2C-H
2,5-dimethoxyphenethylamine
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2C-H (2,5-dimethoxyphenethylamine) is a synthetic psychedelic of the phenethylamine class. It is the unsubstituted parent scaffold of the 2C series, from which potent derivatives like 2C-B are built. 2C-H is a weak partial agonist at 5-HT₂A receptors, with binding affinity too low to produce meaningful psychoactive effects.[1][2]
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First synthesized in 1932 by Johannes Buck as part of a systematic exploration of mescaline analogues, 2C-H sat unexamined for decades.[3] Alexander Shulgin's 1991 PiHKAL described it as "probably inactive" yet celebrated it as the structural launchpad from which the pharmacologically active 2C family — 2C-B, 2C-I, 2C-E — was built.[2] In 2021, 2C-H gained independent research significance when it was identified as the minimal anti-inflammatory pharmacophore for 5-HT₂A receptor agonists.[4]
Subjective effects have not been established — no controlled human trial has characterized 2C-H's experiential properties by any route.[2] If psychoactive concentrations were achieved via non-oral routes, the compound's unusual receptor profile — strong 5-HT₁A preference over 5-HT₂A — would predict an experience qualitatively different from typical 2C psychedelics.[1] Rapid enzymatic breakdown by monoamine oxidase is the primary barrier to oral activity.[5]
2C-H is not expected to produce physical dependence, and no toxic dose or adverse event specific to the compound has been documented.[6] The primary pharmacological risk is its potent MAO-B inhibition, which could produce dangerous monoamine interactions if combined with serotonergic or dopaminergic substances.[5] Nearly every pharmacological parameter remains uncharacterized — the current understanding rests on in vitro data, structural analogy, and Shulgin's original assessment.
History[edit]
Discovery
2C-H was first synthesized in 1932 by Johannes Buck at Burroughs Wellcome as part of a systematic study of mescaline analogues.[3] The compound retained methoxy groups at the 2- and 5-positions of the phenyl ring while eliminating the substitution pattern that gives mescaline its psychoactive potency. Buck established the basic synthetic route from 2,5-dimethoxybenzaldehyde but did not investigate the compound's psychopharmacology.
The 2C series and Shulgin's legacy
2C-H received its most significant documentation as Compound #32 in Alexander and Ann Shulgin's 1991 PiHKAL.[2] Shulgin listed both dose and duration as "unknown" and described the compound as "probably inactive," yet recognized its structural importance — calling it "one of the most magnificent launching pads" for the substituted 2C compounds. His observation that "the 4-position is where the action is" framed 2C-H as the blank canvas from which 2C-B, 2C-I, 2C-E, and the rest of the series were derived.
Scheduling and modern research
2C-H was classified as Schedule I in the United States under the Synthetic Drug Abuse Prevention Act of 2012, and as Schedule III in Canada in 2016 — both actions targeting the 2C structural class broadly rather than 2C-H based on individual evidence of abuse.[7] The compound's independent pharmacological significance emerged in 2021, when Flanagan et al. identified the 2,5-dimethoxyphenethylamine scaffold as the minimal anti-inflammatory pharmacophore for 5-HT₂A receptor agonists in a rat model of allergic asthma[4] — the first published study to establish a role for 2C-H beyond its status as a synthetic intermediate.
The name "2C-H" follows Shulgin's nomenclature: "2C" denotes the two-carbon ethylamine chain linking the phenyl ring to the amine, and "H" indicates hydrogen at the 4-position — the absence of a substituent. A persistent source of confusion involves the abbreviation "DMPEA," which in the scientific literature almost universally refers to 3,4-dimethoxyphenethylamine — a positional isomer investigated in connection with the schizophrenia "pink spot" hypothesis[8] — rather than to 2C-H (the 2,5-isomer). The two compounds are structurally and pharmacologically distinct.
Chemistry[edit]
Structural class
2C-H belongs to the substituted phenethylamine family and is the parent compound of the 2C series. Its IUPAC name is 2-(2,5-dimethoxyphenyl)ethanamine. The molecule consists of a phenyl ring bearing methoxy groups at positions 2 and 5, connected to a two-carbon ethylamine chain. The 4-position — the site that determines psychedelic potency across the 2C family — carries no substituent, which accounts for the compound's pharmacological weakness relative to derivatives like 2C-B (4-bromo) and 2C-I (4-iodo).
| Molecular formula | C₁₀H₁₅NO₂ |
| Molecular weight | 181.23 g/mol |
Structure-activity relationships
The 2,5-dimethoxy motif is the pharmacologically necessary scaffold for all 2C compounds. Removal of either methoxy group modestly reduces receptor affinity in vitro but dramatically attenuates psychedelic activity in animal models, confirming that both groups contribute to receptor engagement geometry.[9] Potency across the series is driven primarily by the 4-position substituent — its steric bulk, electronic character, and lipophilicity determine binding strength at the 5-HT₂A receptor.
2C-H's empty 4-position makes it the weakest member of its family.
