2C (psychedelics)
2C is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds.
Most of the early 2C drugs were developed by Alexander Shulgin in the 1970s and 1980s and were reviewed in his 1991 book PiHKAL. 2C-B is the most popular of the 2C drugs.
Use and effects
The 2C drugs are orally active, are used at oral doses of 6 to 150mg depending on the drug, and have durations of 3 to 48hours depending on the drug. However, many have doses in the range of 10 to 60mg and durations in the range of 4 to 12hours. The 2C drugs produce psychedelic effects, such as perceptual enhancement, psychedelic visuals, and euphoria. Some, such as 2C-B, have also been reported to produce some entactogen-like effects, but findings in this area appear to be mixed.Interactions
The 2C drugs are metabolized by the monoamine oxidase enzymes, including both MAO-A and MAO-B. As a result, they may be potentiated by monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, moclobemide, and selegiline. This may lead to overdose and serious toxicity. There are anecdotal reports of strong potentiation of 2C-B by MAOIs, including hospitalization. There is no known reversal agent for 2C drugs, and medical management for overdose involves treatment of symptoms until toxicity within the body subsides.Pharmacology
Pharmacodynamics
Actions
The 2C drugs act as agonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. They are partial agonists of the serotonin 5-HT2A receptor. Most of the 2C drugs have much lower affinity for the serotonin 5-HT1A receptor than for the serotonin 5-HT2A receptor. Most of the 2C drugs have also shown about 5- to 15-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor and about 15- to 100-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT1A receptor. The psychedelic effects of the 2C drugs are thought to be mediated specifically by activation of the serotonin 5-HT2A receptor.Unlike many other phenethylamines, 2C drugs, including 2C-C, 2C-D, 2C-E, 2C-I, and 2C-T-2 among others, are inactive as monoamine releasing agents and reuptake inhibitors. Most of the 2C drugs are agonists of the rat and mouse trace amine-associated receptor 1. However, most are inactive as agonists of the human TAAR1. The 2C drugs show very weak monoamine oxidase inhibition, including of monoamine oxidase A and/or monoamine oxidase B.
Effects
In accordance with their psychedelic effects in humans, the 2C drugs produce the head-twitch response and wet dog shakes, behavioral proxies of psychedelic effects, in rodents. At least some 2C drugs, such as 2C-D and 2C-E, produce hyperlocomotion at lower doses in rodents. All 2C drugs produce hypolocomotion at higher doses in rodents. 2C drugs, including 2C-C, 2C-D, 2C-E, and 2C-I, substitute partially to fully for psychedelics like DOM, DMT, and LSD and/or for the entactogen MDMA in rodent drug discrimination tests. However, none of the assessed 2C drugs substituted for dextromethamphetamine, suggesting that they lack amphetamine-type or stimulant-like effects.In contrast to most psychedelics, at least two assessed 2C drugs, 2C-C and 2C-P, have shown reinforcing effects in rodents, including conditioned place preference and self-administration. The mechanism by which these effects are mediated is unknown. However, it may be related to reduced expression of the dopamine transporter and increased DAT phosphorylation, in turn resulting in increased extracellular dopamine levels in certain brain areas. These 2C drugs might have misuse potential in humans. Similar reinforcing effects in animals have been observed for NBOMe analogues of 2C drugs, including 25B-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, and 25N-NBOMe.
Similarly to DOI, tolerance has been found to gradually develop to the head-twitch response induced by 2C-T-7 with chronic administration in rodents.
Various 2C drugs show potent anti-inflammatory effects mediated by serotonin 5-HT2A receptor activation. Among these include 2C-I, 2C-B, 2C-H, and 2C-iBu. Others, such as 2C-B-Fly and 2C-T-33, were less effective. 2C-iBu has shown a greater separation between anti-inflammatory effects and psychedelic-like effects in animals than other 2C drugs and is being investigated for possible use as a pharmaceutical drug.
Pharmacokinetics
The 2C drugs are orally active. They are metabolized by O-demethylation and deamination. This is mediated specifically by monoamine oxidase enzymes MAO-A and MAO-B, whereas cytochrome P450 enzymes appear to metabolize only some 2C drugs and to have only a very small role.Chemistry
The 2C drugs, also known as 4-substituted 2,5-dimethoxyphenethylamines, are substituted phenethylamines and can be thought of as synthetic analogues of the naturally occurring phenethylamine psychedelic mescaline. They are the phenethylamine analogues of the amphetamine DOx drugs like DOM, DOB, and DOI as well as of the phenylisobutylamine 4C drugs like Ariadne and 4C-B. The N-benzylphenethylamines such as 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe are derivatives of the 2C drugs. Certain FLY drugs such as 2C-B-FLY are also 2C derivatives.Syntheses
The chemical syntheses of 2C drugs have been described.Analysis
The chemical analysis of 2C drugs has been described.History
, the 2C positional isomer of mescaline, was first synthesized by Max Jansen and was reported to produce psychedelic effects similar to those of mescaline in 1931. However, subsequent studies in the 1960s and 1970s suggested that 2,4,5-TMPEA may actually be inactive as a psychedelic in animals and humans.2C-D was the first of the 2C drugs after 2C-O to be discovered. It was synthesized and studied in animals by Beng T. Ho and colleagues at the Texas Research Institute of Mental Sciences and they published their findings in 1970. Alexander Shulgin synthesized 2C-B and 2C-D in 1974 and discovered their psychedelic effects in self-experiments conducted in 1974 and 1975. He published his findings in the scientific literature in 1975. However, Shulgin had previously tested sub-threshold doses of 2C-D in 1964 and 1965. 2C-T was first described by Shulgin and David E. Nichols in 1976. 2C-I was first described by Shulgin and colleagues in 1977 and initial psychoactivity was reported by Shulgin in 1978. Shulgin also first synthesized 2C-E in 1977. He reviewed several of these 2C drugs in a literature review in 1979. Subsequently, numerous other 2C drugs have been synthesized and characterized. Shulgin comprehensively reviewed and described the 2C drugs in his 1991 book PiHKAL. He coined the term "2C", this term being an acronym for the two carbon atoms between the benzene ring and the amino group of the 2C drugs and a means to distinguish them from the three-carbon DOx drugs.
