APICA: Difference between revisions

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'''2NE1''' (also known as '''APICA''', and '''SDB-001''') is a novel synthetic designer [[psychoactive class::cannabinoid]] that produces subjective effects somewhat similar to those of [[cannabis]] when [[routes of administration|administered]]. It has been shown to act as a potent [[agonist]] for the CB1 and CB2 [[cannabinoid]] [[receptors]].<ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience. 2015;6(8);1445-1458;doi:10.1021/acschemneuro.5b00107 (Pubmed / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/25921407</ref>

The name "2NE1" appears to be a reference to the South Korean all-girl K-Pop group,<ref>2NE1 (Wikipedia) | https://en.wikipedia.org/wiki/2NE1</ref> a naming convention shared by the closely related chemical [[AKB48]]. In 2011, the two chemicals were first identified in Japan as a mixture in a product sold under the name "Fragrance Powder".<ref>Nahoko Uchiyama, Maiko Kawamura, Ruri Kikura-Hanajiri, Yukihiro Goda. "Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide(APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products" Forensic Toxicology (2012) 30: 114-125. https://doi.org/10.1007/s11419-012-0136-7</ref>. 2NE1 has since been available for sale as a grey-area [[research chemical]] through online vendors.

The name "2NE1" appears to be a reference to the South Korean all-girl K-Pop group,<ref>2NE1 (Wikipedia) | https://en.wikipedia.org/wiki/2NE1</ref> a naming convention shared by the closely related chemical [[AKB48]]. In 2011, the two chemicals were first identified in Japan as a mixture in a product sold under the name "Fragrance Powder".<ref>Nahoko Uchiyama, Maiko Kawamura, Ruri Kikura-Hanajiri, Yukihiro Goda. "Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide(APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products" Forensic Toxicology (2012) 30: 114-125. https://doi.org/10.1007/s11419-012-0136-7</ref> 2NE1 has since been available for sale as a grey-area [[research chemical]] through online vendors.

Synthetic cannabinoids are commonly [[smoked]] or [[vaporized]] to achieve a quick [[onset]] of effects and rapid [[offset]]. There is little information available about the use of 2NE1 via other [[routes of administration]], although as with other synthetic cannabinoids 2NE1 could be expected to be [[orally]] active when dissolved in a lipid, which may significant extend its [[duration]]. It is insoluble in water, but dissolves in ethanol and lipids.{{citation needed}}

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==Chemistry==

2NE1, or N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide, is a synthetic [[Chemical class::indole cannabinoid]]. Like many synthetic cannabinoids, it can be considered to be composed of four linked structures: core, bridge, head and tail.<ref>Synthetic cannabinoids in Europe - Interactive: demystifying the chemistry (EMCDDA) | http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids</ref>. In 2NE1, the core indole group is substituted at R1 with a pentyl chain tail and at R3 with a carboxamide bridge linking to an adamantyl head. 2NE1 can be considered an analog of both [[AKB48]], which features an indazole ~~group instead~~ of 2NE1's indole, and [[STS-135]], in which the pentyl tail is further substituted with a terminal fluorine.

2NE1, or N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide, is a synthetic [[Chemical class::indole cannabinoid]]. Like many synthetic cannabinoids, it can be considered to be composed of four linked structures: core, bridge, head, and tail.<ref>Synthetic cannabinoids in Europe - Interactive: demystifying the chemistry (EMCDDA) | http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids</ref> In 2NE1, the core indole group is substituted at R1 with a pentyl chain tail and at R3 with a carboxamide bridge linking to an adamantyl head. 2NE1 can be considered an analog of both [[AKB48]], which features an indazole in place of 2NE1's indole group, and [[STS-135]], in which the pentyl tail is further substituted with a terminal fluorine.

