103215/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-date=26 January 2018 | url-status=dead | access-date=19 March 2023}}</ref> | The FDA approved lisdexamfetamine for ADHD treatment in adults on the 23th of April 2008 <ref name="FDAAdultApproval">{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/021977s001ltr.pdf|title=FDA Adult Approval of Vyvanse – FDA Label and Approval History|website=Accessdate.fda.gov|access-date=12 March 2022}}</ref>, followed by an approval for use in treating binge eating disorder in adults in January 2015. <ref>{{cite press release | title=FDA expands uses of Vyvanse to treat binge-eating disorder | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 January 2015 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-url=https://web.archive.org/web/20180126103215/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-date=26 January 2018 | url-status=dead | access-date=19 March 2023}}</ref> | ||
==Chemistry== | ==Chemistry== | ||
Lisdexamphetamine is a [https://en.wikipedia.org/wiki/Codrug codrug] composed of the amino acid <small>L</small>-lysine, covalently bonded to | Lisdexamphetamine is a [https://en.wikipedia.org/wiki/Codrug codrug] composed of the amino acid <small>L</small>-lysine, covalently bonded to dextroamphetamine.<ref name="pmid17407369">{{cite journal | vauthors = Blick SK, Keating GM | title = Lisdexamfetamine | journal = Paediatric Drugs | volume = 9 | issue = 2 | pages = 129–135; discussion 136–138 | date = 2007 | pmid = 17407369 | doi = 10.2165/00148581-200709020-00007 | url = }}</ref> Amphetamine is comprised of a [[phenethylamine]] core featuring a phenyl ring bound to an amino (NH<sub>2</sub>) group through an ethyl chain with an additional methyl substitution at R<sub>α</sub>. 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. | ||
==Pharmacology== | ==Pharmacology== | ||
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 | 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. | ||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
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 | 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 <small>d</small>-amphetamine, a central nervous system stimulant. Thus lisdexamfetamine functions as an extended release version of dexamphetamine. Because <small>d</small>-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 <small>d</small>-amphetamine is enzymatically [[Rate-Limiting Step|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. | ||
===Pharmacodymanics=== | ===Pharmacodymanics=== | ||
Amphetamine is a [[Agonist|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]].<ref>{{cite journal | vauthors=((Miller, G. M.)) | journal=Journal of neurochemistry | title=The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity | volume=116 | issue=2 | pages=164–176 | date= January 2011 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101/ | issn=0022-3042 | doi=10.1111/j.1471-4159.2010.07109.x}}</ref><ref>{{Citation |title=Drug banks amphetamine targets |url=http://www.drugbank.ca/drugs/DB00182#targets}}</ref><ref>TA1 receptor | http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364</ref> 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 [[Thought acceleration|cognitive]] and [[Stimulation|physical stimulation]] within the user. | |||
<small>d</small>-amphetamine's affinity for the TAAR1 receptor is twice that of <small>l</small>-amphetamine.<ref>{{cite journal | vauthors=((Lewin, A. H.)), ((Miller, G. M.)), ((Gilmour, B.)) | journal=Bioorganic & medicinal chemistry | title=Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | volume=19 | issue=23 | pages=7044–7048 | date=1 December 2011 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236098/ | issn=0968-0896 | doi=10.1016/j.bmc.2011.10.007}}</ref> As a result, <small>d</small>-amphetamine produces three to four times as much central nervous system (CNS) stimulation as <small>l</small>-amphetamine. <small>l</small>-amphetamine, on the other hand, has stronger cardiovascular and peripheral effects. | |||
===Conversion rate=== | ===Conversion rate=== | ||
29.7% of the weight of lisdexamfetamine dimesylate (the usual prescribed form) is | 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.<ref>{{Citation | title=Elvanse 20mg, 30mg, 40mg, 50mg, 60mg & 70mg Capsules, hard - Summary of Product Characteristics (SmPC) - (emc) | url=https://www.medicines.org.uk/emc/medicine/27442/SPC/}}</ref><ref>[https://39f93cda-b262-4d28-a694-bf36a6802943.filesusr.com/ugd/1da6d0_55267f5b04204cb58bcc848398c0286f.pdf Stimulant Equivalency Table]</ref> | ||
