Para-Chloroamphetamine

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Distinguish|para-Chloromethamphetamine}} {{DISPLAYTITLE:''para''-Chloroamphetamine}} {{Drugbox | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 462272984 | drug_name = ''para''-Chloroamphetamine | image = Para-Chloroamphetamine.svg | image_class = skin-invert-image | width = 250px

| tradename = | routes_of_administration = Oral | class = Serotonin–norepinephrine–dopamine releasing agent; Serotonergic neurotoxin; Antidepressant; Stimulant

| legal_DE = NpSG | legal_UK = Class A

| bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = {{Abbrlink|IM|Intramuscular Injection}}: 3–7{{nbsp}}hours<ref name="Shulgin1978" /> | excretion =

| IUPHAR_ligand = 4592 | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 64-12-0 | UNII = 897NVD4A52 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 358967 | PubChem = 3127 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 3015 | synonyms = PCA; pCA; ''p''-Chloroamphetamine; 4-Chloroamphetamine; 4-CA; Ro 4-6614/001; NSC-287208; 4-Chloro-α-methylphenethylamine; 1-(4-Chlorophenyl)propan-2-amine

| IUPAC_name = 1-(4-Chlorophenyl)propan-2-amine | C=9 | H=12 | Cl=1 | N=1 | SMILES = Clc1ccc(cc1)CC(N)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C9H12ClN/c1-7(11)6-8-2-4-9(10)5-3-8/h2-5,7H,6,11H2,1H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = WWPITPSIWMXDPE-UHFFFAOYSA-N }}

'''''para''-Chloroamphetamine''' ('''PCA'''), also known as '''4-chloroamphetamine''' ('''4-CA'''), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family.<ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 }}</ref><ref name="Fuller1992" /><ref name="Fuller1986" /><ref name="Fuller1978" /> It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.<ref name="Fuller1992" /><ref name="Fuller1986" />

PCA has also been clinically studied as an appetite suppressant and antidepressant, but findings of neurotoxicity in animals discouraged further evaluation.<ref name="BlanckaertVanquekelbergheCoopman2018" /><ref name="Shulgin1978">{{cite book | veditors = Iversen LL, Iversen SD, Snyder SH | last=Shulgin | first=Alexander T. | title=Stimulants | chapter=Psychotomimetic Drugs: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_6 | pages=243–333 | chapter-url=https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 | url=https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261 | quote=Considerable clinical application of 4-CA has been made, and it has been found effective as an antidepressant when used chronically at levels of 75 mg/day (van Praag et al., 1971; van Praag and Korf, 1976). There are very few side effects noted and the drug is tolerated very well. However, indications of raphe-nucleus degeneration (Yunger et al., 1974) and related neurotoxicity (Harvey and McMaster, 1976) in experimental animals have discouraged further clinical study. [...] There were no reports from the clinical studies of 4-CA that suggested any psychotomimetic action. }}</ref> It has also been encountered as a designer drug, although it never achieved popularity, again perhaps due to its neurotoxicity.<ref name="LuethiLiechti2020">{{cite journal | vauthors = Luethi D, Liechti ME | title = Designer drugs: mechanism of action and adverse effects | journal = Arch Toxicol | volume = 94 | issue = 4 | pages = 1085–1133 | date = April 2020 | pmid = 32249347 | pmc = 7225206 | doi = 10.1007/s00204-020-02693-7 | bibcode = 2020ArTox..94.1085L | url = | quote = Compared with amphetamine, an increase in serotonergic toxicity has been reported for the para-chlorinated derivative 4-chloroamphetamine, likely explained by highly potent serotonergic activity coupled with considerably potent dopaminergic activity (Colado et al. 1993; Fuller 1992; Johnson et al. 1990; Luethi et al. 2019b; Miller et al. 1986). However, unlike other halogenated stimulants, such as 4-fluoroamphetamine, 4-chloroamphetamine never achieved popularity as a designer drug, possibly because of its well-documented neurotoxicity. }}</ref><ref name="BlanckaertVanquekelbergheCoopman2018">{{cite journal | vauthors = Blanckaert P, Vanquekelberghe S, Coopman V, Risseeuw MD, Van Calenbergh S, Cordonnier J | title = Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy - a risk to public health | journal = Forensic Sci Int | volume = 288 | issue = | pages = 173–180 | date = July 2018 | pmid = 29753935 | doi = 10.1016/j.forsciint.2018.04.023 | hdl = 1854/LU-8569680 | url = | quote = Psychoactive effects of 4-CMA and 4-CA were evaluated in humans while researching both compounds as antidepressants. In the dosages used (80-90 mg daily, in 3 doses), no significant acute psychoactive effects were noticed; adverse effects were also low, although an effect on sleep and nausea was mentioned [7].| hdl-access = free }}</ref>

