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Isopropylphenidate: Difference between revisions

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{{SubstanceBox/Isopropylphenidate}}
{{SubstanceBox/Isopropylphenidate}}


'''Isopropylphenidate''' (also known as '''IPH''', '''IPPH''', and '''IPPD''') is synthetic [[psychoactive class::stimulant]] of the [[chemical class::piperidine]] chemical class that produces [[stimulating]], [[Motivation enhancement|motivating]], and [[Focus enhancement|focus enhancing]] effects when [[Routes of administration|administered]]. It is a structural analog of the widely-prescribed ADHD medication [[methylphenidate]] and is reported to produce near identical cognitive and physical effects, albeit with less of a [[euphoria|euphoric]] "rush" component and a drawn-out [[duration|duration of action]], properties that many find preferable for use as a study-aid or productivity enhancer.<ref name="IPPH">Markowitz, J. S., Zhu, H., & Patrick, K. S. (2013). Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability. Journal of Child and Adolescent Psychopharmacology, 23(10), 648-654. https://doi.org/10.1089/cap.2013.0074</ref><ref name="IPPHadhd">John S. Markowitz; Kennerly S. Patrick; Haojie Zhu (Sep 27, 2012). "Patent US20120245201 - Isopropylphenidate for Treatment of Attention-Deficit/Hyperactivity Disorder and Fatigue-Related Disorders and Conditions". Retrieved 15 August 2014.</ref>
'''Isopropylphenidate''' (also known as '''IPH''', '''IPP''', '''IPPH''', '''IPD''' and '''IPPD''') is a novel lesser-known [[psychoactive class::stimulant]] of the [[chemical class::phenidate]] chemical class. It is a structural analog of the widely-prescribed ADHD medication [[methylphenidate]]. It is a [[norepinephrine]]-[[dopamine]] [[reuptake inhibitor]] ('''NDRI''').


Isopropylphenidate has been investigated for its potential use as a replacement for [[methylphenidate]] in the treatment of ADHD and related disorders.<ref name="IPPHadhd" /> One study found that it displayed the same basic activity as a [[norepinephrine]]-[[dopamine]] [[reuptake inhibitor]] ('''NDRI'''), possessing, along with both [[methylphenidate]] and [[ethylphenidate]], an appreciably high affinity for the dopamine transporter and effects on its cellular reuptake. It displayed comparably minor effects on [[norepinephrine]], however, which was theorized to mean it may possess a more desirable safety and toxicity profile.<ref name="IPPH" />
Isopropylphenidate has been investigated for its potential use as a replacement for [[methylphenidate]] in the treatment of ADHD and related disorders.<ref name="IPPHadhd" /> One study found that it displayed the same basic activity as a [[norepinephrine]]-[[dopamine]] [[reuptake inhibitor]] ('''NDRI'''), possessing, along with both [[methylphenidate]] and [[ethylphenidate]], an appreciably high affinity for the dopamine transporter and effects on its cellular reuptake. It displayed comparably minor effects on [[norepinephrine]], however, which was theorized to mean it may possess a more desirable safety and toxicity profile.<ref name="IPPH" />


Isopropylphenidate has an extremely short history of [[recreational drug use|recreational use]] in human and has yet to be documented being sold on the streets. It was initially released following the banning of [[ethylphenidate]], which on April 2015 became illegal in the United Kingdom following a temporary-then-permanent blanket ban. Shortly after, it became made available for sale on the online gray market as a [[research chemical]] for global distribution.
[[Subjective effects]] include [[stimulation]], [[motivation enhancement]], [[appetite suppression]], and [[euphoria]]. Its cognitive and physical effects are reported to be similar to methylphenidate, albeit with less of a [[euphoria|euphoric]] "rush" component and a drawn-out [[duration|duration of action]]. These properties have led some to claim it may be preferable for use as a study-aid or productivity enhancer.<ref name="IPPH">{{cite journal | vauthors=((Markowitz, J. S.)), ((Zhu, H.-J.)), ((Patrick, K. S.)) | journal=Journal of Child and Adolescent Psychopharmacology | title=Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability | volume=23 | issue=10 | pages=648–654 | date= December 2013 | url=http://www.liebertpub.com/doi/10.1089/cap.2013.0074 | issn=1044-5463 | doi=10.1089/cap.2013.0074}}</ref><ref name="IPPHadhd">{{Citation | vauthors=((Markowitz, J. S.)), ((Patrick, K. S.)), ((Zhu, H.)) | title=Isopropylphenidate for Treatment of Attention-Deficit/Hyperactivity Disorder and Fatigue-Related Disorders and Conditions | url=https://patents.google.com/patent/US20120245201A1/en}}</ref>