==Pharmacology==

2NE1 acts as a full agonist of the cannabinoid receptors, with similar potency at both [[CB1]] and [[CB2]]. In vivo experiments measuring the response of rats to 2NE1 and similar drugs found that 2NE1 had similar potency to Δ9-[[THC]] and around a third the potency of [[JWH-018]]. In comparison to these other cannabinoids, 2NE1 appeared to elicit a longer duration of effect. Caution should be exercised in interpreting studies using animals as effects may differ significantly in humans.<ref>Banister SD, Wilkinson SM, Longworth M, et al. The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse. ACS Chemical Neuroscience. 2013;4(7):1081-1092. doi:10.1021/cn400035r. (PMC/NCBI) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715837/</ref> Pharmacological studies have reported EC50 values of 6.89 ± 0.11nM at CB1 and 7.54 ± 0.11nM at CB2. <ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience (2015). 6(8). 1445-1458. doi:10.1021/acschemneuro.5b00107</ref> It is likely that 2NE1 shares many of the in vivo properties of [[Δ9-THC]]. However, the role of these interactions and how they result in the cannabinoid high has yet to be scientifically validated.

2NE1 acts as a full agonist of the cannabinoid [[receptors]], with similar potency at both [[CB1]] and [[CB2]]. In vivo experiments measuring the response of rats to 2NE1 and similar drugs found that 2NE1 had similar potency to Δ9-[[THC]] and around a third the potency of [[JWH-018]]. In comparison to these other cannabinoids, 2NE1 appeared to elicit a longer duration of effect. Caution should be exercised in interpreting studies using animals, however, as effects may differ significantly in humans.<ref>Banister SD, Wilkinson SM, Longworth M, et al. The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse. ACS Chemical Neuroscience. 2013;4(7):1081-1092. doi:10.1021/cn400035r. (PMC/NCBI) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715837/</ref>

Pharmacological studies have reported EC50 values of 6.89 ± 0.11nM at CB1 and 7.54 ± 0.11nM at CB2.<ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience (2015). 6(8). 1445-1458. doi:10.1021/acschemneuro.5b00107</ref> It is likely that 2NE1 shares many of the in vivo properties of [[Δ9-THC]]. However, the role of these interactions and how they result in the cannabinoid high has yet to be scientifically validated.

In vivo metabolic studies on 2NE1 have shown that the drug is fully metabolized with none of the original compound detectable in urine. The major metabolites were mono- or dihydroxylated on the adamantyl ring system and monohydroxylated on the pentyl chain<ref>Tim Sobolevsky, Ilya Prasolov and Grigory Rodchenkov. "Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue". Drug Testing and Analysis. 2015;7(2);131-142;doi:10.1002/dta.1756 (Pubmed / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/25428705</ref>.

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The toxicity and long-term health effects of recreational 2NE1 use do not seem to have been studied in any scientific context and the [[Toxicity::exact toxic dosage is unknown]]. This is because 2NE1 has very little history of human usage. Anecdotal evidence from people who have tried 2NE1 within the community suggests that there do not seem to be any negative health effects attributed to simply trying this substance at low to moderate doses by itself and using it sparingly (but nothing can be completely guaranteed). It has been reported that overdose on this substance will cause physical discomfort including heart palpitations, vertigo and sedation at much lower than dangerous doses, usually causing the user to suffer large amounts of [[anxiety]] or to fall asleep.

It has often been recommended that those with severe pre-existing mental conditions should not ingest these substances due to the way they strongly amplify [[emotion enhancement|one's current state of mind and emotions]]. Also, as with [[THC]] and [[cannabis]], prolonged usage of synthetic [[cannabinoids]] including 2NE1 may increase one's disposition to mental illness and psychosis<ref>Causal association between cannabis and psychosis: examination of the evidence - The British Journal of Psychiatry Jan 2004, 184 (2) 110-117 | http://bjp.rcpsych.org/content/184/2/110.short</ref>, particularly in vulnerable individuals with risk factors for psychotic illnesses (like a past or family history of schizophrenia).<ref>Every-Palmer, S. [[Synthetic cannabinoid]] use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011.</ref><ref>“Spice” Girls: Synthetic Cannabinoid Intoxication - The Journal of Emergency Medicine Volume 40, Issue 3, March 2011, Pages 296–299 (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0736467910008802</ref><ref>A Teenager With Agitation: Higher Than She Should Have Climbed - Pediatric Emergency Care: June 2010 - Volume 26 - Issue 6 - pp 462-465 | http://journals.lww.com/pec-online/Abstract/2010/06000/A_Teenager_With_Agitation__Higher_Than_She_Should.16.aspx</ref>