The subjective experience will differ due to the slower, more steady release of active substance in the [[prodrug]]. An equivalent dose of | 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. | ||
==Subjective effects== | ==Subjective effects== | ||
While the subjective effects are | 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 | Peripheral effects (such as increased heart rate and higher body temperature) are reported to be less prominent than formulations that partly contain <small>l</small>-amphetamine, such as Adderall or the [[racemic]] amphetamine sulphate sold illicitly. | ||
{{Preamble/SubjectiveEffects}} | {{Preamble/SubjectiveEffects}} | ||
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{{effects/auditory| | {{effects/auditory| | ||
*'''[[Effect::Auditory enhancement|Enhancements]]''' | *'''[[Effect::Auditory enhancement|Enhancements]]''' | ||
*'''[[Effect::Auditory hallucinations|Hallucinations]]''' - Use of lisdexamfetamine and other amphetamines, at a strong or heavy dose, can occasionally cause mild auditory hallucinations. These hallucinations most commonly occur amongst a source of white noise, such as a fan, and typically consist of quiet phantom music or voices. Lisdexamfetamine may also cause auditory hallucinations in the form of | *'''[[Effect::Auditory hallucinations|Hallucinations]]''' - Use of lisdexamfetamine and other amphetamines, at a strong or heavy dose, can occasionally cause mild auditory hallucinations. These hallucinations most commonly occur amongst a source of white noise, such as a fan, and typically consist of quiet phantom music or voices. Lisdexamfetamine may also cause auditory hallucinations in the form of stimulant psychosis. | ||
}} | }} | ||
{{effects/aftereffects| | {{effects/aftereffects| | ||
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*'''[[Effect::Wakefulness]]''' | *'''[[Effect::Wakefulness]]''' | ||
Making sure to eat well and to hydrate are recommended to decrease the severity of comedown effects. Using mild sedatives is also a common strategy for | Making sure to eat well and to hydrate are recommended to decrease the severity of comedown effects. Using mild sedatives is also a common strategy for stimulant comedowns. | ||
}} | }} | ||
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==Toxicity and Harm Potential== | ==Toxicity and Harm Potential== | ||
In rodents and primates, sufficiently high doses of | 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 [[responsible drug use|harm reduction practices]] when using this drug. | It is strongly recommended that one use [[responsible drug use|harm reduction practices]] when using this drug. | ||
===Tolerance and addiction potential=== | ===Tolerance and addiction potential=== | ||
Addiction is a serious risk with heavy recreational | 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 | 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. | ||
=== | ===Psychosis=== | ||
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 | |||
===Dangerous interactions=== | ===Dangerous interactions=== | ||
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==Legal status== | ==Legal status== | ||
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.{{citation needed}}<br /> | |||
It requires a special certificate while traveling within the [https://en.wikipedia.org/wiki/Schengen_Area Schengen Area], which covers most of Europe, but not the United Kingdom.<ref name="swe" /><ref>http://www.felleskatalogen.no/medisin/elvanse-shire-pharmaceutical-contracts-ltd-588199</ref> | It requires a special certificate while traveling within the [https://en.wikipedia.org/wiki/Schengen_Area Schengen Area], which covers most of Europe, but not the United Kingdom.<ref name="swe" /><ref>http://www.felleskatalogen.no/medisin/elvanse-shire-pharmaceutical-contracts-ltd-588199</ref> | ||
*'''Australia''': It is a Schedule 8 drug. | *'''Australia''': It is a Schedule 8 drug.{{citation needed}} | ||
*'''Canada''': Lisdexamfetamine, as well as other amphetamines, is a Schedule I drug.<ref>{{Citation | year=2022 | title=Consolidated federal laws of Canada, Controlled Drugs and Substances Act | url=https://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-15.html}}</ref> | *'''Canada''': Lisdexamfetamine, as well as other amphetamines, is a Schedule I drug.<ref>{{Citation | year=2022 | title=Consolidated federal laws of Canada, Controlled Drugs and Substances Act | url=https://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-15.html}}</ref> | ||
