2C (psychedelics)

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring.^[1][2][3] 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.^[4]

General structure of a 2C compound

Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines i Have Known And Loved).^[3] Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group.^[5][1][3] 2C-B is the most popular of the 2C drugs.^[3]

Use

The 2C drugs are orally active, are used at oral doses of 6 to 150 mg depending on the drug, and have durations of 3 to 48 hours depending on the drug.^[1][6][5][7] However, many have doses in the range of 10 to 60 mg and durations in the range of 4 to 12 hours.^[1] The 2C drugs produce psychedelic effects.^[1][5][8][3] Some, such as 2C-B, have also been reported to have some entactogenic qualities, though findings appear to be mixed.^{[8][3][9][10]}

Doses and durations of 2C drugs

Compound	Chemical name	Dosage	Duration
2C-AL	4-Allyl-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-B	4-Bromo-2,5-dimethoxyphenethylamine	10–35 mg	4–8 hours
2C-Bu	4-Butyl-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-C	4-Chloro-2,5-dimethoxyphenethylamine	20–40 mg	4–8 hours
2C-CN	4-Cyano-2,5-dimethoxyphenethylamine	>22 mg	Unknown
2C-CP	4-Cyclopropyl-2,5-dimethoxyphenethylamine	15–35 mg	3–6 hours
2C-D	4-Methyl-2,5-dimethoxyphenethylamine	20–60 mg	4–6 hours
2C-E	4-Ethyl-2,5-dimethoxyphenethylamine	10–25 mg	6–12 hours
2C-EF	4-Fluoroethyl-2,5-dimethoxyphenethylamine	10–25 mg	Unknown
2C-F	4-Fluoro-2,5-dimethoxyphenethylamine	≥250 mg	Unknown
2C-G	3,4-Dimethyl-2,5-dimethoxyphenethylamine	20–35 mg	18–30 hours
2C-G-3	3,4-Trimethylene-2,5-dimethoxyphenethylamine	16–25 mg	12–24 hours
2C-G-5	3,4-Norbornyl-2,5-dimethoxyphenethylamine	10–16 mg	32–48 hours
2C-H	2,5-Dimethoxyphenethylamine	Unknown	Unknown
2C-I	4-Iodo-2,5-dimethoxyphenethylamine	14–22 mg	6–10 hours
2C-iBu	4-Isobutyl-2,5-dimethoxyphenethylamine	≥5 mg	~20 hours
2C-iP	4-Isopropyl-2,5-dimethoxyphenethylamine	8–25 mg	8–12 hours
2C-N	4-Nitro-2,5-dimethoxyphenethylamine	100–150 mg	4–6 hours
2C-O	4-Methoxy-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-O-4	4-Isopropoxy-2,5-dimethoxyphenethylamine	>60 mg	Unknown
2C-O-22	4-(2,2,2-Trifluoroethoxy)-2,5-dimethoxyphenethylamine	≥57 mg	Unknown
2C-P	4-Propyl-2,5-dimethoxyphenethylamine	6–10 mg	5–16 hours
2C-Ph (2C-BI-1)	4-Phenyl-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-SE	4-Methylseleno-2,5-dimethoxyphenethylamine	~100 mg	6–8 hours
2C-T (2C-T-1)	4-Methylthio-2,5-dimethoxyphenethylamine	60–100 mg	3–5 hours
2C-T-2	4-Ethylthio-2,5-dimethoxyphenethylamine	12–25 mg	6–8 hours
2C-T-3 (2C-T-20)	4-Methallylthio-2,5-dimethoxyphenethylamine	15–40 mg	8–14 hours
2C-T-4	4-Isopropylthio-2,5-dimethoxyphenethylamine	8–20 mg	12–18 hours
2C-T-7	4-Propylthio-2,5-dimethoxyphenethylamine	10–30 mg	8–15 hours
2C-T-8	4-Cyclopropylmethylthio-2,5-dimethoxyphenethylamine	30–50 mg	10–15 hours
2C-T-9	4-tert-Butylthio-2,5-dimethoxyphenethylamine	60–100 mg	12–18 hours
2C-T-13	4-(2-Methoxyethylthio)-2,5-dimethoxyphenethylamine	25–40 mg	6–8 hours
2C-T-15	4-Cyclopropylthio-2,5-dimethoxyphenethylamine	>30 mg	Several hours
2C-T-16	4-Allylthio-2,5-dimethoxyphenethylamine	10–25 mg	4–6 hours
2C-T-17	4-sec-Butylthio-2,5-dimethoxyphenethylamine	60–100 mg	10–15 hours
2C-T-19	4-Butylthio-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-T-21	4-(2-Fluoroethylthio)-2,5-dimethoxyphenethylamine	8–20 mg	7–10 hours
2C-T-21.5	4-(2,2-Difluoroethylthio)-2,5-dimethoxyphenethylamine	12–30 mg	8–14 hours
2C-T-22	4-(2,2,2-Trifluoroethylthio)-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-T-25	4-Isobutylthio-2,5-dimethoxyphenethylamine	>30 mg	Unknown
2C-T-27	4-Benzylthio-2,5-dimethoxyphenethylamine	≥80 mg	Unknown
2C-T-28	4-(3-Fluoropropylthio)-2,5-dimethoxyphenethylamine	8–20 mg	8–10 hours
2C-T-30	4-(4-Fluorobutylthio)-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-T-33	4-(3-Methoxybenzylthio)-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-T-36 (2C-T-TFM)	4-Trifluoromethylthio-2,5-dimethoxyphenethylamine	Unknown	Unknown
2C-tBu	4-tert-Butyl-2,5-dimethoxyphenethylamine	>5–10 mg	Unknown
2C-TFE	4-(2,2,2-Trifluoroethyl)-2,5-dimethoxyphenethylamine	5–15 mg	12–24 hours
2C-TFM	4-Trifluoromethyl-2,5-dimethoxyphenethylamine	3–6 mg	≥5–10 hours
2C-V	4-Ethenyl-2,5-dimethoxyphenethylamine	~25 mg	~5 hours
2C-YN	4-Ethynyl-2,5-dimethoxyphenethylamine	~50 mg	~2 hours
Refs: [1][6][3][7][5][2][11][12][13][4]

