Serotonin releasing agent

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

Contents

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 [2] [3] However, these SRAs were withdrawn from the market due to toxicity in the 1990s and no SRAs were available or employable for clinical study for many years.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 comparisons

Selectivities and serotonin increases

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 or more. [24] [26] [8] [2] [3] Relatedly, genetic ablation of the serotonin transporter (SERT), which results in complete loss of SERT-mediated serotonin reuptake, is associated with 4- to 6-fold elevations in brain serotonin levels. [27] 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

Certain SRAs, such as fenfluramine and chlorphentermine, do not produce locomotor activation (a stimulant-like effect) in animals. [28] [14] [29] [30] Moreover, fenfluramine robustly inhibits the locomotor hyperactivity and rewarding effects induced by psychostimulants like amphetamine and phentermine. [28] [14] [29] 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). [28] [29] [10] Fenfluramine also suppresses the subjective effects and positive mood effects of amphetamine and phentermine in humans. [10] [28] [9] [31]

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). [32] [33] The reasons for these conflicting findings are unclear. [32] [33] 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. [34] [35] [36] 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. [32] [24] [8] This increased locomotor activity could be blocked by a serotonin 5-HT1B receptor antagonist. [32] 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. [37]

In contrast to fenfluramine and mCPP, the SSRI fluoxetine has no impact on locomotor activity alone or in combination with SB-242084. [24] [38] In addition to its modulation of locomotion, the suppressive effects of fenfluramine on drug self-administration are blocked by SB-242084. [39]

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. [34] [40] [38] [41] [30] 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). [34] [40] [38] Suppression of locomotor activity by fenfluramine and its metabolite dexnorfenfluramine is not blocked by fluoxetine, indicating that it is not due to serotonin release. [34] [41] 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. [40] [41] [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. [42] [43] The increased locomotion induced by SRAs that cause this effect appears to be critically dependent on serotonin 5-HT1B receptor signaling. [32] [13] [34] [40] [33] Conversely, 5-HT2C receptor antagonists markedly enhance the hyperlocomotion of MDMA. [13] [30] [33]

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. [44] [45] [46] [43] mCPP had no effect on place conditioning, at least in one study. [44] [47] SSRIs have shown highly mixed effects on place conditioning, with fluoxetine producing CPP, zimelidine producing CPP or having no effect, and citalopram producing CPA. [44] [45] Though zimelidine was reported to produce CPP in one study, it could also block the CPP induced by amphetamine. [45] [48]

Effects on intracranial self-stimulation (ICSS) can be used to measure the reinforcing and misuse-related effects of drugs. [49] [39] [50] [51] ICSS is enhanced by amphetamine and is reduced by the serotonin 5-HT2C receptor agonist Ro 60-0175, by the SRA and serotonin 5-HT2C receptor agonist fenfluramine, and by the κ-opioid receptor agonist U-69,593 in rats. [39] [50] [51] The serotonin–norepinephrine–dopamine releasing agents (SNDRAs) and serotonin receptor agonists (+)-MDMA and naphthylaminopropane (NAP; PAL-287) showed mixed effects on ICSS, either augmenting or suppressing ICSS depending on the ICSS frequencies. [49] [50] [51] The serotonin 5-HT2C receptor antagonist SB-242084 completely blocked the suppressive effects of Ro 60-0175 and fenfluramine on ICSS, whereas it did not influence the effects of amphetamine or U-69,593 on ICSS. [39] [50] [51] SB-242084 partially reduced the ICSS suppressive effects of (+)-MDMA and NAP and augmented their facilitatory effects on ICSS. [49] [50] [51] Conversely, the non-selective serotonin receptor antagonist methysergide completely blocked the ICSS depression produced by MDMA. [49] [51] [52] These findings suggest that serotonin 5-HT2C receptor activation plays a major role in the anti-reinforcing effects of SRAs, but that other serotonin receptors may also be involved. [49] [39] [50] [51]

Psychedelic-like effects

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. [53] [24] [54] 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. [55] [56] [57] [58] 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 [54] [59] [60] and PCA has not been reported to produce hallucinogenic effects in humans. [53] [61] [62] In contrast to fenfluramine, PCA is notably not a serotonin 5-HT2A receptor agonist [59] or may only act as one at high doses, [60] 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. [63] [64] 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. [53] [61] [65] [66] [60] 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. [53] [62]

Antidepressant-like effects

SSRIs like fluoxetine, as well as non-selective SRIs, are used and claimed to be clinically effective in the treatment of depression. [67] 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] [68]

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; [69] α-methyltryptamine (αMT), which was previously marketed in the Soviet Union under the brand name Indopan; [70] 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. [71] [72] [73]

Examples and use of SRAs

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. [74]

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. [75] [76] Psilocin is a partial releaser of serotonin, with an Emax Tooltip maximal efficacy of 54%. [76] [75] 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. [75] 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.