==Use and effects== PCA was studied clinically as an appetite suppressant and antidepressant and its effects in these studies were described.<ref name="BlanckaertVanquekelbergheCoopman2018" /><ref name="Shulgin1978" /><ref name="vanPraagSchutBosma1971">{{cite journal | vauthors = van Praag HM, Schut T, Bosma E, van den Bergh R | title = A comparative study of the therapeutic effects of sone 4-chlorinated amphetamine derivatives in depressive patients | journal = Psychopharmacologia | volume = 20 | issue = 1 | pages = 66–76 | date = 1971 | pmid = 5565748 | doi = 10.1007/BF00404060 | url = }}</ref><ref name="vanPraagKorf1973">{{cite journal | vauthors = van Praag HM, Korf J | title = 4-Chloramphetamines. Chance and trend in the development of new antidepressants | journal = J Clin Pharmacol New Drugs | volume = 13 | issue = 1 | pages = 3–14 | date = January 1973 | pmid = 4566121 | doi = 10.1002/j.1552-4604.1973.tb00063.x | url = }}</ref> It has been said to have only slight stimulant effects and to behave more like an antidepressant than a stimulant.<ref name="BlanckaertVanquekelbergheCoopman2018" /> At doses of 80 to 90{{nbsp}}mg daily, in 3{{nbsp}}doses, it produced no significant acute psychoactive effects and produced few adverse effects.<ref name="BlanckaertVanquekelbergheCoopman2018" /><ref name="Shulgin1978" /> However, sleep disturbances and nausea were mentioned.<ref name="BlanckaertVanquekelbergheCoopman2018" /> No hallucinogenic effects have been reported.<ref name="ShulginManningDaley2011" /><ref name="Shulgin1978" /><ref name="HalberstadtGeyer2018" /><ref name="HalberstadtChathaKlein2020" />

The profile of PCA is analogous to that of naphthylaminopropane (NAP; PAL-287), a highly potent and well-balanced SNDRA with only weak stimulant-like effects.<ref name="RothmanBloughBaumann2008">{{cite journal | vauthors = Rothman RB, Blough BE, Baumann MH | title = Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction | journal = Exp Clin Psychopharmacol | volume = 16 | issue = 6 | pages = 458–474 | date = December 2008 | pmid = 19086767 | pmc = 2683464 | doi = 10.1037/a0014103 | url = }}</ref> It is thought that concomitant robust serotonin release suppresses the stimulating and rewarding effects of dopamine release.<ref name="RothmanBloughBaumann2008" /><ref name="RothmanBaumann2006b">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs | journal = Ann N Y Acad Sci | volume = 1074 | issue = 1| pages = 245–260 | date = August 2006 | pmid = 17105921 | doi = 10.1196/annals.1369.064 | bibcode = 2006NYASA1074..245R | url = }}</ref>

==Pharmacology== ===Monoamine releasing agent=== PCA acts as a serotonin, norepinephrine, and dopamine releasing agent (SNDRA).<ref name="Forsyth2012">{{cite journal | vauthors = Forsyth AN | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref><ref name="Marona-LewickaRheeSprague1995">{{cite journal | vauthors = Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE | title = Psychostimulant-like effects of p-fluoroamphetamine in the rat | journal = European Journal of Pharmacology| volume = 287 | issue = 2 | pages = 105–113 | date = December 1995 | pmid = 8749023 | doi = 10.1016/0014-2999(95)00478-5 | url = }}</ref> Its {{Abbrlink|EC50|half-maximal effective concentration}} values for monoamine release are 28.3{{nbsp}}nM for serotonin, 23.5 to 26.2{{nbsp}}nM for norepinephrine, and 42.2 to 68.5{{nbsp}}nM for dopamine in rat brain synaptosomes, making it a potent and well-balanced SNDRA.<ref name="Forsyth2012" /><ref name="Blough2008" /><ref name="FitzgeraldGannonWalther2024">{{cite journal | vauthors = Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE | title = Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones | journal = Neuropharmacology | volume = 245 | issue = | article-number = 109827 | date = March 2024 | pmid = 38154512 | doi = 10.1016/j.neuropharm.2023.109827 | pmc = 10842458 | url = }}</ref><ref name="Nicole2022">{{cite web | vauthors = Nicole L | title=In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones | date=2022 | website=ProQuest | url=https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/ | access-date=5 December 2024 | quote = FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...] }}</ref> It is also a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), with {{Abbrlink|IC50|half-maximal effective concentration}} values of 490{{nbsp}}nM for serotonin, 320{{nbsp}}nM for norepinephrine, and 3,600{{nbsp}}nM for dopamine in human embryonic kidney 293 (HEK293) cells.<ref name="LuethiWalterZhou2019">{{cite journal | vauthors = Luethi D, Walter M, Zhou X, Rudin D, Krähenbühl S, Liechti ME | title = Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones | journal = Front Pharmacol | volume = 10 | issue = | article-number = 438 | date = 2019 | pmid = 31068823 | pmc = 6491784 | doi = 10.3389/fphar.2019.00438 | doi-access = free | url = https://www.researchgate.net/publication/332605664}}</ref>