It has often been recommended that those with severe pre-existing mental conditions should not ingest these substances due to the way they strongly amplify [[emotion enhancement|one's current state of mind and emotions]]. Also, as with [[THC]] and [[cannabis]], prolonged usage of synthetic [[cannabinoids]] including 2NE1 may increase one's disposition to mental illness and psychosis,<ref>Causal association between cannabis and psychosis: examination of the evidence - The British Journal of Psychiatry Jan 2004, 184 (2) 110-117 | http://bjp.rcpsych.org/content/184/2/110.short</ref> particularly in vulnerable individuals with risk factors for psychotic illnesses (like a past or family history of schizophrenia).<ref>Every-Palmer, S. [[Synthetic cannabinoid]] use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011.</ref><ref>“Spice” Girls: Synthetic Cannabinoid Intoxication - The Journal of Emergency Medicine Volume 40, Issue 3, March 2011, Pages 296–299 (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0736467910008802</ref><ref>A Teenager With Agitation: Higher Than She Should Have Climbed - Pediatric Emergency Care: June 2010 - Volume 26 - Issue 6 - pp 462-465 | http://journals.lww.com/pec-online/Abstract/2010/06000/A_Teenager_With_Agitation__Higher_Than_She_Should.16.aspx</ref>

As synthetic cannabinoids are active in the milligram range (with below 5mg being a common dose), it is important to [[Dosage|use proper precautions when dosing]] to avoid a negative experience and injury to one self or others.

