Serotonin releasing agent

Chlorphentermine, a highly selective SRA that is no longer marketed.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.[1]

SRAs, for instance fenfluramine, dexfenfluramine, and chlorphentermine, have been used clinically as appetite suppressants.[2][3] However, these SRAs were withdrawn from the market due to toxicity in the 1990s and no SRAs were available or employable for clinical study for many years.[2][3][4] In any case, a low-dose formulation was reintroduced for treatment of Dravet syndrome in 2020 and this allowed clinical and research use of SRAs in humans once again.[5]

Aside from use as appetite suppressants, SSRAs have been proposed as novel antidepressants and anxiolytics, with the potential for a faster onset of action and superior effectiveness relative to the selective serotonin reuptake inhibitors (SSRIs).[6][7]

A closely related type of drug is a serotonin reuptake inhibitor (SRI), for instance fluoxetine.

Effects and comparison with SRIs

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See also: Empathogen § Mechanism of action, and Hyperlocomotion § Drugs inducing and reversing hyperlocomotion

Selectivities and serotonin increases

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A number of somewhat selective SRAs have been well-studied, for instance fenfluramine and meta-chlorophenylpiperazine (mCPP).[8][9] Although fenfluramine and mCPP are efficacious SRAs, they are also highly potent agonists of serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and particularly 5-HT2C receptors.[8][2][10][9][11] Direct activation of serotonin receptors such as the serotonin 5-HT2C receptor with fenfluramine has been shown to be therapeutically relevant in humans, as dexfenfluramine produces appetite suppressant effects even when its serotonin release is blocked by concomitant treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine.[9][2] Similarly, mCPP is an extremely potent agonist of the serotonin 5-HT2C receptor and produces robust effects thought to be 5-HT2C receptor-mediated in in animals and humans, such as anxiety and panic.[8][10][12][13][11] In addition to serotonin receptor agonism, fenfluramine is also a norepinephrine releasing agent with several-fold lower potency compared to serotonin release.[4] As such, the serotonin 5-HT2 receptor agonism and other actions of these agents may modify their effects, and a fully selective SRA could produce very different effects.[8][2][14]

More selective SRAs than agents like fenfluramine and mCPP have been developed,[7] for instance the 2-aminoindane MMAI[15][1][16] and certain cathinones.[17] Chlorphentermine is also notable in being a highly selective SRA, including having negligible activity as an agonist of all three of the serotonin 5-HT2 receptors.[3] 4-Methylthioamphetamine (4-MTA) was originally described as a selective SRA,[18] but was subsequently found to efficiently induce dopamine release as well,[19] and is also known to act as a potent monoamine oxidase A (MAO-A) inhibitor.[20] MMA has been found to act as a highly selective SRA, but has also been reported to produce psychedelic-like effects in both animals and humans.[6][21][22][23]

SRAs achieve far greater increases in serotonin levels than SRIs and have substantially more robust of effects, both in animals and in terms of subjective effects in humans.[3][24][6][25][16] Whereas the SSRI fluoxetine can increase serotonin levels in the hypothalamus in rats by up to 4-fold, the SRA dexfenfluramine can increase serotonin levels as much as 9- to 16-fold.[24][26][8][2][3] SRIs produce subtle interoceptive cues that are difficult for animals to recognize in drug discrimination testing, whereas SRAs produce robust cues that are easily recognized and learned.[16]

Stimulant-like and rewarding effects

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See also: Hyperlocomotion § Serotonin releasing agents

Certain SRAs, such as fenfluramine and chlorphentermine, do not produce locomotor activation (a stimulant-like effect) in animals.[27][14][28][29] Moreover, fenfluramine robustly inhibits the locomotor hyperactivity and rewarding effects induced by psychostimulants like amphetamine and phentermine.[27][14][28] Whereas amphetamine and phentermine produce strong locomotor stimulation in rodents, combination of fenfluramine and phentermine results in only weak locomotor activation and substantial reduction in conditioned place preference (CPP).[27][28][10] Fenfluramine also suppresses the subjective effects and positive mood effects of amphetamine and phentermine in humans.[10][27][9][30]