As of 2017, isopropylphenidate continues to remain available and ambiguously legal in many parts of the world, distributed almost exclusively by online [[research chemical]] vendors.
Isopropylphenidate has an extremely short history of [[recreational drug use|recreational use]] in humans. It was initially released following the banning of [[ethylphenidate]], which on April 2015 became illegal in the United Kingdom following a temporary-then-permanent blanket ban. Shortly after, it became made available for sale on the online gray market as a [[research chemical]] for global distribution. As of 2022, isopropylphenidate continues to remain available and ambiguously legal in many parts of the world, distributed almost exclusively by online [[research chemical]] vendors.


==Chemistry==
==Chemistry==
Isopropylphenidate is a synthetic molecule of the substituted [[phenethylamine]] and [[piperidine]] classes. It contains a phenethylamine core featuring a phenyl ring bound to an amino (NH<sub>2</sub>) group via an ethyl chain. It is structurally similar to [[amphetamine]], featuring a substitution at R<sub>α</sub> which is then incorporated into a piperidine ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains an isopropyl acetate bound to R<sub>2</sub> of its molecular structure, a noticeable departure from [[methylphenidate]], which contains a methyl group in this position.  
Isopropylphenidate is a synthetic molecule of the [[substituted phenethylamine]], [[amphetamine|substituted amphetamines]] and [[phenidate]] classes. It contains a phenethylamine core featuring a phenyl ring bound to an amino (NH<sub>2</sub>) group via an ethyl chain. It is structurally similar to [[amphetamine]], featuring a substitution at R<sub>α</sub> which is then incorporated into a [[piperidine]] ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains an isopropyl acetate bound to R<sub>β</sub> of its molecular structure, a noticeable departure from [[methylphenidate]], which contains a methyl group in this position.  


Isopropylphenidate structurally diverges from [[ethylphenidate]] and [[methylphenidate]] by the length of the carbon chain on their acetate group. ''Iso-'' regards the side chain of one carbon atom branching into two bound methyl groups, ''phen-'' indicates the phenyl ring, ''id-'' is contracted from the piperidine ring, and ''-ate'' indicates the acetate group. Isopropylphenidate is a chiral compound, and has been documented as being produced as a racemic mixture and exclusively as either of its enantiomers.<ref name="IPPHSynthesis">Lachman, L., & Malspeis, L. (1962). U.S. Patent No. 3060089. Washington, DC: U.S. Patent and Trademark Office. Therapeutic lower alkyl esters of alpha-phenyl-alpha-piperidyl-(2)-acetic acid</ref>
Isopropylphenidate structurally diverges from [[ethylphenidate]] and [[methylphenidate]] by the length of the carbon chain on their acetate group. ''Iso-'' regards the side chain of one carbon atom branching into two bound methyl groups, ''phen-'' indicates the phenyl ring, ''id-'' is contracted from the piperidine ring, and ''-ate'' indicates the acetate group. Isopropylphenidate is a chiral compound, and has been documented as being produced as a racemic mixture and exclusively as either of its enantiomers.<ref name="IPPHSynthesis">{{Citation | vauthors=((Leon, L.)), ((Louis, M.)) | title=Therapeutic lower alkyl esters of alpha-phenyl-alpha-piperidyl-(2)-acetic acid | url=https://patents.google.com/patent/US3060089A/en}}</ref>