Interactions

See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

The 2C drugs are metabolized by the monoamine oxidase (MAO) enzymes, including both MAO-A and MAO-B.^[1][14] As a result, they may be potentiated by monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, moclobemide, and selegiline.^[1][14][15] This may lead to overdose and serious toxicity.^[1][14][15]

Pharmacology

Pharmacodynamics

Actions

The 2C drugs act as agonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors.^{[16][17][18][19][20]} They are partial agonists of the serotonin 5-HT_2A receptor.^[16][17] Most of the 2C drugs have much lower affinity for the serotonin 5-HT_1A receptor than for the serotonin 5-HT_2A receptor.^{[16][17][18][19]} Most of the 2C drugs have also shown about 5- to 15-fold higher affinity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor and about 15- to 100-fold higher affinity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_1A receptor.^[17] The psychedelic effects of the 2C drugs are thought to be mediated specifically by activation of the serotonin 5-HT_2A receptor.^[16][18][20]

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.^{[16][21][18][17][20]} Most of the 2C drugs are agonists of the rat and mouse trace amine-associated receptor 1 (TAAR1).^{[16][22][23][17]} However, most are inactive as agonists of the human TAAR1.^{[16][22][23][17]} The 2C drugs show very weak monoamine oxidase inhibition, including of monoamine oxidase A (MAO-A) and/or monoamine oxidase B (MAO-B).^[16]

2C drugs at serotonin 5-HT₁ and 5-HT₂ receptors

Drug	5-HT1A			5-HT1B	5-HT2A			5-HT2B			5-HT2C
	Ki (nM)	EC50 (nM)	Emax (%)	Ki (nM)	Ki (nM)	EC50 (nM)	Emax (%)	Ki (nM)	EC50 (nM)	Emax (%)	Ki (nM)	EC50 (nM)	Emax (%)
2C-B	130–311	ND	ND	104.4	6.9–27.6	1.89–80	5–99%	13.5	75–130	52–89%	43–89.5	0.031–0.264	104–116%
2C-C	190–740	>10,000	<25%	252.9	5.47–13	9.27–200	49–102%	ND	280	81%	5.4–90	24.2	94%
2C-D	440–1,630	>10,000	<25%	ND	23.9–32.4	43.5–350	41–125%	ND	230	77%	12.7–150	71.1	100%
2C-E	307.3–1,190	>10,000	<25%	ND	4.50–43.9	2.5–110	40–125%	25.1	190	66%	5.4–104.1	0.233–18.0	98–106%
2C-H	70	ND	ND	ND	1,600	2,408–9,400	28–67%	ND	6,200	46%	4,100	ND	ND
2C-I	180–970	4,900	102%	ND	3.5–9.3	3.83–60	15–82%	ND	150	70%	10.2–40	2.8	79–100%
2C-N	2,200	ND	ND	ND	23.5	170	20–48%	ND	730	74%	370	ND	40–50%
2C-P	110	ND	ND	ND	8.1	90	63%	ND	130	72%	40	ND	ND
2C-T-1	1,035	ND	ND	ND	49	2.0	75%	ND	57	58%	347	ND	ND
2C-T-2	370–1,740	3,000	76%	857.5	9–39.9	0.354–80	67–128%	6	130	75%	14.2–69	0.0233–3.8	87–107%
2C-T-4	470–916	ND	ND	ND	27.9–54	5.5–220	56–87%	ND	63–160	68–75%	180–295	ND	ND
2C-T-7	520–878	ND	ND	ND	5.3–6.5	1.2–130	49–101%	ND	52–350	45–75%	39–54	ND	ND
Notes: The smaller the value, the more avidly the drug binds to or activates the site. Refs: [17][18][19][16][24][25][26][27]