In spite of the preceding however, it has also been reported that the SRA dexfenfluramine weakly but dose-dependently stimulates locomotor activity in rodents.[24] Combination of dexfenfluramine with the selective serotonin 5-HT2C receptor antagonist SB-242084 results in dexfenfluramine dramatically and dose-dependently enhancing locomotion.[24] However, it has also been reported that serotonin 5-HT2B and 5-HT2C receptor antagonism with SB-206553 does not allow fenfluramine to produce robust hyperactivity, although further addition of amphetamine does produce marked hyperlocomotion (greater than with amphetamine alone).[31][32] The reasons for these conflicting findings are unclear.[31][32] In any case, in other research, serotonin 5-HT2B receptor knockout or selective serotonin 5-HT2B receptor antagonism with RS-127445 has been found to abolish MDMA-induced serotonin release and locomotor hyperactivity.[33][34][35] As with reported findings with fenfluramine, whereas the SRA and serotonin 5-HT2C receptor agonist mCPP decreases locomotor activity normally, it increases locomotor activity in serotonin 5-HT2C receptor knockout mice or with serotonin 5-HT2C receptor antagonism.[31][24][8] This increased locomotor activity could be blocked by a serotonin 5-HT1B receptor antagonist.[31] However, other research suggests that the serotonin 5-HT2A receptor is also involved in mCPP-induced hyperlocomotion in the context of serotonin 5-HT2C receptor inactivation.[36]

In contrast to fenfluramine and mCPP, the SSRI fluoxetine has no impact on locomotor activity alone or in combination with SB-242084.[24][37] In addition to its modulation of locomotion, the suppressive effects of fenfluramine on drug self-administration are blocked by SB-242084.[38]

Whereas certain SRAs like fenfluramine and chlorphentermine do not increase locomotor activity, other SRAs, including MDMA, MDEA, MBDB, para-chloroamphetamine (PCA), (S)-MDA, and α-ethyltryptamine (αET), are able to dose-dependently increase locomotor activity.[33][39][37][40][29] Moreover, this effect appears to be serotonin-dependent, as it can be blocked by pretreatment with SSRIs like fluoxetine (which prevent the serotonin-releasing effects of SRAs).[33][39][37] Suppression of locomotor activity by fenfluramine and its metabolite dexnorfenfluramine is not blocked by fluoxetine, indicating that it is not due to serotonin release.[33][40] MMAI dose-dependently suppresses locomotor activity similarly to fenfluramine and this is likewise not blocked by fluoxetine, nor by the non-selective serotonin receptor antagonist metitepine.[39][40][1] However, it was antagonized by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA).[1] MDAI suppresses locomotor activity initially, but there is rebound locomotor stimulation at a high dose, and this was similar to the profile of MDMA.[41][42] The increased locomotion induced by SRAs that cause this effect appears to be critically dependent on serotonin 5-HT1B receptor signaling.[31][13][33][39][32] Conversely, 5-HT2C receptor antagonists markedly enhance the hyperlocomotion of MDMA.[13][29][32]

In terms of reinforcing properties, MDMA produces dose-dependent CPP, MDAI produces CPP, MBDB produces weak CPP, fenfluramine produces conditioned place aversion (CPA), and MMAI has no effect on place conditioning at lower doses but produces CPA similarly to fenfluramine at high doses.[43][44][45][42] mCPP had no effect on place conditioning, at least in one study.[43][46] SSRIs have shown highly mixed effects on place conditioning, with fluoxetine producing CPP, zimelidine producing CPP or having no effect, and citalopram producing CPA.[43][44] Though zimelidine was reported to produce CPP in one study, it could also block the CPP induced by amphetamine.[44][47]

Psychedelic-like effects

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Fenfluramine dose-dependently induces the head-twitch response, a behavioral proxy of psychedelic-like effects, and this is assumed to be due to activation of serotonin 5-HT2A receptors.[48][24][49] Conversely, fluoxetine does not produce head twitches at any dose.[24] In accordance with animal findings, very high doses of fenfluramine have been reported to produce LSD-like psychedelic effects in humans.[50][51][52][53] The psychedelic effects of fenfluramine may be mediated by direct serotonin 5-HT2A receptor agonism, as other SRAs like MDMA, PCA, and chlorphentermine have been reported not to produce the head-twitch response in animals[49][54][55] and PCA has not been reported to produce hallucinogenic effects in humans.[48][56][57] In contrast to fenfluramine, PCA is notably not a serotonin 5-HT2A receptor agonist[54] or may only act as one at high doses,[55] chlorphentermine shows very weak or negigible activity at the serotonin 5-HT2 receptors,[3] and MDMA is a relatively low-potency and low-efficacy partial agonist of the serotonin 5-HT2A receptor.[58][59] In conflict with the preceding findings however, PCA has been reported to robustly induce the head-twitch response in animals in other studies, and this appeared to be dependent on induction of serotonin release as opposed to direct serotonin 5-HT2A receptor agonism, since it could be largely blocked by an SRI or by serotonin synthesis inhibitor.[48][56][60][61][55] In any case, SRAs are described as not inherently hallucinogenic in humans, and hence the induction of the head-twitch response with them has been considered a false-positive for psychedelic effects.[48][57]