==Pharmacology==
==Pharmacology==
No formal in vivo human studies carried out using isopropylphenidate; however in vivo rat studies and in vitro studies have been performed to observe the stimulatory effects in rats, and evaluate the monoamine transporter binding affinities and affinities for various hydrolytic enzymes respectively.<ref name="IPPH" /><ref name="PhenidateHydrolysis">Portoghese, P. S., & Malspeis, L. (1961), Relative hydrolytic rates of certain alkyl (b) dl-α-(2-piperidyl)-phenylacetates. J. Pharm. Sci., 50: 494–501. https://doi.org/10.1002/jps.2600500611</ref> The results of these studies suggest that isopropylphenidate has a very similar pharmacology to its parent compound [[methylphenidate]], with the notable differences between the two substances being isopropylphenidate displaying significantly less activity as a [[norepinephrine]] [[reuptake inhibitor]] and the CES1 hydrolytic enzyme, which is exclusively responsible for hydrolysing both substances to ritalinic acid, having an 8 times lower affinity for isopropylphenidate compared to methylphenidate.  
Formal in-vivo human studies using isopropylphenidate have not been conducted. However, in vivo rat studies have found stimulatory effects; in vitro studies have evaluated the monoamine transporter binding affinities and affinities for various hydrolytic enzymes respectively.<ref name="IPPH" /><ref name="PhenidateHydrolysis">{{cite journal | vauthors=((Portoghese, P. S.)), ((Malspeis, L.)) | journal=Journal of Pharmaceutical Sciences | title=Relative Hydrolytic Rates of Certain Alkyl (b) dl-α-(2-Piperidyl)-phenylacetates | volume=50 | issue=6 | pages=494–501 | date= June 1961 | url=https://linkinghub.elsevier.com/retrieve/pii/S0022354915331865 | issn=00223549 | doi=10.1002/jps.2600500611}}</ref> The results of these studies suggest that isopropylphenidate has a very similar pharmacology to its parent compound [[methylphenidate]], with the notable differences between the two substances being isopropylphenidate displaying significantly less activity as a [[norepinephrine]] [[reuptake inhibitor]] and the CES1 hydrolytic enzyme, which is exclusively responsible for hydrolysing both substances to ritalinic acid, having an 8 times lower affinity for isopropylphenidate compared to methylphenidate.  


These differences result in the substance having more notable [[dopamine|dopaminergic]] activity than [[norepinephrine|adrenergic]] activity compared to methylphenidate at equivalent effective dosages, and in the substance having a longer duration than methylphenidate and a greater potency than methylphenidate at a given dosage. The greater potency of isopropylphenidate compared to methylphenidate is most significant with oral administration as the difference in potency is a result of the lower affinity of CES1 increasing the bioavailability of isopropylphenidate compared to methylphenidate, which is notably low for methylphenidate when administered orally due to first-pass metabolism in the liver by CES1.<ref name="MPHBioavailability">Kimko, H. C., Cross, J. T., & Abernethy, D. R. (1999). Pharmacokinetics and Clinical Effectiveness of Methylphenidate. Clinical Pharmacokinetics, 37(6), 457-470. https://doi.org/10.2165/00003088-199937060-00002</ref>
These differences result in the substance having more notable [[dopaminergic]] activity than [[norepinephrine|adrenergic]] activity compared to methylphenidate at equivalent effective dosages, and in the substance having a longer duration than methylphenidate and a greater potency than methylphenidate at a given dosage. The greater potency of isopropylphenidate compared to methylphenidate is most significant with oral administration as the difference in potency is a result of the lower affinity of CES1 increasing the bioavailability of isopropylphenidate compared to methylphenidate, which is notably low for methylphenidate when administered orally due to first-pass metabolism in the liver by CES1.<ref name="MPHBioavailability">{{cite journal | vauthors=((Kimko, H. C.)), ((Cross, J. T.)), ((Abernethy, D. R.)) | journal=Clinical Pharmacokinetics | title=Pharmacokinetics and Clinical Effectiveness of Methylphenidate: | volume=37 | issue=6 | pages=457–470 | date= 1999 | url=http://link.springer.com/10.2165/00003088-199937060-00002 | issn=0312-5963 | doi=10.2165/00003088-199937060-00002}}</ref>


Despite the notable differences between the two substances, isopropylphenidate is still thought to act primarily as both a [[dopamine]] [[reuptake inhibitor]] and a [[norepinephrine]] [[reuptake inhibitor]], meaning that it effectively boosts the levels of the norepinephrine and dopamine [[neurotransmitter|neurotransmitters]] in the brain by binding to and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft. This allows dopamine and norepinephrine to accumulate within the brain, resulting in stimulatory effects.
Despite the notable differences between the two substances, isopropylphenidate is still thought to act primarily as both a [[dopamine]] [[reuptake inhibitor]] and a [[norepinephrine]] [[reuptake inhibitor]], meaning that it effectively boosts the levels of the norepinephrine and dopamine [[neurotransmitters]] in the brain by binding to and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft. This allows dopamine and norepinephrine to accumulate within the brain, resulting in stimulatory effects.