====Short-term effects==== In animals, doses of PCA of 0.5 to 5{{nbsp}}mg/kg acutely produce a variety of behavioral and neurochemical effects thought to be due to serotonin release.<ref name="Fuller1992">{{cite journal | vauthors = Fuller RW | title = Effects of p-chloroamphetamine on brain serotonin neurons | journal = Neurochem Res | volume = 17 | issue = 5 | pages = 449–456 | date = May 1992 | pmid = 1528354 | doi = 10.1007/BF00969891 | url = }}</ref><ref name="Sanders-BushSteranka1978" /><ref name="SpragueJohnsonSchmidt1996">{{cite journal | vauthors = Sprague JE, Johnson MP, Schmidt CJ, Nichols DE | title = Studies on the mechanism of p-chloroamphetamine neurotoxicity | journal = Biochem Pharmacol | volume = 52 | issue = 8 | pages = 1271–1277 | date = October 1996 | pmid = 8937435 | doi = 10.1016/0006-2952(96)00482-0 | url = }}</ref> Consequent enhancement of serotonergic signaling, serotonergic effects like myoclonus, the serotonin behavioral syndrome, including tremor, rigidity, Straub tail, hindlimb abduction, lateral head weaving, and reciprocal forepaw treading, inhibition of startle response sensitization, suppression of sexual behavior in females, and the head-twitch response.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978" /> Non-behavioral or physiological effects include activation of the hypothalamic–pituitary–adrenal axis (HPA axis), increased prolactin secretion, and increased plasma renin activity.<ref name="Fuller1992" /> PCA and other SRAs like MDMA and α-ethyltryptamine (αET) produce locomotor hyperactivity in animals and this is thought to be serotonin-dependent.<ref name="Geyer1996" /> It is mimicked by serotonin 5-HT1B receptor activation.<ref name="Geyer1996" /> However, PCA is also reported to produce amphetamine-like hyperactivity and stereotypy, as well as amphetamine-like enhancement of conditioned avoidance responding that is independent of serotonergic signaling.<ref name="Sanders-BushSteranka1978" />

PCA does not show effects like those of the selective norepinephrine and dopamine releasing agent (NDRA) amphetamine in animals but instead fully substitutes for other serotonin releasing agents like (+)-MBDB and MMAI in rodent drug discrimination tests.<ref name="Marona-LewickaRheeSprague1995" /> The findings with PCA are in contrast to those with ''para''-fluoroamphetamine (PFA), which acts as a selective NDRA similarly to amphetamine,<ref name="WeeAndersonBaumann2005">{{cite journal | vauthors = Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL | title = Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 313 | issue = 2 | pages = 848–854 | date = May 2005 | pmid = 15677348 | doi = 10.1124/jpet.104.080101 | s2cid = 12135483 }}</ref> fully substitutes for amphetamine in animals, and fails to substitute for (+)-MBDB or MMAI.<ref name="Marona-LewickaRheeSprague1995" /> As touched on, PCA can robustly produce the head-twitch response, which is a behavioral proxy of psychedelic-like effects.<ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title=Behavioral Neurobiology of Psychedelic Drugs | chapter=Effect of Hallucinogens on Unconditioned Behavior | veditors = Halberstadt AL, Vollenweider FX, Nichols DE | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | series = Current Topics in Behavioral Neurosciences | volume=36 | date=2018 | isbn=978-3-662-55878-2 | pmid=28224459 | pmc=5787039 | doi=10.1007/7854_2016_466 | doi-access=free | pages=159–199 | quote = Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.}}</ref><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | article-number = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = | quote = Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).}}</ref><ref name="OrikasaSloley1988">{{cite journal | vauthors = Orikasa S, Sloley BD | title = Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin, p-chloroamphetamine, and tryptamine in mice | journal = Psychopharmacology (Berl) | volume = 95 | issue = 1 | pages = 124–131 | date = 1988 | pmid = 3133691 | doi = 10.1007/BF00212780 | url = | quote = Head-twitch response (HTR) in mice was induced by intracerebroventricular injection of tryptamine (TRA) as well as serotonin (5-HT) and p-chloroamphetamine (PCA). Pretreatment with 5,7-dihydroxytryptamine enhanced both the 5-HT-induced and the TRA-induced HTR. The PCA-induced HTR, however, was attenuated by the drug. On the other hand, pretreatment with 6-hydroxydopamine did not alter the 5-HT response but enhanced both the PCA- and the TRA-induced response. These results suggest that 5-HT may directly stimulate the post-synaptic receptors, while the PCA response may be based on the release of endogenous 5-HT.}}</ref><ref name="Fuller1992" /> However, PCA does not seem to produce hallucinogenic effects in humans, and hence its activity in the head-twitch paradigm has been described as a false-positive for psychedelic effects.<ref name="HalberstadtGeyer2018" /><ref name="HalberstadtChathaKlein2020" /><ref name="WojtasGołembiowska2023">{{cite journal | vauthors = Wojtas A, Gołembiowska K | title = Molecular and Medical Aspects of Psychedelics | journal = Int J Mol Sci | volume = 25 | issue = 1 | date = December 2023 | page = 241 | pmid = 38203411 | pmc = 10778977 | doi = 10.3390/ijms25010241 | doi-access = free | url = | quote = While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].}}</ref> The head-twitch response with PCA appears to be dependent on induction of serotonin release and not on direct serotonin receptor agonism by PCA, as it is blocked by destruction of presynaptic serotonergic nerve terminals or by serotonin synthesis inhibition.<ref name="HalberstadtGeyer2018" /><ref name="OrikasaSloley1988" /><ref name="OgrenRoss1977" /> Relatedly, PCA is said not to be a serotonin 5-HT2A receptor agonist (at concentrations up to 10,000{{nbsp}}nM).<ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = | quote = [...] both groups were administered (±)-para-chloroamphetamine (PCA, 5 mg/kg, IP)—a selective serotonin-releasing agent (43). [...] Importantly, PCA is not a 5-HT2AR agonist (fig. S10A), [...] and does not induce a HTR in wild type mice (fig. S10C). [...] In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49).}}</ref> However, PCA might nonetheless act as a direct serotonin 5-HT2 receptor agonist at high doses, as head twitches induced by it are not blocked by serotonin synthesis inhibition at these doses.<ref name="OgrenRoss1977">{{cite journal | vauthors = Ogren SO, Ross SB | title = Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones | journal = Acta Pharmacol Toxicol (Copenh) | volume = 41 | issue = 4 | pages = 353–368 | date = October 1977 | pmid = 303437 | doi = 10.1111/j.1600-0773.1977.tb02674.x | url = }}</ref> Although PCA has been reported to produce the head-twitch response, a more modern study reported that it did not do so, at least unless the serotonin transporter (SERT) was artificially expressed in a population of medial prefrontal cortex (mPFC) serotonergic neurons that normally lack the SERT.<ref name="VargasDunlapDong2023" />