Antidepressant-like effects

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SSRIs like fluoxetine, as well as non-selective SRIs, are used and claimed to be clinically effective in the treatment of depression.[62] SRAs produce far more robust of increases in serotonin levels than SRIs.[24][26][8][2][3][6] On the basis of these findings, it has been proposed that SSRAs may be more effective antidepressants than SSRIs and may have a faster onset of action.[6][25] Accordingly, SSRAs like MMAI and 4-MTA, as well as non-selective SRAs like fenfluramine, show antidepressant-like effects in animal tests, for instance in the chronic mild stress (CMS) test and the forced swim test (FST), and show greater magnitudes of effects than SSRIs ike sertraline.[6][25][63]

In addition to its antidepressant-like effects, MMAI has shown anxiolytic-like effects in animals.[25] Relatedly, SRAs have been suggested for potential treatment of anxiety disorder, panic disorder, obsessive–compulsive disorder (OCD), and other conditions as well.[7]

Although SRAs might be more effective than SRIs for uses like depression treatment, SRAs may also have greater risks than SRIs, for instance higher risk of serotonin syndrome.[6] Tachyphylaxis to their beneficial therapeutic effects might also occur.[6]

A few SRAs have in fact already been clinically studied and/or marketed as antidepressants in the past. These include αET, which was previously marketed in the United States under the brand name Monase;[64] α-methyltryptamine (αMT), which was previously marketed in the Soviet Union under the brand name Indopan;[65] fenfluramine, which has been clinically studied for depression but was never approved for this use;[8] and PCA, which has been clinically studied for depression but was discontinued due to animal findings of serotonergic neurotoxicity.[66][67][68]

Examples and use of SRAs

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Fenfluramine, chlorphentermine, and aminorex, which are also amphetamines and relatives, were formerly used as appetite suppressants but were discontinued due to concerns of cardiac valvulopathy. This side effect has been attributed to their serotonin release and/or the additional action of potent agonism of the 5-HT2B receptor in the case of fenfluramine. Indeloxazine is said to be an SRA and norepinephrine reuptake inhibitor (NRI) that was formerly used as an antidepressant, nootropic, and neuroprotective.[69]

Amphetamines like MDMA, MDEA, MDA, and MBDB, among other relatives (see MDxx), are recreational drugs termed entactogens. They act as serotonin–norepinephrine–dopamine releasing agents (SNDRAs) and also agonize serotonin receptors, such as those in the 5-HT2 subfamily.

Some tryptamines, such as DMT, bufotenin, and psilocin, are SRAs as well as non-selective serotonin receptor agonists.[70][71] Psilocin is a partial releaser of serotonin, with an EmaxTooltip maximal efficacy of 54%.[71][70] These drugs are serotonergic psychedelics, which is a consequence of their ability to activate the 5-HT2A receptor. Other tryptamines, including tryptamine itself, αET, and αMT, are SNDRAs and non-selective serotonin receptor agonists.[70] αET and αMT were originally thought to act as monoamine oxidase inhibitors (MAOIs) and were formerly used as antidepressants, but are now encountered solely as recreational drugs. αET and αMT are described as being entactogen-like.

List of SRAs

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Pharmaceutical drugs

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Amphetamines

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Tryptamines

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Others

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Recreational drugs and research chemicals

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Amphetamines

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Ring-extended amphetamines
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Cathinones
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Phenyloxazolamines