*'''Germany''': Lisdexamfetamine is controlled under Anlage III BtMG (''Narcotics Act, Schedule III'')<ref>{{cite web|url=https://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html|title=Anlage III BtMG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 19, 2019|language=de}}</ref> as of July 17, 2013.<ref>{{cite web|url=https://www.bgbl.de/xaver/bgbl/start.xav#__bgbl__//*%5B@attr_id=%27bgbl113s2274.pdf%27%5D|title=Siebenundzwanzigste Verordnung zur Änderung betäubungsmittelrechtlicher Vorschriften|publisher=Bundesanzeiger Verlag|access-date=December 19, 2019|language=de}}</ref> It can only be prescribed on a narcotic prescription form.<ref>{{cite web|url=https://www.gesetze-im-internet.de/btmvv_1998/__8.html|title=§ 8 BtMVV|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 19, 2019|language=de}}</ref> | *'''Germany''': Lisdexamfetamine is controlled under Anlage III BtMG (''Narcotics Act, Schedule III'')<ref>{{cite web|url=https://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html|title=Anlage III BtMG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 19, 2019|language=de}}</ref> as of July 17, 2013.<ref>{{cite web|url=https://www.bgbl.de/xaver/bgbl/start.xav#__bgbl__//*%5B@attr_id=%27bgbl113s2274.pdf%27%5D|title=Siebenundzwanzigste Verordnung zur Änderung betäubungsmittelrechtlicher Vorschriften|publisher=Bundesanzeiger Verlag|access-date=December 19, 2019|language=de}}</ref> It can only be prescribed on a narcotic prescription form.<ref>{{cite web|url=https://www.gesetze-im-internet.de/btmvv_1998/__8.html|title=§ 8 BtMVV|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 19, 2019|language=de}}</ref> | ||
*'''Norway''': Lisdexamfetamine is a Class A drug under particularly strict control. | *'''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).<ref name="swe">{{Citation | title=Elvanse - FASS Allmänhet | url=https://www.fass.se/LIF/product?userType=2&nplId=20140730000117}}</ref> | *'''Sweden''': Lisdexamfetamine is a Class II narcotic, with strict requirements for prescription. It has been placed under "utökad övervakning" (extended surveillance).<ref name="swe">{{Citation | title=Elvanse - FASS Allmänhet | url=https://www.fass.se/LIF/product?userType=2&nplId=20140730000117}}</ref> | ||
*'''Switzerland''': Lisdexamphetamine is a controlled substance as of October 1, 2014 specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | *'''Switzerland''': Lisdexamphetamine is a controlled substance as of October 1, 2014 specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | ||
*'''United Kingdom''': Lisdexamfetamine is a Class B | *'''United Kingdom''': Lisdexamfetamine is a Schedule II, Class B controlled drug.<ref>https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation</ref> | ||
*'''United States''': Lisdexamfetamine is a Schedule II controlled drug.<ref>{{Citation | title=21 U.S. Code § 812 - Schedules of controlled substances | url=https://www.law.cornell.edu/uscode/text/21/812#b_4}}</ref> | *'''United States''': Lisdexamfetamine is a Schedule II controlled drug.<ref>{{Citation | title=21 U.S. Code § 812 - Schedules of controlled substances | url=https://www.law.cornell.edu/uscode/text/21/812#b_4}}</ref> | ||
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*[[Responsible use]] | *[[Responsible use]] | ||
*[[Stimulants]] | *[[Stimulants]] | ||
*[[Amphetamine]] | *[[Amphetamine]] | ||
*[[Methylphenidate]] | *[[Methylphenidate]] | ||
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*[http://en.wikipedia.org/wiki/Lisdexamfetamine Lisdexamfetamine (Wikipedia)] | *[http://en.wikipedia.org/wiki/Lisdexamfetamine Lisdexamfetamine (Wikipedia)] | ||
*[https://isomerdesign.com/PiHKAL/explore.php?id=10644 Lisdexamfetamine (Isomer Design)] | *[https://isomerdesign.com/PiHKAL/explore.php?id=10644 Lisdexamfetamine (Isomer Design)] | ||
*[https:// | *[https://go.drugbank.com/drugs/DB01255 Lisdexamfetamine (DrugBank)] | ||
*[https://www.drugs.com/mtm/lisdexamfetamine.html Lisdexamfetamine (Drugs.com)] | |||
*[https://medlineplus.gov/druginfo/meds/a601234.html Dextroamphetamine and Amphetamine (MedicinePlus)] | *[https://medlineplus.gov/druginfo/meds/a601234.html Dextroamphetamine and Amphetamine (MedicinePlus)] | ||