==Subjective effects==
==Subjective effects==
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*'''[[Effect::Mouth numbing]]''' - When administered [[sublingual|sublingually]] a long-lasting numbing sensation has been reported to occur.  
*'''[[Effect::Mouth numbing]]''' - When administered [[sublingual|sublingually]] a long-lasting numbing sensation has been reported to occur.  
*'''[[Effect::Teeth grinding]]''' - This component can be considered to be less intense when compared with that of [[MDMA]].
*'''[[Effect::Teeth grinding]]''' - This component can be considered to be less intense when compared with that of [[MDMA]].
}}
{{effects/aftereffects|
The effects which occur during the [[offset]] of a [[stimulant]] experience generally feel negative and uncomfortable in comparison to the effects which occurred during its [[peak]]. This is often referred to as a "comedown" and occurs because of [[neurotransmitter]] depletion. Its effects commonly include:
*'''[[Effect::Anxiety]]'''
*'''[[Effect::Cognitive fatigue]]'''
*'''[[Effect::Depression]]'''
*'''[[Effect::Irritability]]'''
*'''[[Effect::Motivation suppression]]'''
*'''[[Effect::Thought deceleration]]'''
*'''[[Effect::Wakefulness]]'''


}}
}}
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}}
}}
{{effects/aftereffects|
The effects which occur during the [[offset]] of a [[stimulant]] experience generally feel negative and uncomfortable in comparison to the effects which occurred during its [[peak]]. This is often referred to as a "comedown" and occurs because of [[neurotransmitter]] depletion. Its effects commonly include:
*'''[[Effect::Anxiety]]'''
*'''[[Effect::Cognitive fatigue]]'''
*'''[[Effect::Depression]]'''
*'''[[Effect::Irritability]]'''
*'''[[Effect::Motivation suppression]]'''
*'''[[Effect::Thought deceleration]]'''
*'''[[Effect::Wakefulness]]'''


}}
}}
}}
===Experience reports===
===Experience reports===
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{{#ask: [[Category:Isopropylphenidate]][[Category:Experience]]|format=ul|Columns=1}}
{{#ask: [[Category:Isopropylphenidate]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:
Additional experience reports can be found here:
* [https://erowid.org/experiences/subs/exp_Isopropylphenidate.shtml Erowid Experience Vaults: Isopropylphenidate]
 
*[https://erowid.org/experiences/subs/exp_Isopropylphenidate.shtml Erowid Experience Vaults: Isopropylphenidate]


==Toxicity and harm potential==
==Toxicity and harm potential==
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===Psychosis===
===Psychosis===
{{Main|Stimulant psychosis}}
{{Main|Stimulant psychosis}}
Abuse of compounds within the stimulant class at high dosages for prolonged periods of time can potentially result in a stimulant psychosis that may present with a variety of symptoms (e.g., [[paranoia]], [[External hallucinations|hallucinations]], or [[delusions]]).<ref name="stimpsychosis">Shoptaw, S. J., Kao, U., & Ling, W. (2009). Treatment for amphetamine psychosis. ''The Cochrane Library''. https://doi.org/10.1002/14651858.CD003026.pub3</ref> A review on treatment for amphetamine, [[dextroamphetamine]], and [[methamphetamine]] abuse-induced psychosis states that about 5–15% of users fail to recover completely.<ref name="stimpsychosis" /><ref>Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York: Oxford University Press. p. 329. ISBN 9780195030570.</ref> The same review asserts that, based upon at least one trial, [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="stimpsychosis" />
Abuse of compounds within the stimulant class at high dosages for prolonged periods of time can potentially result in a stimulant psychosis that may present with a variety of symptoms (e.g., [[paranoia]], [[External hallucinations|hallucinations]], or [[delusions]]).<ref name="stimpsychosis">{{cite journal | vauthors=((Shoptaw, S. J.)), ((Kao, U.)), ((Ling, W.)) | veditors=((Cochrane Drugs and Alcohol Group)) | journal=Cochrane Database of Systematic Reviews | title=Treatment for amphetamine psychosis | date=21 January 2009 | url=https://doi.wiley.com/10.1002/14651858.CD003026.pub3 | issn=14651858 | doi=10.1002/14651858.CD003026.pub3}}</ref> A review on treatment for amphetamine, [[dextroamphetamine]], and [[methamphetamine]] abuse-induced psychosis states that about 5–15% of users fail to recover completely.<ref name="stimpsychosis" /><ref>{{cite book | vauthors=((Hofmann, F. G.)) | date= 1983 | title=A handbook on drug and alcohol abuse: the biomedical aspects | publisher=Oxford University Press | edition=2nd ed | isbn=9780195030563}}</ref> The same review asserts that, based upon at least one trial, [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="stimpsychosis" />


===Dangerous interactions===
===Dangerous interactions===
{{DangerousInteractions/Intro}}
{{DangerousInteractions/Intro}}
{{DangerousInteractions/Stimulants|self=isopropylphenidate}}
{{DangerousInteractions/Stimulants|self=isopropylphenidate}}
{{DangerousInteractions/MAOI|nt=dopamine}}
{{DangerousInteractions/MAOI|nt=dopamine}}
*'''[[MDMA]]''' - The neurotoxic effects of MDMA may be increased when combined with other stimulants.
*'''[[Cocaine]]''' - This combination may increase strain on the heart.