While extracellular serotonin levels and serotonergic signaling are acutely increased by PCA, there is a concomitant depletion of serotonin stores.<ref name="Fuller1992" /> The depletion includes a decrease in total serotonin content, 5-hydroxyindoleacetic acid (5-HIAA) content, and tryptophan hydroxylase activity.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978" /> The acute depletion of serotonin stores by PCA is likely due to inhibition of tryptophan hydroxylase.<ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> How this occurs is unclear, as PCA does not inhibit tryptophan hydroxylase ''in vitro'' except at very high concentrations.<ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> The initial serotonin depletion by lower doses of PCA are not permanent and can readily reverse after a few hours.<ref name="Fuller1978" /> As such, low doses of PCA, such as 2{{nbsp}}mg/kg, are regarded as non-neurotoxic.<ref name="SpragueJohnsonSchmidt1996" /> The dopaminergic and noradrenergic systems are also substantially impacted by acute PCA.<ref name="Sanders-BushSteranka1978" /> However, dopamine and norepinephrine levels are only slightly changed.<ref name="Sanders-BushSteranka1978" /> In addition, the effects on the dopaminergic and noradrenergic systems are of relatively short duration and return to normal within 24{{nbsp}}hours, analogously to the case of the serotonin system.<ref name="Sanders-BushSteranka1978" /> In line with the preceding neurochemical findings, tolerance to various of the behavioral effects of acute PCA has been found to develop.<ref name="Sanders-BushSteranka1978" />

Due to its activity as a serotonin releasing agent, PCA is employed in scientific research to acutely enhance and study serotonin signaling.<ref name="Fuller1986" /><ref name="Geyer1996">{{cite journal | vauthors = Geyer MA | title = Serotonergic functions in arousal and motor activity | journal = Behav Brain Res | volume = 73 | issue = 1–2 | pages = 31–35 | date = 1996 | pmid = 8788473 | doi = 10.1016/0166-4328(96)00065-4 | url = }}</ref>

====Long-term serotonergic neurotoxicity==== At higher doses (e.g., 10{{nbsp}}mg/kg) and for longer amounts of exposure, PCA produces extremely long-lasting depletion of serotonin and loss of serotonergic function that is considered to reflect serotonergic neurotoxicity.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978" /><ref name="SpragueJohnsonSchmidt1996" /> This includes depletion of serotonin content, 5-HIAA content, serotonin turnover, tryptophan hydroxylase, serotonin reuptake capacity, and serotonin transporters for weeks or months.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> As an example, brain serotonin continued to be reduced by 41% after 38{{nbsp}}days.<ref name="Fuller1992" /> In addition, many serotonin-containing nerve fibers become undetectable and appear to be lost.<ref name="Fuller1992" /> There have also been observations of nerve degeneration in the days after PCA administration.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> Different serotonergic areas and projections are differentially susceptible to the neurotoxicity of PCA, with the dorsal raphe nuclei more susceptible and the median raphe nuclei, raphe obscurus, raphe pallidus, dentate gyrus, hypothalamus, and spinal cord all resistant.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978" /> PCA is selective for serotonin, without causing depletion of norepinephrine or dopamine.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978">{{cite journal | vauthors = Sanders-Bush E, Steranka LR | title = Immediate and long-term effects of p-chloroamphetamine on brain amines | journal = Ann N Y Acad Sci | volume = 305 | issue = 1| pages = 208–221 | date = June 1978 | pmid = 360935 | doi = 10.1111/j.1749-6632.1978.tb31525.x | bibcode = 1978NYASA.305..208S | url = }}</ref>