Mechanism of action

List of SRAs

Pharmaceutical drugs

Amphetamines

Tryptamines

Others

Recreational drugs and research chemicals

Amphetamines

Ring-extended amphetamines
Cathinones

Phenyloxazolamines

Aminoindanes

Aminotetralins

Phenylpiperazines

Tryptamines

Others

See also

Related Research Articles

<span class="mw-page-title-main">Empathogen</span> Class of psychoactive drugs that produce empathic experiences

Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine, sold under the brand name Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

<span class="mw-page-title-main">Trazodone</span> Antidepressant medication

Trazodone, sold under many brand names, is an antidepressant medication used to treat major depressive disorder, anxiety disorders, and insomnia. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken orally.

<span class="mw-page-title-main">Aminorex</span> Chemical compound

Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a Schedule I controlled substance.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

<i>meta</i>-Chlorophenylpiperazine Stimulant

meta-Chlorophenylpiperazine (mCPP) is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as "ecstasy" in Europe and the United States.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the para-chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Norfenfluramine</span> Never-marketed drug of the amphetamine family

Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family and a major active metabolite of the appetite suppressants fenfluramine and benfluorex. The compound is a racemic mixture of two enantiomers with differing activities, dexnorfenfluramine and levonorfenfluramine.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

<span class="mw-page-title-main">SB-242084</span> Chemical compound

SB-242084 is a selective antagonist of the serotonin 5-HT2C receptor which is used in scientific research.

<i>para</i>-Chloroamphetamine Chemical compound

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. 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.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

5-HT2C receptor agonists are a class of drugs that activate 5-HT2C receptors. They have been investigated for the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.

<span class="mw-page-title-main">Head-twitch response</span> Head movement in rodents upon 5-HT2A receptor activation

The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats when the serotonin 5-HT2A receptor is activated. Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin consistently induce the HTR in rodents. Because of this, the HTR is widely employed in scientific research as an animal behavioral model of hallucinogen effects and in the discovery of new psychedelic drugs.

<span class="mw-page-title-main">5-MBPB</span> Chemical compound

5-MBPB is an amphetamine and phenylisobutylamine derivative which is structurally related to MDMA and has been sold as a designer drug. It can be described as the benzofuran-5-yl analogue of MBDB or the butanamine homologue of 5-MAPB, and is also a structural isomer of 5-EAPB and 6-EAPB. Anecdotal reports suggest this compound has been sold as a designer drug in various European countries since early 2015, but the first definitive identification was made in December 2015 by a forensic laboratory in Slovenia.

<span class="mw-page-title-main">Locomotor activity</span> Behavioral measure in animals

Locomotor activity is a measure of animal behavior which is employed in scientific research.

<i>para</i>-Bromomethamphetamine Pharmaceutical compound

para-Bromomethamphetamine, also known as 4-bromomethamphetamine (4-BMA), is a monoaminergic drug of the amphetamine family related to para-chloroamphetamine. It was studied by József Knoll and colleagues in the 1970s and 1980s.

<span class="mw-page-title-main">SB-221284</span> Pharmaceutical compound

SB-221284 is a selective serotonin 5-HT2C and 5-HT2B receptor antagonist which is used in scientific research.