Stereochemistry and physical properties
2C-H is achiral — the ethylamine side chain carries no α-carbon substitution, unlike the amphetamine-derived DOx series where an α-methyl group creates distinct enantiomers. The free base is a colorless, viscous liquid that absorbs atmospheric carbon dioxide readily.[1] The hydrochloride salt melts at 138–139°C.[1]
No published solubility or stability data exist for either form.
Pharmacology[edit]
Mechanism of action
2C-H acts as a weak partial agonist at serotonin 5-HT₂A and 5-HT₂C receptors.[1] Its binding strength at 5-HT₂A is roughly 30- to 80-fold weaker than pharmacologically active 2C compounds such as 2C-B and 2C-I.[1][9] This weakness is consistent with the established principle that 4-position substitution drives potency in the 2C series — 2C-H has none.[9]
An unusual feature is 2C-H's relatively strong affinity for the 5-HT₁A receptor — the highest in the 2C series.[1] The selectivity ratio (approximately 23:1 for 5-HT₁A over 5-HT₂A) would predict calming or modulatory effects rather than psychedelic activity, if the compound reached the brain in sufficient concentration.
MAO-B inhibition
2C-H is the most potent MAO-B inhibitor among tested 2C compounds, with an IC₅₀ of 1.7 µM.[5] No significant MAO-A inhibition was detected.[5]
This selective MAO-B activity has two consequences: it explains 2C-H's oral inactivity — the unsubstituted 4-position leaves the terminal amine fully exposed to rapid enzymatic breakdown in the gut and liver before the compound can reach the bloodstream — and it introduces pharmacologically relevant monoamine interactions if the compound bypasses first-pass metabolism via non-oral routes.[5]
Anti-inflammatory pharmacophore
Flanagan et al. (2021) identified 2C-H as the minimal structural unit necessary for anti-inflammatory activity among 5-HT₂A agonists, using a rat model of allergic asthma.[4] The anti-inflammatory effects showed no correlation with the calcium signaling pathway or behavioral psychedelic potency, demonstrating that the anti-inflammatory and psychoactive properties of 5-HT₂A agonists operate through separable signaling mechanisms.[4]
A 2024 follow-up confirmed this functional selectivity by showing that structurally similar agonists produce divergent anti-inflammatory outcomes despite comparable receptor activation.[10]
Psychoactivity
No published human trials of 2C-H exist. Shulgin described both dose and duration as "unknown" in PiHKAL, annotating that the compound is "probably inactive" due to monoamine oxidase degradation.[2] The mechanistic basis is now confirmed: rapid MAO-B-mediated breakdown would prevent meaningful absorption via the oral route,[5] and the weak 5-HT₂A binding means that even if some compound reached the brain, receptor occupancy at any practical dose would be negligible.[1]
Pharmacokinetics
No human pharmacokinetic data for 2C-H have been published. Oral bioavailability is expected to be very low due to extensive first-pass MAO-B metabolism.[5] Non-oral routes (intranasal, intravenous) would bypass this degradation but have not been studied in humans.
The 2C series as a class undergoes liver metabolism primarily through O-demethylation and N-acetylation.[11] No metabolite studies specific to 2C-H exist. Key parameters — peak plasma time, half-life, and protein binding — remain entirely uncharacterized.
Neuroscience[edit]
Where it acts
No neuroimaging or electrophysiology data specific to 2C-H exist. Based on class pharmacology, 2C compounds produce psychedelic effects through 5-HT₂A activation on layer V neurons in the prefrontal cortex, disrupting the brain's normal filtering of sensory and cognitive information and destabilizing the default mode network.[6][12] Whether 2C-H can achieve sufficient receptor occupancy to trigger these network-level changes at any dose or route remains unknown.
2C-H's unusual 5-HT₁A preference introduces a theoretical wrinkle: if it reached the brain via a non-oral route, its pharmacological signature might favor 5-HT₁A-mediated calming over 5-HT₂A-mediated perceptual disruption — a qualitatively different profile from typical 2C psychedelics.[1]
Why it matters
2C-H exemplifies biased agonism at the 5-HT₂A receptor — the principle that different agonists stabilize different receptor conformations, activating distinct downstream signaling cascades.[4][13] Its anti-inflammatory activity dissociates cleanly from both the calcium signaling pathway and psychedelic behavioral output, suggesting the 2,5-dimethoxyphenethylamine scaffold preferentially engages an anti-inflammatory conformation while inadequately activating the one responsible for psychedelic effects.
If these pathways can be structurally dissected, 2C-H derivatives could yield non-psychedelic anti-inflammatory therapeutics — a direct translational application of the biased agonism framework.
- Can non-oral administration bypass MAO-B degradation sufficiently to achieve meaningful brain concentrations, and would the resulting experience be 5-HT₁A-dominant?
- What is the precise molecular mechanism by which the 2,5-dimethoxyphenethylamine scaffold confers anti-inflammatory activity?
- Does 2C-H promote neuroplasticity at any dose, and if so, through which signaling pathways?