2C-D was extensively studied by Hanscarl Leuner under the names DMM-PEA and LE-25 in psychedelic-assisted psychotherapy in Germany in the 1970s and 1980s. It was also informally studied by Darrell Lemaire as a potential "smart drug" in the 1970s and 1980s. He additionally developed the TWEETIO drugs such as 2CD-5-ETO via structural modification of the 2Cs. 2C-B was legitimately marketed and sold as an over-the-counter sexual enhancer under brand names like Erox in several European countries such as Germany in the 1980s and early 1990s. It was sold in adult stores, smart shops, and some nightclubs.
2C-B was first encountered as a novel designer drug in the United States in 1979. It gained popularity as a recreational drug and MDMA alternative in the mid-1980s. The drug became a controlled substance in the United States in 1994 or 1995. It has been said to be the most popular of the 2C drugs in terms of recreational use. Numerous other 2C drugs besides 2C-B have also since been made controlled substances.
Society and culture
Legal status
Canada
As of October 12, 2016, the 2C-x family of substituted phenethylamines are controlled substances in Canada.List of 2C drugs
Related compounds
| Name | Chemical name | Structure | Ref |
| 2C-DB | 2,5-Dimethoxy-4,6-dibromophenethylamine | ||
| N-Methyl-2C-B | N-Methyl-4-bromo-2,5-dimethoxyphenethylamine | ||
| N-Ethyl-2C-B | N-Ethyl-4-bromo-2,5-dimethoxyphenethylamine | ||
| 2C-B-OH | 4-Bromo-2,5-dimethoxy-N-hydroxyphenethylamine | ||
| 25B-NB | N-Benzyl-4-bromo-2,5-dimethoxyphenethylamine | ||
| N-Methyl-2C-I | N-Methyl-4-iodo-2,5-dimethoxyphenethylamine | ||
| β-Methyl-2C-B | 4-Bromo-2,5-dimethoxy-β-methylphenylethylamine | ||
| β-Keto-2C-B | 4-Bromo-2,5-dimethoxy-β-ketophenylethylamine | ||
| β-Keto-2C-I | 4-Iodo-2,5-dimethoxy-β-ketophenylethylamine | ||
| 2C-B-AN | 4-Bromo-N--2,5-dimethoxyphenethylamine | ||
| 25D-NM-NDEAOP | N-Methyl-N--2,5-dimethoxy-4-methylphenethylamine | ||
| 25B-NAcPip | N--4-bromo-2,5-dimethoxyphenethylamine | ||
| XOB | N--4-bromo-2,5-dimethoxyphenethylamine | ||
| TCB-2 | octa-1,3,5-trien-7-yl]methanamine | ||
| 2CB-Ind | methanamine | ||
| ZC-B | 3-azetidine | ||
| 2C-B-PYR | 3-pyrrolidine | ||
| 2C-B-3PIP | 3-piperidine | ||
| LPH-5 | -3-piperidine | ||
| DEMPDHPCA-2C-D | 1-Methyl-3--5--3,6-dihydro-2H-pyridine | ||
| DOM-CR | 5,8-Dimethoxy-7-methyl-1,2,3,4-tetrahydroisoquinoline | ||
| DOB-CR | 5,8-Dimethoxy-7-bromo-1,2,3,4-tetrahydroisoquinoline | ||
| N-Methyl-DOM-CR | 2,7-Dimethyl-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline | ||
| 2C-B-morpholine | 2-morpholine | ||
| 2C-B-aminorex | 5--4,5-dihydro-1,3-oxazol-2-amine | ||
| 2C-B-PP | 1-piperazine | ||
| 2C-B-BZP | 1-piperazine | ||
| 2C-B-5-hemiFLY-α6 | 8-Bromo-6-methoxy-2a,3,4,5-tetrahydro-2H-naphthofuran-4-amine | ||
| 2CB7 | methanamine | ||
| 2C-2-TOM | 5-Methoxy-4-methyl-2-methylthiophenethylamine | ||
| 2C-5-TOM | 2-Methoxy-4-methyl-5-methylthiophenethylamine | ||
| 2C-2-TOET | 4-Ethyl-5-methoxy-2-methylthiophenethylamine | ||
| 2C-5-TOET | 4-Ethyl-2-methoxy-5-methylthiophenethylamine | ||
| 2T-2CTFM-3PIP | 3-piperidine |