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Aminoindanes

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Aminotetralins

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Phenylpiperazines

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Tryptamines

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Others

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See also

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References

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  45. ^ Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE (January 1996). "Reinforcing effects of certain serotonin-releasing amphetamine derivatives". Pharmacol Biochem Behav. 53 (1): 99–105. doi:10.1016/0091-3057(95)00205-7. PMID 8848466.
  46. ^ Rocha B, Di Scala G, Jenck F, Moreau JL, Sandner G (April 1993). "Conditioned place aversion induced by 5-HT(1C) receptor antagonists". Behav Pharmacol. 4 (2): 101–106. doi:10.1097/00008877-199304000-00002. PMID 11224176.
  47. ^ Kruszewska A, Romandini S, Samanin R (June 1986). "Different effects of zimelidine on the reinforcing properties of d-amphetamine and morphine on conditioned place preference in rats". Eur J Pharmacol. 125 (2): 283–286. doi:10.1016/0014-2999(86)90038-5. PMID 2943599.
  48. ^ a b c d Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". In Halberstadt AL, Vollenweider FX, Nichols DE (eds.). Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459. 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.
  49. ^ a b Heal DJ, Gosden J, Smith SL, Atterwill CK (March 2023). "Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines". Neuropharmacology. 225: 109375. doi:10.1016/j.neuropharm.2022.109375. PMID 36529260. This point is exemplified by the observation that the selective 5-HT releasing agent, fenfluramine, induces head-twitches (Joshi et al., 1983; Gada et al., 1984; Darmani, 1998), whereas MDMA, which releases 5-HT, dopamine and noradrenaline (Nash and Nichols, 1991; Kankaanpää et al., 1998; Rothman et al., 2001; Starr et al., 2012; Brandt et al., 2020) does not induce head twitches (Fantegrossi et al., 2005; Heal, unpublished observations). [...] Fenfluramine is a 5-HT releasing agent that is structurally and pharmacologically related to MDMA that induces head-twitches (Green and Heal, 1985; Heal et al., 1992) and at supratherapeutic doses is hallucinogenic in humans (Levin, 1973; Griffith et al., 1975).
  50. ^ Gunne LM (1977). "Effects of Amphetamines in Humans". Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence. Berlin, Germany; Heidelberg, Germany: Springer. pp. 247–260. ISBN 9783642667091. However, LEVIN recently (1972, 1974) reported on abuse of fenfluramine among LSD and cannabis abusers in South Africa. This group of abusers seems to have appreciated the hallucinogenic LSD-Iike effects, which fenfluramine exerts when applied in high doses (200—600 mg). At this dose level, the fenfluramine abusers (a total of 115) experienced euphoria with laughing attacks, followed some hours later by depressive symptoms. They reported visual and olfactory hallucinations, anxiety, sometimes with attacks of panic, nausea, and diarrhea.
  51. ^ Connell, P. H. (1979). "Drug dependence liability of anorectic drugs: a clinical viewpoint, with particular reference to fenfluramine". Current Medical Research and Opinion. 6 (sup1): 153–159. doi:10.1185/03007997909117502. ISSN 0300-7995. Griffith et a1.6 compared fenfluramine with d-amphetamine and noted that fenfluramine was usually identified as LSD by subjects, and LSD scale scores after fenfluramine were significantly elevated. Three subjects receiving 240 mg fenfluramine experienced a psychedelic state characterized by visual and olfactory hallucination, cyclic alterations of mood, distorted time sense, fleeting paranoia, and sexual ideation. They noted that fenfluramine was a weak hallucinogen and, although sharing some features in common with amphetamine, "its overall profile of effects is quite different".
  52. ^ Griffith, John D. (1977). "Structure-Activity Relationships of Several Amphetamine Drugs in Man". Cocaine and Other Stimulants. Advances in Behavioral Biology. Vol. 21. Boston, MA: Springer US. pp. 705–715. doi:10.1007/978-1-4684-3087-5_36. ISBN 978-1-4684-3089-9. Fenfluramine (60, 120, 240 mg orally) [...] caused a marked dilation of pupils and elevation of the LSD Scale. [...] Fenfluramine was more often identified as an "LSD" or "barbiturate-like" substance. An unexpected response [...] was observed among 3 subjects who manifested hallucinatory states characterized by visual and olfactory hallucinations, rapid and polar changes of mood, distorted time sense, fleeting paranoia, and sexual hallucinations. [...] The remaining five subjects receiving the largest dose of fenfluramine experienced a chlorpromazine-like sedation without hallucinations or other psychedelic effects (Griffith, Nutt, and Jasinski, 1975). Chlorphentermine (50, 100, 200 mg) was similarly assessed. In certain respects, chlorphentermine resembles fenfluramine (Fig. 4), especially in terms of its mydriatic and sedative effects [...] On the other hand, chlorphentermine [...] is not hallucinogenic. [...] the utility of [amphetamine aromatic ring substitution] may be limited by the emergence of certain side-effects [...] e.g., dysphoria, sedation, and/or psychedelic properties.