There are behavioral consequences of the serotonergic neurotoxicity of PCA.<ref name="Fuller1992" /><ref name="Sanders-BushSteranka1978" /> Affected animals are still quite normal in overall appearance.<ref name="Fuller1992" /> However, hypoactivity, increased defecation in the open field test, and failed acquisition of shock avoidance in the Y-maze task are all apparent.<ref name="Fuller1992" /> In addition, increased locomotion in response to the dopamine agonist apomorphine has been observed, which is consistent with findings that serotonin may inhibit certain aspects of dopamine signaling.<ref name="Fuller1992" /> Failure of acquisition of a two-way conditioned avoidance response has been observed, and this could be completely prevented with the SRI zimelidine (see more on this below).<ref name="Fuller1992" /> Various other changes and deficits have been seen as well.<ref name="Fuller1992" /> The effects of the non-selective serotonin receptor agonist and serotonergic psychedelic 5-MeO-DMT have been found to be greatly potentiated following PCA, which may reflect receptor supersensitivity in an attempt at compensation for serotonin depletion.<ref name="Fuller1992" /> Conversely, the behavioral and physiological serotonergic effects of acute low-dose PCA challenge are attenuated after high-dose neurotoxic PCA exposure, which may reflect reduced available serotonin stores for release.<ref name="Fuller1992" />

=====Mechanisms of neurotoxicity===== Although the ultimate cause is cytotoxicity to serotonergic neurons, the mechanisms leading to the serotonergic neurotoxicity of PCA are unknown.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> However, uptake of PCA into neurons by the serotonin transporter (SERT) appears to be required.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> Serotonin reuptake inhibitors (SRIs) like fluoxetine can block both the acute short-term effects and the long-term serotonergic neurotoxicity of PCA.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> In addition, they can be given 4{{nbsp}}hours after PCA administration, when acute serotonin depletion has already occurred, and will still completely protect against the long-term neurotoxicity.<ref name="Fuller1992" /> However, the SRI must be long-lasting; the short-acting SRI clomipramine, given before PCA, prevented acute serotonin depletion, but PCA outlasted clomipramine in the body, and the same degree of long-term neurotoxicity occurred as if clomipramine had not been administered.<ref name="Fuller1992" />

It has been theorized that a toxic metabolite of PCA may be formed and that this metabolite is responsible for its neurotoxicity.<ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> However, no compelling evidence in support of this hypothesis has emerged.<ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Sanders-BushSteranka1978" /> Severe depletion of serotonin by the combination of ''para''-chlorophenylalanine (PCPA) and reserpine substantially protects against the serotonergic neurotoxicity of PCA.<ref name="Fuller1992" /> This might be due to serotonin forming neurotoxic metabolites, for instance 5,6-dihydroxytryptamine (5,6-DHT), in the context of PCA's actions.<ref name="Fuller1992" /> Similarly to prophylactic serotonin depletion, α-methyl-''p''-tyrosine, which depletes dopamine, protects against the serotonergic neurotoxicity of PCA as well.<ref name="Fuller1992" /> It thus appears that dopamine is involved in the neurotoxicity of PCA, which is notable as PCA is a potent dopamine releasing agent in addition to inducing the release of serotonin.<ref name="Fuller1992" />

It has been reported that direct intracerebroventricular injection of PCA into the brain, in contrast to peripheral administration, failed to produce serotonergic neurotoxicity.<ref name="Fuller1992" /> This was the case even with continuous infusion for two days.<ref name="Fuller1992" /> This seems like it may lend credence to the toxic metabolite theory of PCA neurotoxicity, as a peripherally formed metabolite of PCA might be required for neurotoxicity to occur.<ref name="Fuller1992" /> However, no toxic metabolite has still yet been identified and no other support for the hypothesis has surfaced.<ref name="Fuller1992" /> Inhibiting the metabolism of PCA does not reduce tryptophan hydroxylase inactivation, suggesting that a metabolite is not responsible for this effect.<ref name="Sanders-BushSteranka1978" />

There are species differences in the neurotoxicity of PCA between rats and mice, which may help to shed light on the underlying mechanisms.<ref name="Sanders-BushSteranka1978" />

