Analysis of information sources in references of the Wikipedia article "Serotonin releasing agent" in English language version.
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.
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.
Until recently, it has been challenging to characterise the effects of SSRAs in humans because of the lack of available licensed pharmacological probes. However, in 2020, low dose fenfluramine (up to 26 mg daily; racemic mixture) was licensed for the treatment of Dravet epilepsy41.
The 5-HT2C and 5-HT2A receptors have been implicated in the etiology and treatment of various psychiatric disorders. Activation of 5-HT2C receptors, with agonists such as mCPP and MK-212, results in feelings of anxiety and panic in humans (Mueller, Murphy, & Sunderland, 1985; Charney, Woods, Goodman, & Heninger, 1987; Lowy & Meltzer, 1988; Kahn & Wetzler, 1991; Klein, Zohar, Geraci, Murphy, & Uhde, 1991; Southwick et al., 1997; Benjamin, Geraci, McCann, Greenberg, & Murphy, 1999; Gatch, 2003) and induces anxiogenic-like behaviors in animals (Kennett, Whitton, Shah, & Curzon, 1989; Benjamin, Lal, & Meyerson, 1990; Rodgers et al., 1992; Shepherd, Grewal, Fletcher, Bill, & Dourish, 1994; Bilkei-Gorzo, Gyertyan, & Levay, 1998; Bagdy, Graf, Anheuer, Modos, & Kantor, 2001; Jones, Duxon, & King, 2002; Martin, Ballard, & Higgins, 2002; Campbell & Merchant, 2003; de Mello Cruz et al., 2005; Millan, 2006; Hackler et al., 2007; Cornelio & Nunes-de-Souza, 2007). 5-HT2C receptor antagonists, on the other hand, can block the anxiogenic-like behavior produced by 5-HT2C receptor agonists (Kennett et al., 1989; Bagdy et al., 2001; Campbell & Merchant, 2003; de Mello Cruz et al., 2005; Cornelio and Nunes-de-Souza, 2007; Hackler et al., 2007) and also are anxiolytic when administered alone (Kennett, Bailey, Piper, & Blackburn, 1995; Kennett et al., 1997; Wood et al., 2001; Wood, 2003; Hackler et al., 2007).
5-HT2A/2C receptor agonists such as meta-chlorophenylpiperazine (mCPP) exert strong anxiogenic effects in a variety of animal models of anxiety [102, 198].
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.
In contrast, Sanders et al (2007) demonstrated a sustained reduction in operant responding for food following both chronic SSRI treatment and constitutive knockout of the serotonin transporter (SERT-KO), which produces a chronic, 6-fold elevation in extracellular 5-HT (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004). [...] Genetic deletion of the SERT produces a selective 4- to 6-fold elevation in extracellular 5-HT levels (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004), providing a selective method of examining how chronically elevated 5-HT contributes to behavior.
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.
Selective agonists of the 5-HT2C receptor have generally been found to recapitulate the attenuating effects of indirect serotonin agonists on behavioral models of addiction, suggesting 5-HT2C receptor activation is a key molecular mechanism by which serotonin exerts its anti-addictive effects. For example, the rate-suppressing effects of both the indirect serotonin receptor agonist fenfluramine and the 5-HT2C receptor agonist Ro 60-0175 in an ICSS procedure are blocked by pretreatment with the 5-HT2C receptor selective antagonist SB 242084 (Bauer et al., 2015). Likewise, Ro 60-0175 blocks cocaine-seeking behavior in rats, an effect completely reversed by SB 242084 (Burbassi and Cervo, 2008).
Studies using the ICSS paradigm: As previously mentioned, different studies suggest that 5-HT-mediated effects of MDMA may oppose and limit DA-mediated abuse-related effects. Recently, Bauer et al. (2015) reported that antagonism of the 5-HT2C receptor significantly attenuated the rate-decreasing effects and increased the rate-increasing effects produced by MDMA in rats trained to lever press to receive ICSS of the medial forebrain bundle. These data suggest that 5-HT2C receptors at least partially mediate the rate-decreasing effects produced by MDMA, and blockade of these receptors may increase the expression of abuse-related rate-increasing effects. In agreement with this observation, the nonselective 5-HT receptor antagonist methysergide blocked rate-decreasing effects and enhanced rate-increasing effects produced by MDMA in rats (Lin et al., 1997). Hence, it seems that drug-induced release of 5-HT, acting at least partly through 5-HT2C receptors, can oppose and limit other effects of MDMA that contribute to reward, reinforcement, and drug abuse.
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). [...]
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.
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).
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".
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.
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.
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).
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].
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).
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.
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.
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].
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.
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.
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].
Until recently, it has been challenging to characterise the effects of SSRAs in humans because of the lack of available licensed pharmacological probes. However, in 2020, low dose fenfluramine (up to 26 mg daily; racemic mixture) was licensed for the treatment of Dravet epilepsy41.
Until recently, it has been challenging to characterise the effects of SSRAs in humans because of the lack of available licensed pharmacological probes. However, in 2020, low dose fenfluramine (up to 26 mg daily; racemic mixture) was licensed for the treatment of Dravet epilepsy41.