  53. ^ Griffith JD, Nutt JG, Jasinski DR (November 1975). "A comparison of fenfluramine and amphetamine in man". Clin Pharmacol Ther. 18 (5 Pt 1): 563–570. doi:10.1002/cpt1975185part1563. PMID 1102234. dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally [...] Fenfluramine [...] caused a marked dilation of pupils [...] While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.
  54. ^ a b 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 (February 2023). "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science. 379 (6633): 700–706. Bibcode:2023Sci...379..700V. doi:10.1126/science.adf0435. PMC 10108900. PMID 36795823.
  55. ^ a b c Ogren SO, Ross SB (October 1977). "Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones". Acta Pharmacol Toxicol (Copenh). 41 (4): 353–368. doi:10.1111/j.1600-0773.1977.tb02674.x. PMID 303437.
  56. ^ a b Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167: 107933. doi:10.1016/j.neuropharm.2019.107933. PMC 9191653. PMID 31917152. 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).
  57. ^ a b Wojtas A, Gołembiowska K (December 2023). "Molecular and Medical Aspects of Psychedelics". Int J Mol Sci. 25 (1): 241. doi:10.3390/ijms25010241. PMC 10778977. PMID 38203411. 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].
  58. ^ Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
  59. ^ Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB (March 2014). "Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function". Psychopharmacology (Berl). 231 (5): 875–888. doi:10.1007/s00213-013-3303-6. PMC 3945162. PMID 24142203.
  60. ^ Fuller RW (May 1992). "Effects of p-chloroamphetamine on brain serotonin neurons". Neurochem Res. 17 (5): 449–456. doi:10.1007/BF00969891. PMID 1528354. Additional acute behavioral effects of PCA thought to be due to serotonin release include inhibition of startle sensitization (24), suppression of sexual behavior in female rats (25) and the head twitch response in mice (26).
  61. ^ Orikasa S, Sloley BD (1988). "Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin, p-chloroamphetamine, and tryptamine in mice". Psychopharmacology (Berl). 95 (1): 124–131. doi:10.1007/BF00212780. PMID 3133691. 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.
  62. ^ Schloss P, Williams DC (1998). "The serotonin transporter: a primary target for antidepressant drugs". J Psychopharmacol. 12 (2): 115–121. doi:10.1177/026988119801200201. PMID 9694022.
  63. ^ Porsolt RD, Anton G, Blavet N, Jalfre M (February 1978). "Behavioural despair in rats: a new model sensitive to antidepressant treatments". Eur J Pharmacol. 47 (4): 379–391. doi:10.1016/0014-2999(78)90118-8. PMID 204499.
  64. ^ Glennon RA, Dukat MG (December 2023). "α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant". ACS Pharmacol Transl Sci. 6 (12): 1780–1789. doi:10.1021/acsptsci.3c00139. PMC 10714429. PMID 38093842.
  65. ^ Barceloux DG (20 March 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 196–199. ISBN 978-0-471-72760-6.
  66. ^ Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6. 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.
  67. ^ Blanckaert P, Vanquekelberghe S, Coopman V, Risseeuw MD, Van Calenbergh S, Cordonnier J (July 2018). "Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy - a risk to public health". Forensic Sci Int. 288: 173–180. doi:10.1016/j.forsciint.2018.04.023. hdl:1854/LU-8569680. PMID 29753935. 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].
  68. ^ van Praag HM, Schut T, Bosma E, van den Bergh R (1971). "A comparative study of the therapeutic effects of sone 4-chlorinated amphetamine derivatives in depressive patients". Psychopharmacologia. 20 (1): 66–76. doi:10.1007/BF00404060. PMID 5565748.
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  70. ^ a b c Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (October 2014). "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology. 231 (21): 4135–44. doi:10.1007/s00213-014-3557-7. PMC 4194234. PMID 24800892.
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  72. ^ Dailey JW, Reith ME, Steidley KR, Milbrandt JC, Jobe PC (October 1998). "Carbamazepine-induced release of serotonin from rat hippocampus in vitro". Epilepsia. 39 (10): 1054–1063. doi:10.1111/j.1528-1157.1998.tb01290.x. PMID 9776325. S2CID 20382623.
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  74. ^ Kawata Y, Okada M, Murakami T, Kamata A, Zhu G, Kaneko S (June 2001). "Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin release". British Journal of Pharmacology. 133 (4): 557–567. doi:10.1038/sj.bjp.0704104. PMC 1572811. PMID 11399673.
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