@@ Line 6: / Line 6: @@
 '''2NE1''' (also known as '''APICA''', and '''SDB-001''') is a novel synthetic designer [[psychoactive class::cannabinoid]] that produces subjective effects somewhat similar to those of [[cannabis]] when [[routes of administration|administered]]. It has been shown to act as a potent [[agonist]] for the CB1 and CB2 [[cannabinoid]] [[receptors]].<ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience. 2015;6(8);1445-1458;doi:10.1021/acschemneuro.5b00107 (Pubmed / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/25921407</ref>
-The name "2NE1" appears to be a reference to the South Korean all-girl K-Pop group,<ref>2NE1 (Wikipedia) | https://en.wikipedia.org/wiki/2NE1</ref> a naming convention shared by the closely related chemical [[AKB48]]. In 2011, the two chemicals were first identified in Japan as a mixture in a product sold under the name "Fragrance Powder".<ref>Nahoko Uchiyama, Maiko Kawamura, Ruri Kikura-Hanajiri, Yukihiro Goda. "Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide(APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products" Forensic Toxicology (2012) 30: 114-125. https://doi.org/10.1007/s11419-012-0136-7</ref>. 2NE1 has since been available for sale as a grey-area [[research chemical]] through online vendors.
+The name "2NE1" appears to be a reference to the South Korean all-girl K-Pop group,<ref>2NE1 (Wikipedia) | https://en.wikipedia.org/wiki/2NE1</ref> a naming convention shared by the closely related chemical [[AKB48]]. In 2011, the two chemicals were first identified in Japan as a mixture in a product sold under the name "Fragrance Powder".<ref>Nahoko Uchiyama, Maiko Kawamura, Ruri Kikura-Hanajiri, Yukihiro Goda. "Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide(APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products" Forensic Toxicology (2012) 30: 114-125. https://doi.org/10.1007/s11419-012-0136-7</ref> 2NE1 has since been available for sale as a grey-area [[research chemical]] through online vendors.
 Synthetic cannabinoids are commonly [[smoked]] or [[vaporized]] to achieve a quick [[onset]] of effects and rapid [[offset]]. There is little information available about the use of 2NE1 via other [[routes of administration]], although as with other synthetic cannabinoids 2NE1 could be expected to be [[orally]] active when dissolved in a lipid, which may significant extend its [[duration]]. It is insoluble in water, but dissolves in ethanol and lipids.{{citation needed}}
@@ Line 13: / Line 13: @@
 ==Chemistry==
-NE1, or N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide, is a synthetic [[Chemical class::indole cannabinoid]]. Like many synthetic cannabinoids, it can be considered to be composed of four linked structures: core, bridge, head and tail.<ref>Synthetic cannabinoids in Europe - Interactive: demystifying the chemistry (EMCDDA) | http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids</ref>. In 2NE1, the core indole group is substituted at R<sub>1</sub> with a pentyl chain tail and at R<sub>3</sub> with a carboxamide bridge linking to an adamantyl head. 2NE1 can be considered an analog of both [[AKB48]], which features an indazole group instead of 2NE1's indole, and [[STS-135]], in which the pentyl tail is further substituted with a terminal fluorine.
+NE1, or N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide, is a synthetic [[Chemical class::indole cannabinoid]]. Like many synthetic cannabinoids, it can be considered to be composed of four linked structures: core, bridge, head, and tail.<ref>Synthetic cannabinoids in Europe - Interactive: demystifying the chemistry (EMCDDA) | http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids</ref> In 2NE1, the core indole group is substituted at R<sub>1</sub> with a pentyl chain tail and at R<sub>3</sub> with a carboxamide bridge linking to an adamantyl head. 2NE1 can be considered an analog of both [[AKB48]], which features an indazole in place of 2NE1's indole group, and [[STS-135]], in which the pentyl tail is further substituted with a terminal fluorine.
 ==Pharmacology==
-NE1 acts as a full agonist of the cannabinoid receptors, with similar potency at both [[CB1]] and [[CB2]]. In vivo experiments measuring the response of rats to 2NE1 and similar drugs found that 2NE1 had similar potency to Δ9-[[THC]] and around a third the potency of [[JWH-018]]. In comparison to these other cannabinoids, 2NE1 appeared to elicit a longer duration of effect. Caution should be exercised in interpreting studies using animals as effects may differ significantly in humans.<ref>Banister SD, Wilkinson SM, Longworth M, et al. The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse. ACS Chemical Neuroscience. 2013;4(7):1081-1092. doi:10.1021/cn400035r. (PMC/NCBI) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715837/</ref> Pharmacological studies have reported EC<sub>50</sub> values of 6.89 ± 0.11nM at CB1 and 7.54 ± 0.11nM at CB2. <ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience (2015). 6(8). 1445-1458. doi:10.1021/acschemneuro.5b00107</ref> It is likely that 2NE1 shares many of the in vivo properties of [[Δ9-THC]]. However, the role of these interactions and how they result in the cannabinoid high has yet to be scientifically validated.