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  21. ↑ Johnson MP, Frescas SP, Oberlender R, Nichols DE (May 1991). "Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)". Journal of Medicinal Chemistry. 34 (5): 1662–1668. doi:10.1021/jm00109a020. PMID   1674539.
  22. ↑ Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". Br J Pharmacol. doi:10.1111/bph.17361. PMID   39354889. In addition to a direct receptor effect, the ortho-methoxy also may prevent the ligand from being a substrate for the 5-HT reuptake carrier (SERT). For example, when the 2-methoxy moiety was removed from DOM, the resulting compound, 3-methoxy-4-methylamphetamine (MMA), no longer fully substituted in rats trained to discriminate LSD in a two-lever drug discrimination task (Johnson et al., 1991). Rather, full substitution occurred in rats trained to discriminate the 5-HT releasing agent MDMA or another analogue that induced release of neuronal 5-HT. Furthermore, the S enantiomer of MMA inhibited neuronal uptake of 5-HT with an EC50 of 99 nM, whereas DOM was without effect at the SERT.
  23. ↑ Shulgin A, Shulgin A (1991). Pihkal: A Chemical Love Story. Transform Press. ISBN   0-9630096-0-5. Some years ago a report appeared in the forensic literature of Italy, of the seizure of a small semi-transparent capsule containing 141 milligrams of a white powder that was stated to be a new hallucinogenic drug. This was shown to contain an analogue of DOM, 3-methoxy-4-methylamphetamine, or MMA. The Italian authorities made no mention of the net weight contained in each dosage unit, but it has been found that the active level of MMA in man is in the area of 40-60 milligrams. The compound can apparently be quite dysphoric, and long lived.
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  36. ↑ Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (March 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". J Neurosci. 28 (11): 2933–2940. doi:10.1523/JNEUROSCI.5723-07.2008. PMC   6670669 . PMID   18337424. Here we show that acute pharmacological inhibition or genetic ablation of the 5-HT2B receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT2B receptor dependence of MDMA-stimulated release of endogenous 5-HT from superfused midbrain synaptosomes suggests that 5-HT2B receptors act, unlike any other 5-HT receptor, presynaptically to affect MDMA-stimulated 5-HT release.
  37. ↑ Dalton GL, Lee MD, Kennett GA, Dourish CT, Clifton PG (April 2004). "mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes". Neuropharmacology. 46 (5): 663–671. doi:10.1016/j.neuropharm.2003.11.012. PMID   14996544.
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  50. 1 2 3 4 5 6 Bauer CT, Banks ML, Blough BE, Negus SS (September 2015). "Role of 5-HT₂C receptors in effects of monoamine releasers on intracranial self-stimulation in rats". Psychopharmacology (Berl). 232 (17): 3249–3258. doi:10.1007/s00213-015-3982-2. PMC   4536134 . PMID   26041338.
  51. 1 2 3 4 5 6 7 Bauer, Clayton (2013). Determinants of Abuse-Related Effects of Monoamine Releasers in Rats (Thesis). VCU Libraries. doi:10.25772/an08-sz65. Next, the mechanism by which serotonin exerts it response rate-decreasing effects was investigated - specifically, the hypothesis that the 5HT2C receptor mediates serotonin's abuse-limiting effects of monoamine releasers was tested. The data collected suggest that the 5HT2C receptor contributes to, but is not exclusively responsible for, the abuse-limiting effects produced by serotonin release. [...] The receptors through which 5HT may be able to modulate abuse-related effects of DA have also been studied (for review, Alex and Pehek, 2007). One of these receptors, the 5HT2C receptor, appears to be especially relevant to 5HT's ability do decrease dopaminergic activity. [...] similar to fenfluramine, 5HT2C antagonism was sufficient to block most of the rate-decreasing effects produced by PAL-287. [...] Thus the data collected with SB 242,084 as a pretreatment to fenfluramine and PAL-287 would support the hypothesis that the 5HT2C receptor plays a major role in the abuse-limiting effects produced by 5HT release. [...] examined the effect of MDMA in the presence and absence of a non-selective 5HT antagonist (methysergide) and showed that the antagonist blocked the rate-decreasing effects produced by MDMA without changing the threshold levels of responding (Lin et al., 1997). This finding implicated 5HT receptors in mediating the rate-decreasing effects of MDMA in ICSS, but did not identify the specific 5HT receptor subtype involved. The present study showed that pretreatment with a selective 5HT2C antagonist attenuated but did not fully block (+)MDMA's rate-decreasing effects. Similar to results gathered with PAL-287, greater facilitation was seen in the presence of SB 242,084 pretreatment. The partial blockade of the rate-decreasing (and unmasking of greater rate-increasing) effects achieved with SB 242,084 supports the role of the 5HT2C receptor in mediating abuse-limiting effects, but, taken together with the full blockade produced in the methysergide study, indicates that other serotonergic receptors also contribute to the rate-decreasing effects produced by (+)MDMA. It is interesting that antagonism of the 5HT2C receptor appeared sufficient to almost entirely block the rate-decreasing effects produced by PAL287 but not (+)MDMA despite these compounds sharing very similar selectivities to release DA vs. 5HT (Rothman et al., 2005; Wang et al., 2007). [...]
  52. ↑ Lin HQ, Jackson DM, Atrens DM, Christie MJ, McGregor IS (January 1997). "Serotonergic modulation of 3,4-methylenedioxymethamphetamine (MDMA)-elicited reduction of response rate but not rewarding threshold in accumbal self-stimulation". Brain Res. 744 (2): 351–357. doi:10.1016/S0006-8993(96)01210-3. PMID   9027397.
  53. 1 2 3 4 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.
  54. 1 2 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).
  55. ↑ 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.
  56. ↑ 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".
  57. ↑ 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.
  58. ↑ 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.
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  61. 1 2 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).
  62. 1 2 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].
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  64. ↑ 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.
  65. ↑ 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).
  66. ↑ 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.
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  71. ↑ Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). 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.
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