=====Structure–activity relationships of neurotoxicity===== The drug is the most potent serotonergic neurotoxin of a series of amphetamines.<ref name="Fuller1992" /><ref name="Fuller1978">{{cite journal | vauthors = Fuller RW | title = Structure-activity relationships among the halogenated amphetamines | journal = Ann N Y Acad Sci | volume = 305 | issue = 1| pages = 147–159 | date = June 1978 | pmid = 152079 | doi = 10.1111/j.1749-6632.1978.tb31518.x | bibcode = 1978NYASA.305..147F | url = }}</ref> In terms of structure–activity relationships, the α-methyl group appears to be essential for the neurotoxicity, and the α-ethyl analogue is less potent as a neurotoxin.<ref name="Fuller1992" /><ref name="Fuller1978" /> Other side chain homologues with shorter or longer chains were less potent or inactive.<ref name="Fuller1992" /><ref name="Fuller1978" /> Moving the chloro substituent to other positions on the phenyl ring, as in ''ortho''-chloroamphetamine (OCA) and ''meta''-chloroamphetamine (MCA), resulted in no significant serotonergic depletion, in contrast to the marked depletion with PCA.<ref name="Fuller1992" /><ref name="Fuller1978" /> However, this was found to be due to rapid metabolism in the case of MCA, and inhibiting its metabolism resulted in potent neurotoxicity as with PCA.<ref name="Fuller1978" /> Conversely, OCA still does not produce apparent neurotoxicity.<ref name="Fuller1978" />

''para''-Bromoamphetamine (PBA) and ''para''-bromomethamphetamine (PBMA) show similar serotonergic neurotoxicity to PCA and PCMA.<ref name="Fuller1978" /> Conversely, ''para''-fluoroamphetamine decreases serotonin levels but its effects appear to be much less persistent than those of PCA.<ref name="Fuller1978" /> Other 4-substituted amphetamines have reduced neurotoxicity (4-trifluoromethylamphetamine, 4-phenoxyamphetamine) or are inactive (4-methylamphetamine, ''para''-methoxyamphetamine (PMA)) in terms of serotonin depletion.<ref name="Fuller1978" /> Fenfluramine and norfenfluramine, which are 3-trifluoromethylamphetamines, produce very long-lasting serotonergic neurotoxicity similarly to PCA but are slightly less active.<ref name="Fuller1978" />

The closely related ''N''-methylated derivative, ''para''-chloromethamphetamine (PCMA), which is rapidly and extensively metabolized to ''para''-chloroamphetamine ''in vivo'', has neurotoxic properties as well, and is only slightly less potent than PCA in this regard.<ref name="Fuller1992" /><ref name="Fuller1978" /> Other ''N''-alkylated analogues of PCA also metabolize at least in part into PCA and produce serotonergic neurotoxicity.<ref name="Fuller1992" /><ref name="Fuller1978" /> However, they show reduced activity, which may be due to their extent of conversion into PCA being reduced.<ref name="Fuller1978" />

In contrast to PCA, the phentermine (i.e., α-methylated) analogue of PCA, chlorphentermine, which acts as a highly selective SRA,<ref name="RothmanBaumann2002">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic and adverse actions of serotonin transporter substrates | journal = Pharmacology & Therapeutics | volume = 95 | issue = 1 | pages = 73–88 | date = July 2002 | pmid = 12163129 | doi = 10.1016/s0163-7258(02)00234-6 }}</ref><ref name="RothmanBaumann2006a">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}</ref> does not appear to produce serotonergic neurotoxicity.<ref name="LovenbergWalkerBaumgarten1976">{{cite book | vauthors = Lovenberg W, Walker MN, Baumgarten HG | title = Clinical Pharmacology of Serotonin | chapter = Chlorinated amphetamines: drugs or toxins | series = Monographs in Neural Sciences | volume = 3 | pages = 109–114 | date = 1976 | pmid = 790166 | doi = 10.1159/000399342 | isbn = 978-3-8055-2328-8 | chapter-url = | quote = A methylated analogue of p-chloroamphetamine is chlorphentermine (fig. 1). This compound is marketed as an appetite suppressant Pre-Sate® and it seemed of interest to reevaluate the effects of this compound on the serotonergic system. One day following the administration of 20 mg/kg to rats there appeared to be little loss of tryptophan hydroxylase in any of the brain regions; e.g., mesencephalic tegmentum 124 %, mesencephalic tectum 95.7 % and striatum 103.5 %, of control values. While this preliminary experiment would suggest that chlorphentermine is not neurotoxic, it would seem in view of the similarity of its structure to p-chloroamphetamine that considerably more detailed experiments should be done to evaluate the long-term effects of this drug and its potential neurotoxicity.}}</ref>

Rigid analogues of PCA, like 6-chloro-2-aminotetralin (6-CAT), have also been assessed.<ref name="Fuller1978" /> 6-CAT depletes serotonin similarly to PCA, but its effects are smaller and shorter-lasting.<ref name="Fuller1978" /> Another analogue, Org 6582, in which a third ring structure has been added, is a selective serotonin reuptake inhibitor (SSRI) and no longer shows the serotonergic neurotoxicity of PCA and 6-CAT.<ref name="Fuller1978" />