The 5-HT2C and 5-HT2A receptors have been implicated in the etiology and treatment of various psychiatric disorders. Activation of 5-HT2C receptors, with agonists such as mCPP and MK-212, results in feelings of anxiety and panic in humans (Mueller, Murphy, & Sunderland, 1985; Charney, Woods, Goodman, & Heninger, 1987; Lowy & Meltzer, 1988; Kahn & Wetzler, 1991; Klein, Zohar, Geraci, Murphy, & Uhde, 1991; Southwick et al., 1997; Benjamin, Geraci, McCann, Greenberg, & Murphy, 1999; Gatch, 2003) and induces anxiogenic-like behaviors in animals (Kennett, Whitton, Shah, & Curzon, 1989; Benjamin, Lal, & Meyerson, 1990; Rodgers et al., 1992; Shepherd, Grewal, Fletcher, Bill, & Dourish, 1994; Bilkei-Gorzo, Gyertyan, & Levay, 1998; Bagdy, Graf, Anheuer, Modos, & Kantor, 2001; Jones, Duxon, & King, 2002; Martin, Ballard, & Higgins, 2002; Campbell & Merchant, 2003; de Mello Cruz et al., 2005; Millan, 2006; Hackler et al., 2007; Cornelio & Nunes-de-Souza, 2007). 5-HT2C receptor antagonists, on the other hand, can block the anxiogenic-like behavior produced by 5-HT2C receptor agonists (Kennett et al., 1989; Bagdy et al., 2001; Campbell & Merchant, 2003; de Mello Cruz et al., 2005; Cornelio and Nunes-de-Souza, 2007; Hackler et al., 2007) and also are anxiolytic when administered alone (Kennett, Bailey, Piper, & Blackburn, 1995; Kennett et al., 1997; Wood et al., 2001; Wood, 2003; Hackler et al., 2007).
5-HT2A/2C receptor agonists such as meta-chlorophenylpiperazine (mCPP) exert strong anxiogenic effects in a variety of animal models of anxiety [102, 198].
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.
In contrast, Sanders et al (2007) demonstrated a sustained reduction in operant responding for food following both chronic SSRI treatment and constitutive knockout of the serotonin transporter (SERT-KO), which produces a chronic, 6-fold elevation in extracellular 5-HT (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004). [...] Genetic deletion of the SERT produces a selective 4- to 6-fold elevation in extracellular 5-HT levels (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004), providing a selective method of examining how chronically elevated 5-HT contributes to behavior.
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.
Selective agonists of the 5-HT2C receptor have generally been found to recapitulate the attenuating effects of indirect serotonin agonists on behavioral models of addiction, suggesting 5-HT2C receptor activation is a key molecular mechanism by which serotonin exerts its anti-addictive effects. For example, the rate-suppressing effects of both the indirect serotonin receptor agonist fenfluramine and the 5-HT2C receptor agonist Ro 60-0175 in an ICSS procedure are blocked by pretreatment with the 5-HT2C receptor selective antagonist SB 242084 (Bauer et al., 2015). Likewise, Ro 60-0175 blocks cocaine-seeking behavior in rats, an effect completely reversed by SB 242084 (Burbassi and Cervo, 2008).
Studies using the ICSS paradigm: As previously mentioned, different studies suggest that 5-HT-mediated effects of MDMA may oppose and limit DA-mediated abuse-related effects. Recently, Bauer et al. (2015) reported that antagonism of the 5-HT2C receptor significantly attenuated the rate-decreasing effects and increased the rate-increasing effects produced by MDMA in rats trained to lever press to receive ICSS of the medial forebrain bundle. These data suggest that 5-HT2C receptors at least partially mediate the rate-decreasing effects produced by MDMA, and blockade of these receptors may increase the expression of abuse-related rate-increasing effects. In agreement with this observation, the nonselective 5-HT receptor antagonist methysergide blocked rate-decreasing effects and enhanced rate-increasing effects produced by MDMA in rats (Lin et al., 1997). Hence, it seems that drug-induced release of 5-HT, acting at least partly through 5-HT2C receptors, can oppose and limit other effects of MDMA that contribute to reward, reinforcement, and drug abuse.
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.
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).
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.
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).
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].
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).
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.
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].
Until recently, it has been challenging to characterise the effects of SSRAs in humans because of the lack of available licensed pharmacological probes. However, in 2020, low dose fenfluramine (up to 26 mg daily; racemic mixture) was licensed for the treatment of Dravet epilepsy41.
In contrast, Sanders et al (2007) demonstrated a sustained reduction in operant responding for food following both chronic SSRI treatment and constitutive knockout of the serotonin transporter (SERT-KO), which produces a chronic, 6-fold elevation in extracellular 5-HT (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004). [...] Genetic deletion of the SERT produces a selective 4- to 6-fold elevation in extracellular 5-HT levels (Bengel et al, 1998; Fabre et al, 2000; Shen et al, 2004), providing a selective method of examining how chronically elevated 5-HT contributes to behavior.
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.
Selective agonists of the 5-HT2C receptor have generally been found to recapitulate the attenuating effects of indirect serotonin agonists on behavioral models of addiction, suggesting 5-HT2C receptor activation is a key molecular mechanism by which serotonin exerts its anti-addictive effects. For example, the rate-suppressing effects of both the indirect serotonin receptor agonist fenfluramine and the 5-HT2C receptor agonist Ro 60-0175 in an ICSS procedure are blocked by pretreatment with the 5-HT2C receptor selective antagonist SB 242084 (Bauer et al., 2015). Likewise, Ro 60-0175 blocks cocaine-seeking behavior in rats, an effect completely reversed by SB 242084 (Burbassi and Cervo, 2008).
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.
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).
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].
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".
