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Isopropylphenidate: Difference between revisions
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==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. 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> | 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. | ||
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> | |||
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 [[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. | ||
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The physical effects of isopropylphenidate are often described as less uncomfortable and euphoric than [[ethylphenidate]]. They can be broken down into several components which progressively intensify proportional to dosage. These are described below and generally include: | The physical effects of isopropylphenidate are often described as less uncomfortable and euphoric than [[ethylphenidate]]. They can be broken down into several components which progressively intensify proportional to dosage. These are described below and generally include: | ||
*'''[[Effect::Stimulation]]''' - Isopropylphenidate is usually considered to be energetic and stimulating in a fashion that is distinct but much weaker than that of [[amphetamine]] or [[methamphetamine]] and stronger than that of [[modafinil]] and [[caffeine]]. At lower to moderate doses, it encourages general productivity, but at higher dosages it encourages physical activities such as dancing, socializing, running, or cleaning. The particular style of stimulation which isopropylphenidate presents can be described as forced. This means that at higher doses, it becomes difficult or impossible to keep still as jaw clenching, involuntarily bodily shakes and vibrations become present, resulting in | *'''[[Effect::Stimulation]]''' - Isopropylphenidate is usually considered to be energetic and stimulating in a fashion that is distinct but much weaker than that of [[amphetamine]] or [[methamphetamine]] and stronger than that of [[modafinil]] and [[caffeine]]. At lower to moderate doses, it encourages general productivity, but at higher dosages it encourages physical activities such as dancing, socializing, running, or cleaning. The particular style of stimulation which isopropylphenidate presents can be described as forced. This means that at higher doses, it becomes difficult or impossible to keep still as jaw clenching, involuntarily bodily shakes and vibrations become present, resulting in unsteadiness of the hands, shaking of the entire body and a general loss of motor control. | ||
*'''[[Effect::Dehydration]]''' | *'''[[Effect::Dehydration]]''' | ||
*'''[[Effect::Appetite suppression]]''' | *'''[[Effect::Appetite suppression]]''' | ||
*'''[[Effect::Vasoconstriction]]''' | *'''[[Effect::Vasoconstriction]]''' | ||
*'''[[Effect::Increased heart rate]]''' | *'''[[Effect::Increased heart rate]]''' | ||
*'''[[Effect::Mouth numbing]]''' - When administered [[sublingual]] | *'''[[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]]. | ||
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*'''[[Effect::Thought acceleration]]''' - Time appears to pass by faster than normal. | *'''[[Effect::Thought acceleration]]''' - Time appears to pass by faster than normal. | ||
*'''[[Effect::Thought connectivity]]''' | *'''[[Effect::Thought connectivity]]''' | ||
*'''[[Effect::Cognitive euphoria]]''' - The euphoric rush associated with isopropylphenidate use (as a result of [[dopamine]] [[reuptake inhibition]]) is very short-lived and compulsive, similar to that of [[cocaine]]. | *'''[[Effect::Cognitive euphoria]]''' - The euphoric rush associated with isopropylphenidate use (as a result of [[dopamine]] [[reuptake inhibition]]) is very short-lived and compulsive, vaguely similar to that of [[cocaine]]. | ||
*'''[[Effect::Increased music appreciation]]''' | *'''[[Effect::Increased music appreciation]]''' | ||
*'''[[Effect::Increased libido]]''' - This component is generally considered mild compared to that of other stimulants. | *'''[[Effect::Increased libido]]''' - This component is generally considered mild compared to that of other stimulants. | ||
*'''[[Effect::Irritability]]''' - At higher dosage ranges this is often felt during the peak of the experience in addition to during the offset. This can potentially be attributed to unusually | *'''[[Effect::Irritability]]''' - At higher dosage ranges this is often felt during the peak of the experience in addition to during the offset. This can potentially be attributed to the unusually high [[dopamine|dopaminergic]] activity it displays relative to [[noradrenaline|noradrenergic]] activity.<ref name="IPPH" /> | ||
*'''[[Effect::Time distortion]]''' - This can be described as the experience of time speeding up and passing much quicker than it would while sober. | *'''[[Effect::Time distortion]]''' - This can be described as the experience of time speeding up and passing much quicker than it would while sober. | ||
*'''[[Effect::Compulsive redosing]]''' - This can be attributed to the mild-to-moderate euphoric rush and relatively short half-life of isopropylphenidate possesses, and is especially prominent when it is insufflated. Those who wish to use it for productivity purposes are advised to only take low to moderate doses strictly through [[Routes of administration#Oral|oral administration]]. [[Routes of administration#Insulfattion|insufflation]] can amplify the urge to redose. Many users report that the compulsive redosing aspects of isopropylphenidate are far more tame and controllable than the majority of [[research chemical]] stimulants, such as [[4F-MPH]], [[a-PHP]] or [[Hexen]], likely due to the absence of a pronounced rush and an extended onset. | *'''[[Effect::Compulsive redosing]]''' - This can be attributed to the mild-to-moderate euphoric rush and relatively short half-life of isopropylphenidate possesses, and is especially prominent when it is insufflated. Those who wish to use it for productivity purposes are advised to only take low to moderate doses strictly through [[Routes of administration#Oral|oral administration]]. [[Routes of administration#Insulfattion|insufflation]] can amplify the urge to redose. Many users report that the compulsive redosing aspects of isopropylphenidate are far more tame and controllable than the majority of [[research chemical]] stimulants, such as [[4F-MPH]], [[a-PHP]] or [[Hexen]], likely due to the absence of a pronounced rush and an extended onset. | ||