=====Use as a neurotoxin in scientific research===== PCA is useful and widely employed as a serotonergic neurotoxin in scientific research.<ref name="Fuller1992" /><ref name="Fuller1986">{{cite journal | vauthors = Fuller RW | title = Biochemical pharmacology of the serotonin system | journal = Adv Neurol | volume = 43 | issue = | pages = 469–480 | date = 1986 | pmid = 2936068 | doi = | url = }}</ref> A variety of scientific findings have been made and published through employment of PCA.<ref name="Fuller1992" /> The drug is advantageous over other serotonergic neurotoxins like 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) in that it is active by systemic administration.<ref name="Fuller1992" /> Conversely, 5,6-DHT and 5,7-DHT do not cross the blood–brain barrier and must be administered directly into the brain.<ref name="Fuller1992" /> PCA also produces a different anatomical pattern of serotonergic neurotoxicity than 5,6-DHT and 5,7-DHT, which can be useful as well if there is a need to study different serotonergic areas or pathways.<ref name="Fuller1992" />

===Other actions=== PCA has been found to act as a relatively potent monoamine oxidase A (MAO-A) inhibitor, with an {{Abbrlink|IC50|half-maximal inhibitory concentration}} of 1,900 to 4,000{{nbsp}}nM.<ref name="Reyes-ParadaIturriaga-VasquezCassels2019">{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Front Pharmacol | volume = 10 | issue = | article-number = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = }}</ref>

PCA has been reported to act as an agonist of the rat trace amine-associated receptor (TAAR1).<ref name="LiuWuLi2020">{{cite journal | vauthors = Liu J, Wu R, Li JX | title = TAAR1 and Psychostimulant Addiction | journal = Cell Mol Neurobiol | volume = 40 | issue = 2 | pages = 229–238 | date = March 2020 | pmid = 31974906 | pmc = 7845786 | doi = 10.1007/s10571-020-00792-8 | url = | quote = Amphetamine-like compounds, including amphetamine (AMPH), methamphetamine (METH), MDMA, 4-OH-amphetamine, 4-Cl-amphetamine could induce cAMP accumulation in the HEK-293 cells expressing [rat] TAAR1, indicating that amphetamines are potent agonists of TAAR1 (Bunzow et al. 2001; Miller et al. 2005). }}</ref><ref name="BunzowSondersArttamangkul2001">{{cite journal | vauthors = Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK | title = Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor | journal = Mol Pharmacol | volume = 60 | issue = 6 | pages = 1181–1188 | date = December 2001 | pmid = 11723224 | doi = 10.1124/mol.60.6.1181 | url = }}</ref> Conversely, it is not a significant agonist of the human TAAR1.<ref name="DiCaraMaggioAloisi2011">{{cite journal | vauthors = Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ | title = Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA) | journal = J Neurosci | volume = 31 | issue = 47 | pages = 16928–16940 | date = November 2011 | pmid = 22114263 | pmc = 6623861 | doi = 10.1523/JNEUROSCI.2502-11.2011 | url = }}</ref> The drug also appears to be inactive as an agonist of the mouse TAAR1.<ref name="DiCaraMaggioAloisi2011" /> TAAR1 agonism has been implicated in modulating the effects of monoamine releasing agents (MRAs).<ref name="JingLi2015">{{cite journal | vauthors = Jing L, Li JX | title = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | journal = Eur J Pharmacol | volume = 761 | issue = | pages = 345–352 | date = August 2015 | pmid = 26092759 | pmc = 4532615 | doi = 10.1016/j.ejphar.2015.06.019 | url = }}</ref> In contrast to PCA, the MRA MDMA is a potent agonist of the mouse TAAR1.<ref name="DiCaraMaggioAloisi2011">{{cite journal | vauthors = Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ | title = Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA) | journal = J Neurosci | volume = 31 | issue = 47 | pages = 16928–16940 | date = November 2011 | pmid = 22114263 | pmc = 6623861 | doi = 10.1523/JNEUROSCI.2502-11.2011 | url = }}</ref><ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref> MDMA-induced ''in-vivo'' brain serotonin and dopamine release and hyperlocomotion are augmented in TAAR1 knockout mice relative to normal mice, whereas the ''in-vivo'' brain serotonin and dopamine release of PCA are not different between normal mice and TAAR1 knockout mice.<ref name="DiCaraMaggioAloisi2011" /><ref name="ZhangMantasAlvarsson2018">{{cite journal | vauthors = Zhang X, Mantas I, Alvarsson A, Yoshitake T, Shariatgorji M, Pereira M, Nilsson A, Kehr J, Andrén PE, Millan MJ, Chergui K, Svenningsson P | title = Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine | journal = Front Pharmacol | volume = 9 | issue = | article-number = 166 | date = 2018 | pmid = 29545750 | pmc = 5837966 | doi = 10.3389/fphar.2018.00166 | doi-access=free | url = | quote = Di Cara et al. (2011) showed that TAAR1 decreases the amplitude of Methylenedioxymethamphetamine (MDMA) induced dopamine release both in ventral and dorsal striatum. In the same study it was observed that the TAAR1 agonist, o-phenyl-3-iodotyramine (o-PIT) blunted the para-chloroamphetamine (PCA) induced dopamine release in both structures (Di Cara et al., 2011). }}</ref> In the same study, the TAAR1 agonist ''o''-phenyl-3-iodotyramine (''o''-PIT) blunted the dopamine and serotonin release of PCA in mouse synaptosomes ''in vitro'', an effect that was absent in synaptosomes from TAAR1 knockout mice.<ref name="DiCaraMaggioAloisi2011" /><ref name="ZhangMantasAlvarsson2018" /> These findings led to conclusions that TAAR1 agonism by MDMA but not PCA auto-inhibits and constrains its own effects in rodents.<ref name="ZhangMantasAlvarsson2018" /><ref name="DiCaraMaggioAloisi2011" /> Unlike in rodents however, MDMA is not a significant TAAR1 agonist in humans.<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 9 May 2025 }}</ref><ref name="LewinMillerGilmour2011">{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}</ref><ref name="DunlapAndrewsOlson2018">{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-MDMA.pdf | quote = [...] it is unclear if TAAR1 plays any role in the effects of MDMA in humans, as MDMA does not activate human TAAR1 in cellular assays like it does mouse and rat TAAR1.84 }}</ref>