+NE1 acts as a full agonist of the cannabinoid [[receptors]], with similar potency at both [[CB1]] and [[CB2]]. In vivo experiments measuring the response of rats to 2NE1 and similar drugs found that 2NE1 had similar potency to Δ9-[[THC]] and around a third the potency of [[JWH-018]]. In comparison to these other cannabinoids, 2NE1 appeared to elicit a longer duration of effect. Caution should be exercised in interpreting studies using animals, however, as effects may differ significantly in humans.<ref>Banister SD, Wilkinson SM, Longworth M, et al. The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse. ACS Chemical Neuroscience. 2013;4(7):1081-1092. doi:10.1021/cn400035r. (PMC/NCBI) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715837/</ref>
+Pharmacological studies have reported EC<sub>50</sub> values of 6.89 ± 0.11nM at CB1 and 7.54 ± 0.11nM at CB2.<ref>Samuel D. Banister, Jordyn Stuart, Richard C. Kevin, Amelia Edington, Mitchell Longworth, Shane M. Wilkinson, Corinne Beinat, Alexandra S. Buchanan, David E. Hibbs, Michelle Glass, Mark Connor, Iain S. McGregor, and Michael Kassiou. "Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135" Chemical Neuroscience (2015). 6(8). 1445-1458. doi:10.1021/acschemneuro.5b00107</ref> It is likely that 2NE1 shares many of the in vivo properties of [[Δ9-THC]]. However, the role of these interactions and how they result in the cannabinoid high has yet to be scientifically validated.
 In vivo metabolic studies on 2NE1 have shown that the drug is fully metabolized with none of the original compound detectable in urine. The major metabolites were mono- or dihydroxylated on the adamantyl ring system and monohydroxylated on the pentyl chain<ref>Tim Sobolevsky, Ilya Prasolov and Grigory Rodchenkov. "Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue". Drug Testing and Analysis. 2015;7(2);131-142;doi:10.1002/dta.1756 (Pubmed / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/25428705</ref>.
@@ Line 56: / Line 58: @@
 The toxicity and long-term health effects of recreational 2NE1 use do not seem to have been studied in any scientific context and the [[Toxicity::exact toxic dosage is unknown]]. This is because 2NE1 has very little history of human usage. Anecdotal evidence from people who have tried 2NE1 within the community suggests that there do not seem to be any negative health effects attributed to simply trying this substance at low to moderate doses by itself and using it sparingly (but nothing can be completely guaranteed). It has been reported that overdose on this substance will cause physical discomfort including heart palpitations, vertigo and sedation at much lower than dangerous doses, usually causing the user to suffer large amounts of [[anxiety]] or to fall asleep.
-It has often been recommended that those with severe pre-existing mental conditions should not ingest these substances due to the way they strongly amplify [[emotion enhancement|one's current state of mind and emotions]]. Also, as with [[THC]] and [[cannabis]], prolonged usage of synthetic [[cannabinoids]] including 2NE1 may increase one's disposition to mental illness and psychosis<ref>Causal association between cannabis and psychosis: examination of the evidence - The British Journal of Psychiatry Jan 2004, 184 (2) 110-117  | http://bjp.rcpsych.org/content/184/2/110.short</ref>, particularly in vulnerable individuals with risk factors for psychotic illnesses (like a past or family history of schizophrenia).<ref>Every-Palmer, S. [[Synthetic cannabinoid]] use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011.</ref><ref>“Spice” Girls: Synthetic Cannabinoid Intoxication - The Journal of Emergency Medicine  Volume 40, Issue 3, March 2011, Pages 296–299 (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0736467910008802</ref><ref>A Teenager With Agitation: Higher Than She Should Have Climbed - Pediatric Emergency Care: June 2010 - Volume 26 - Issue 6 - pp 462-465 | http://journals.lww.com/pec-online/Abstract/2010/06000/A_Teenager_With_Agitation__Higher_Than_She_Should.16.aspx</ref>
+It has often been recommended that those with severe pre-existing mental conditions should not ingest these substances due to the way they strongly amplify [[emotion enhancement|one's current state of mind and emotions]]. Also, as with [[THC]] and [[cannabis]], prolonged usage of synthetic [[cannabinoids]] including 2NE1 may increase one's disposition to mental illness and psychosis,<ref>Causal association between cannabis and psychosis: examination of the evidence - The British Journal of Psychiatry Jan 2004, 184 (2) 110-117  | http://bjp.rcpsych.org/content/184/2/110.short</ref> particularly in vulnerable individuals with risk factors for psychotic illnesses (like a past or family history of schizophrenia).<ref>Every-Palmer, S. [[Synthetic cannabinoid]] use and psychosis: an explorative study. Journal of Drug and Alcohol Dependence 2011.</ref><ref>“Spice” Girls: Synthetic Cannabinoid Intoxication - The Journal of Emergency Medicine  Volume 40, Issue 3, March 2011, Pages 296–299 (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0736467910008802</ref><ref>A Teenager With Agitation: Higher Than She Should Have Climbed - Pediatric Emergency Care: June 2010 - Volume 26 - Issue 6 - pp 462-465 | http://journals.lww.com/pec-online/Abstract/2010/06000/A_Teenager_With_Agitation__Higher_Than_She_Should.16.aspx</ref>
 As synthetic cannabinoids are active in the milligram range (with below 5mg being a common dose), it is important to [[Dosage|use proper precautions when dosing]] to avoid a negative experience and injury to one self or others.