==Legality==
==Legal status==
{{legalStub}}
{{legalStub}}
*'''United Kingdom''' - Isopropylphenidate is a class B drug in the UK as of 31st May 2017 and is illegal to possess, produce or supply. <ref>The Misuse of Drugs Act 1971 (Amendment) Order 2017 (Legislation.gov.uk) | http://www.legislation.gov.uk/uksi/2017/634/made</ref>
 
*'''Germany''': Isopropylphenidate is controlled under the NpSG (''New Psychoactive Substances Act'')<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/anlage.html|title=Anlage NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 24, 2019|language=de}}</ref> as of November 26, 2016.<ref>{{cite web|url=https://www.bgbl.de/xaver/bgbl/start.xav?startbk=Bundesanzeiger_BGBl&jumpTo=bgbl116s2615.pdf#__bgbl__%2F%2F*%5B%40attr_id%3D%27bgbl116s2615.pdf%27%5D__1576017393518|title=Gesetz zur Bekämpfung der Verbreitung neuer psychoaktiver Stoffe|publisher=Bundesanzeiger Verlag|access-date=December 24, 2019|language=de}}</ref> Production and import with the aim to place it on the market, administration to another person and trading is punishable. Possession is illegal but not penalized.<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/__4.html|title=§ 4 NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 24, 2019|language=de}}</ref>
*'''Switzerland''': Isoprpoylphenidate is a controlled substance specifically named under Verzeichnis E.<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>
*'''Turkey''': Isopropylphenidate is illegal in Turkey as of February 2016.<ref>{{cite web|url=https://www.resmigazete.gov.tr/eskiler/2016/03/20160308-4.pdf|publisher=Resmi Gazete |access-date=January 15, 2020|language=tr|title=Karar Sayısı : 2016/8548}}</ref>
*'''United Kingdom''': Isopropylphenidate is a class B drug in the UK as of 31st May 2017 and is illegal to possess, produce or supply. <ref>{{Citation | title=The Misuse of Drugs Act 1971 (Amendment) Order 2017 | url=https://www.legislation.gov.uk/uksi/2017/634/made}}</ref>
*'''Canada''': Isopropylphenidate is a Schedule III drug in Canada. <ref>{{cite web|url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-15.html|title=Controlled Drugs and Substances Act|access-date=April 8, 2021|language=en}}</ref>
 
==See also==
==See also==
*[[Responsible use]]
*[[Responsible use]]
*[[Designer drug]]
*[[Designer drug]]
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==External links==
==External links==
*[https://en.wikipedia.org/wiki/Isopropylphenidate Isopropylphenidate (Wikipedia)]
*[https://en.wikipedia.org/wiki/Isopropylphenidate Isopropylphenidate (Wikipedia)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=635 Isopropylphenidate (Isomer Design)]


==Literature==
==Literature==
* Markowitz, J. S., Zhu, H., & Patrick, K. S. (2013). Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability. Journal of Child and Adolescent Psychopharmacology, 23(10), 648-654. https://doi.org/10.1089/cap.2013.0074
 
* John S. Markowitz; Kennerly S. Patrick; Haojie Zhu (Sep 27, 2012). "Patent US20120245201 - Isopropylphenidate for Treatment of Attention-Deficit/Hyperactivity Disorder and Fatigue-Related Disorders and Conditions". Retrieved 15 August 2014.
*Markowitz, J. S., Zhu, H., & Patrick, K. S. (2013). Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability. Journal of Child and Adolescent Psychopharmacology, 23(10), 648-654. https://doi.org/10.1089/cap.2013.0074
*John S. Markowitz; Kennerly S. Patrick; Haojie Zhu (Sep 27, 2012). "Patent US20120245201 - Isopropylphenidate for Treatment of Attention-Deficit/Hyperactivity Disorder and Fatigue-Related Disorders and Conditions". Retrieved 15 August 2014.


==References==
==References==
<references />
<references />
[[Category:Psychoactive substance]]
 
[[Category:Research chemical]]
[[Category:Research chemical]]
[[Category:Piperidine]]
[[Category:Phenidate]]
[[Category:Phenidate]]
[[Category:Stimulant]]
[[Category:Stimulant]]
{{#set:Featured=true}}
{{#set:Featured=true}}
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