==Chemistry== PCA, also known as 4-chloroamphetamine, is a phenethylamine and amphetamine derivative.<ref name="Shulgin1978" /><ref name="Fuller1978" />

Analogues of PCA include ''para''-chloromethamphetamine (PCMA/4-CMA), ''para''-bromoamphetamine (PBA/4-BA), ''para''-fluoroamphetamine (PFA/4-FA), ''para''-iodoamphetamine (PIA/4-IA), 4-methylamphetamine (4-MA), ''meta''-chloroamphetamine (MCA/4-CA), ''ortho''-chloroamphetamine (OCA/2-CA), 3,4-dichloroamphetamine (3,4-DCA), 2,4-dichloroamphetamine (2,4-DCA), chlorphentermine, 4-chloromethcathinone (4-CMC; clephedrone), 4-chlorophenylisobutylamine (4-CAB; AEPCA), 6-chloro-2-aminotetralin (6-CAT), 5-iodo-2-aminoindane (5-IAI), and Org 6582, among others.<ref name="ShulginManningDaley2011" /><ref name="Fuller1992" /><ref name="Fuller1978" /><ref name="Shulgin1978" />

==History== PCA was first synthesized by 1936<ref name="Shulgin1978" /> and was first developed for potential medical use in the 1960s.<ref name="Shulgin1978" /><ref name="HollandBuckWeissman1963">{{cite journal | vauthors = Holland GF, Buck CJ, Weissman A | title = Anorexigenic Agents: Aromatic Substituted 1-Phenyl-2-propylamines | journal = J Med Chem | volume = 6 | issue = 5| pages = 519–524 | date = September 1963 | pmid = 14173573 | doi = 10.1021/jm00341a011 | url = }}</ref><ref name="FullerHinesMills1965">{{cite journal | vauthors = Fuller RW, Hines CW, Mills J | title = Lowering of Brain Serotonin Level By Chloroamphetamines | journal = Biochem Pharmacol | volume = 14 | issue = 4| pages = 483–488 | date = April 1965 | pmid = 14322972 | doi = 10.1016/0006-2952(65)90221-2 | url = }}</ref><ref name="vanPraagSchutBosma1971" /><ref name="vanPraagKorf1973" />

==Society and culture== ===Legal status=== ====China==== As of October 2015, 4-CA is a controlled substance in China.<ref>{{cite web | url=http://www.sfda.gov.cn/WS01/CL0056/130753.html | title=关于印发《非药用类麻醉药品和精神药品列管办法》的通知 | publisher=China Food and Drug Administration | date=27 September 2015 | language=zh | access-date=1 October 2015 | archive-url=https://web.archive.org/web/20151001222554/http://www.sfda.gov.cn/WS01/CL0056/130753.html | archive-date=1 October 2015 | url-status=dead }}</ref>

====United States==== PCA is not a scheduled compound in the United States.<ref name="ShulginManningDaley2011" />

==References== {{Reflist|2}}

{{Monoamine neurotoxins}} {{Monoamine releasing agents}} {{Monoamine metabolism modulators}} {{TAAR ligands}} {{Phenethylamines}}

Category:4-Chlorophenyl compounds Category:Abandoned drugs Category:Designer drugs Category:Experimental antidepressants Category:Monoamine oxidase inhibitors Category:Monoaminergic neurotoxins Category:Serotonin-norepinephrine-dopamine releasing agents Category:Substituted amphetamines Category:TAAR1 agonists