Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice
Adam L. Halberstadt, Muhammad Chatha, Stephen J. Chapman and Simon D. Brandt
Journal of Psychopharmacology, 2019, 1 –9
Background : In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models.
Methods : In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxy-phenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxy-amphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-
Results : TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2.
Conclusions : The potency relation-ships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.
Keywords : Psychedelic, head shake, phenylisopropylamine, phenylethylamine, animal model
Mescaline (3,4,5-trimethoxyphenylethylamine), the active constituent of the peyote cactus (Lophophora williamsii), is considered to be a prototypical serotonergic hallucinogen. The first report describing the hallucinogenic effects of mescaline was published by Dr. Arthur Heffter based on self-experiments (Heffter, 1898). Although mescaline has a fairly low potency, with 178– 356 mg of the hydrochloride salt being the usual dosage range in humans (Shulgin and Shulgin, 1991), addition of an α-methyl
group (Shulgin et al., 1961) or replacement of the 4-methoxy group with an ethoxy or propoxy group (Shulgin, 1978) produces a significant increase in potency. Potency is also increased by rearranging the substituents from a 3,4,5-pattern to a 2,4,5-pattern (Shulgin, 1964). The structures of mescaline analogs and their typical dose ranges in humans are shown in Figure 1.
In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. This interest has been driven, in part, by evidence that hallucinogens may possess therapeutic efficacy in a variety of disorders including anxiety, depression, and substance abuse (Carhart-Harris et al., 2016; Griffiths et al., 2016; Grob et al., 2011; Johnson et al., 2014; Ross et al., 2016). Although human trials with these substances all but ceased after the 1960s, these investigations
have cautiously resumed during the last decade.
Another reason for the renewed focus on serotonergic hallucinogens is the large number available as recreational drugs (Blough et al., 2014; Brandt et al., 2017b, 2016; Gatch et al., 2017; Halberstadt et al., 2019; Klein et al., 2018). Mescaline and its α- methyl derivative 3,4,5-trimethoxyamphetamine (TMA) are listed in Schedule I of the United Nations 1971 Convention on Psychotropic Substances. A variety of mescaline analogs have been encountered in Europe, including escaline (3,5-dimethoxy-4- ethoxyphenylethylamine), proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine), 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and TMA-2 (2,4,5-trimethoxyamphetamine) (European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 2004; King, 2014). TMA-2 was first detected in 1999 (EMCDDA, 2004) and escaline, proscaline, 3C-E and 3C-P were detected in 2013 (EMCDDA, 2014). The identification of escaline has also been reported by researchers in Japan (Kaizaki-Mitsumoto et al., 2016). Another related substance, MEM (4-ethoxy-2,5-dimethoxyamphetamine), appeared as a street drug in Canada in 1986 (Dawson and Awdovich, 1987). Given the potential use of hallucinogens as therapeutic agents, and their continuing use, it is necessary to define the pharmacology and structure-activity relationships (SAR) of these substances.
Although rodent behavioral models are routinely used to evaluate the SAR of hallucinogenic drugs (Halberstadt and Geyer, 2018; Nichols, 2018), there has been little systematic investigation
of mescaline analogs in laboratory studies. Mescaline has been tested in a number of drug discrimination (DD) studies (e.g., Glennon and Young, 1982; Hirschhorn and Winter, 1971; McLean et al., 2006; Schechter and Rosecrans, 1972). TMA, TMA-2, and MEM produced full-substitution in rats trained to
discriminate the hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) from saline (Glennon et al., 1982; Glennon and Young, 1982). Conversely, escaline, the 4-ethoxy homolog of mescaline, did not substitute in LSD-trained rats (Monte et al., 1997). The latter finding is surprising because escaline is a hallucinogen in man (Shulgin and Shulgin, 1991).
The goal of the present investigation was to assess the behavioral effects of mescaline and several analogs using the head twitch response (HTR) assay. Serotonergic hallucinogens induce the HTR, a brief paroxysmal head rotation in rats and mice, via activation of the 5-HT2A receptor (Canal and Morgan, 2012; Halberstadt and Geyer, 2014; Halberstadt et al., 2011; Schreiber et al., 1995), which is the site associated with the psychedelic effects of hallucinogens in humans (Kometer et al., 2013; Kraehenmann et al., 2017; Preller et al., 2017; Valle et al., 2016; Vollenweider et al., 1998). The HTR is used as a behavioral proxy in rodents for human hallucinogenic effects because it can reliably distinguish hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists (Gonzalez-Maeso et al., 2007).
Although mescaline and TMA induce the HTR in rodents (Corne and Pickering, 1967; Silva and Calil, 1975), other phenylalkylamines with a 3,4,5-substitution pattern have not been evaluated. Given the results of the DD studies, it is important to determine whether escaline can induce the HTR. In addition, it is not clear whether the activity of mescaline analogs in the HTR assay is affected by structural modifications known to alter the potency of 3,4,5-trialkoxyphenylethylamines in humans. HTR studies were conducted with mescaline analogs in C57BL/6J mice to examine the effects of the following structural modifications: (a) homologation of the 4-position alkoxy group; (b) addition of an α-methyl
group; and (c) relocation of the ring-substituents from a 3,4,5- to a 2,4,5-substitution pattern. The mescaline analogs produced LSD-like behavioral effects in vivo and their relative potencies were consistent with human data.