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.^[16] At least some 2C drugs, such as 2C-D and 2C-E, produce hyperlocomotion at lower doses in rodents.^[16] All 2C drugs produce hypolocomotion at higher doses in rodents.^[16] 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.^[16][18] However, none of the assessed 2C drugs substituted for dextromethamphetamine, suggesting that they lack amphetamine-type or stimulant-like effects.^[16][18]

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 (CPP) and self-administration.^[16][28] The mechanism by which these effects are mediated is unknown.^[16] However, it may be related to reduced expression of the dopamine transporter (DAT) and increased DAT phosphorylation, in turn resulting in increased extracellular dopamine levels in certain brain areas.^[16][28] These 2C drugs might have misuse potential in humans.^[16][28] 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.^{[16][29][30][31][32][33][34]}

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.^[16]

Various 2C drugs show potent anti-inflammatory effects mediated by serotonin 5-HT_2A receptor activation.^[35] Among these include 2C-I, 2C-B, 2C-H, and 2C-iBu.^[35][36] Others, such as 2C-B-Fly and 2C-T-33, were less effective.^[35] 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.^[36][37]

Pharmacokinetics

The 2C drugs are orally active.^[1] They are metabolized by O-demethylation and deamination.^[1][14] This is mediated specifically by monoamine oxidase (MAO) 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.^[14]

History

See also: DOx § History

2,4,5-Trimethoxyphenethylamine (2,4,5-TMPEA; 2C-O or "2C-MeO") was first synthesized by Jansen and was found to produce psychedelic effects similar to those of mescaline (3,4,5-trimethoxyphenethylamine).^[38][39] He published his findings in 1931.^[38][39] 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.^[38]

2C-D (2C-M) was the first of the 2C drugs besides 2C-O to be discovered.^{[2][40][41][42]} It was synthesized and studied in animals by Ho and colleagues and they published their findings in 1970.^{[2][40][41][42]} Alexander Shulgin synthesized 2C-B and 2C-D in 1974 and discovered their psychedelic effects in self-experiments conducted in 1974 and 1975.^{[1][43][2][40][44]} He published his findings in the scientific literature in 1975.^{[1][43][2][40][44]} 2C-T was first described by Shulgin and David E. Nichols in 1976.^[45] 2C-I was first described by Shulgin and colleagues in 1977 and initial psychoactivity was reported by Shulgin in 1978.^[38][46] Shulgin also first synthesized 2C-E in 1977.^[47][48] He reviewed several of these 2C drugs in 1979.^[49] Subsequently, numerous other 2C drugs have been synthesized and characterized.^{[5][6][2][1][43]}

2C-B gained popularity as a recreational drug and MDMA alternative in the mid-1980s and became a controlled substance in the United States in 1994.^[1][3] It is said to be the most popular of the 2C drugs.^[3]

Society and culture

Legal status

Canada

As of October 12, 2016, the 2C-x family of substituted phenethylamines is a controlled substance (Schedule III) in Canada.^[50]

List of 2C drugs

Name	R3	R4	Structure	CAS #
2C-B	H	Br		66142-81-2
2C-Bn	H	CH2C6H5
2C-Bu	H	CH2CH2CH2CH3
2C-C	H	Cl		88441-14-9
2C-C-3 [51]	Cl	Cl
2C-CN	H	C≡N		88441-07-0
2C-D	H	CH3		24333-19-5
2C-E	H	CH2CH3		71539-34-9
2C-EF	H	CH2CH2F		1222814-77-8
2C-F	H	F		207740-15-6
2C-G	CH3	CH3		207740-18-9
2C-G-1	CH2
2C-G-2	(CH2)2
2C-G-3	(CH2)3			207740-19-0
2C-G-4	(CH2)4			952006-59-6
2C-G-5	(CH2)5			207740-20-3
2C-G-6	(CH2)6
2C-G-N	(CH)4			207740-21-4
2C-H	H	H		3600-86-0
2C-I	H	I		69587-11-7
2C-iBu	H	iBu
2C-iP	H	CH(CH3)2		1498978-47-4
2C-tBu	H	C(CH3)3
2C-CP	H	C3H5		2888537-46-8
2C-CPE	H	C5H9
2C-N	H	NO2		261789-00-8
2C-NH2	H	NH2		168699-66-9
2C-PYR	H	Pyrrolidine
2C-PIP	H	Piperidine
2C-O	H	OCH3		15394-83-9
2C-O-4	H	OCH(CH3)2		952006-65-4
2C-MOM [52]	H	CH2OCH3
2C-P	H	CH2CH2CH3		207740-22-5
2C-Ph (2C-BI-1)	H	C6H5
2C-Se	H	Se CH3		1189246-68-1
2C-T	H	SCH3		61638-09-3
2C-T-2	H	SCH2CH3		207740-24-7
2C-T-3[53]	H	SCH2C(=CH2)CH3		648957-40-8
2C-T-4	H	SCH(CH3)2		207740-25-8
2C-T-5[53]
2C-T-6[53]
2C-T-7	H	S(CH2)2CH3		207740-26-9
2C-T-8	H	SCH2CH(CH2)2		207740-27-0
2C-T-9[53]				207740-28-1
2C-T-10[53]
2C-T-11[53]
2C-T-12[53]
2C-T-13	H	S(CH2)2OCH3		207740-30-5
2C-T-14[53]
2C-T-15	H	SCH(CH2)2
2C-T-16[54]	H	SCH2CH=CH2		648957-42-0
2C-T-17	H	SCH(CH3)CH2CH3		207740-32-7
2C-T-18[53]
2C-T-19	H	SCH2CH2CH2CH3
2C-T-21	H	S(CH2)2F		207740-33-8
2C-T-21.5[53]				648957-46-4
2C-T-22[53]				648957-48-6
2C-T-23[53]
2C-T-24[53]
2C-T-25[53]
2C-T-27[53]				648957-52-2
2C-T-28[53]				648957-54-4
2C-T-30[53]
2C-T-31[53]
2C-T-32[53]
2C-T-33[53]
2C-T-DFM	H	SCF2H
CYB210010 (2C-T-TFM)[55]	H	SCF3
2C-T-DFP	H	SCH2CH2CF2H
2C-T-PARGY	H	SCH2C≡CH
2C-DFM [4]: 770	H	CHF2
2C-TFM	H	CF3		159277-08-4
2C-TFE	H	CH2CF3
2C-PFE	H	CF2CF3
2C-PFS	H	SF5
2C-YN	H	C≡CH		752982-24-4
2C-V	H	CH=CH2
2C-AL[56]	H	CH2CH=CH2

Related compounds

See also: DOx (psychedelics), 25-NB, FLY (psychedelics), TWEETIO (psychedelics), and BOx (psychedelics)

Name	Chemical name	Structure	Ref
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 (βk-2C-B)	4-Bromo-2,5-dimethoxy-β-ketophenylethylamine
25D-NM-NDEAOP (25D-NM-NDEPA)	N-Methyl-N-(3-diethylamino-3-oxopropyl)-2,5-dimethoxy-4-methylphenethylamine
25B-NAcPip	N-(Piperidin-1-ylcarbonylmethyl)-4-bromo-2,5-dimethoxyphenethylamine
XOB	N-[(4-Phenylbutoxy)hexyl]-4-bromo-2,5-dimethoxyphenethylamine		[57]
TCB-2	[(7R)-3-Bromo-2,5-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine
2CB-Ind	(5-Bromo-4,7-dimethoxy-2,3-dihydro-1H-inden-1-yl)methanamine
ZC-B	3-(4-Bromo-2,5-dimethoxyphenyl)azetidine
DOM-CR (DOM-THIQ, 2C-D-CR)	5,8-Dimethoxy-7-methyl-1,2,3,4-tetrahydroisoquinoline
DOB-CR (DOB-THIQ, 2C-B-CR)	5,8-Dimethoxy-7-bromo-1,2,3,4-tetrahydroisoquinoline
N-Methyl-DOM-CR (Beatrice-CR, N-methyl-2C-D-CR)	2,7-Dimethyl-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline
LPH-5	(S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine
DEMPDHPCA-2C-D ("compound 45")	1-Methyl-3-(1-oxo-1-diethylaminomethyl)-5-(2,5-dimethoxy-4-methylphenyl)-3,6-dihydro-2H-pyridine		[58]
2C-B-morpholine	2-(4-Bromo-2,5-dimethoxyphenyl)morpholine		[59][60]
2C-B-aminorex	5-(4-Bromo-2,5-dimethoxyphenyl)-4,5-dihydro-1,3-oxazol-2-amine
2C-B-PP	1-(2,5-Dimethoxy-4-bromophenyl)piperazine
2C-B-BZP	1-[(4-Bromo-2,5-dimethoxyphenyl)methyl]piperazine

See also

• 25-NB, 3C, DOx, 4C, FLY
• List of miscellaneous 5-HT2A receptor agonists
• The Shulgin Index
• Substituted amphetamines
• Substituted mescaline analogue
• Substituted methoxyphenethylamine
• Substituted methylenedioxyphenethylamines
• Substituted phenethylamines
• Substituted tryptamines