Subjective Effects[edit]
2C-H has no established subjective effect profile. Shulgin described it as "probably inactive" via the oral route, and no controlled human study has characterized its experiential properties by any route. Effect data sometimes attributed to 2C-H — color enhancement, stimulation, cognitive euphoria — are extrapolated from the broader 2C class and do not reflect substance-specific evidence. If psychoactive concentrations were achieved through non-oral routes, the compound's strong 5-HT₁A preference over 5-HT₂A would predict a qualitatively different experience from typical 2C psychedelics.
2C-H occupies the inactive extreme of the 2C series — the pharmacological inverse of 2C-B or 2C-I, which produce robust psychedelic effects at oral doses of 10–25 mg. Where those compounds demonstrate strong serotonin receptor binding and resist enzymatic breakdown, 2C-H combines the weakest receptor affinity in its class with the highest vulnerability to MAO-B degradation, placing it closer to endogenous trace amines than to recreational psychedelics.
Effect Grid
No common dose range has been established for 2C-H. Unlike its derivatives 2C-B (common dose 15–25 mg oral) and 2C-I (common dose 14–22 mg oral), 2C-H lacks the 4-position substituent that confers both receptor potency and metabolic stability to the 2C series.
The concept of a "common dose" is not applicable to a compound with no established psychoactivity. All subjective effect data conventionally associated with 2C-H are extrapolated from active 2C-class members and do not reflect substance-specific evidence.
Modeled from the effect's dose-dependence curve — not per-substance measurements.
Restlessness · Wakefulness · Excessive sweating · Appetite suppression · Heart rate perception changes · Muscle tension · Nausea · Vasoconstriction · Spontaneous body sensations
Appetite suppression · Heart rate perception changes · Muscle tension · Nausea · Spontaneous body sensations
Timeline
No onset has been characterized. 2C-H is believed to be orally inactive due to rapid MAO-B first-pass metabolism. Shulgin listed duration as 'unknown' in PiHKAL.
No peak effects have been documented. The compound's weak 5-HT₂A affinity (Ki 1,600 nM) and MAO-B vulnerability preclude meaningful psychoactive response at oral doses.
No afterglow period has been characterized. No subjective effects timeline exists for 2C-H by any route.
⚠ Do not drive or operate machinery after ingesting any uncharacterized research chemical.
Safety[edit]
- Acute toxicity
- Negligible
- Chronic toxicity
- No data
- Withdrawal
- None
- Tolerance buildup
- rapid
- Tolerance reset
- 8.5 days
- Physical
- None
- Psychological
- None
- Compulsive redosing
- Negligible
- Dose escalation
- Negligible
- Cross-tol.
- psychedelic 5-HT₂A agonists
Toxicity
No LD₅₀ data, no controlled toxicity studies, and no case reports of adverse events specific to 2C-H exist.[6] The toxic dose is unknown. The compound's very weak serotonin receptor binding and probable oral inactivity suggest lower acute toxicity risk than pharmacologically active 2C compounds, but this has not been verified.
Class-level toxicity
For the 2C series as a class, toxic effects include agitation, aggression, high blood pressure, rapid heart rate, seizures, dangerously elevated body temperature, serotonin syndrome, and stimulant-like toxicity syndrome.[6] At least five deaths have been attributed to active 2C-series members (2C-E, 2C-I, 2C-B) — none involving 2C-H specifically.[6]
MAO-B-related toxicity
2C-H's potent MAO-B inhibition (IC₅₀ = 1.7 µM) introduces a toxicity risk independent of its serotonergic activity.[5] If administered by non-oral routes that bypass first-pass metabolism, systemic 2C-H could elevate dopamine and phenethylamine levels through MAO-B inhibition. Combined with even weak serotonergic activity, this dual mechanism creates interaction-mediated risks not present with most other 2C compounds.
Neurotoxicity
Cell-based studies have observed mitochondrial dysfunction and oxidative stress for 2C-T subclass compounds within the broader 2,5-dimethoxyphenethylamine family.[14] Whether the thioether substituents unique to 2C-T compounds drive this profile — or whether the shared 2C-H scaffold contributes independently — is unknown.
Psychological risks
No psychological adverse events specific to 2C-H have been documented. Given the compound's probable oral inactivity, the acute psychological risks associated with other 2C compounds — anxiety, panic, psychotic episodes, HPPD (HPPD) — are unlikely at oral doses.
If psychoactive concentrations were achieved via non-oral routes, class-level psychological risks would theoretically apply, but no data exist to characterize this scenario. inferred
Tolerance and dependence
No substance-specific tolerance or dependence data for 2C-H exist. Psychedelic serotonin 2A receptor agonists as a class produce rapid tolerance through downregulation, observable within 24 hours of a single dose.[15] Cross-tolerance occurs between psychedelic 5-HT₂A agonists but not with non-psychedelic agonists.[15]
2C-H is not expected to be habit-forming.[6] No reinforcement potential, compulsive redosing, or withdrawal syndromes have been reported or would be predicted.
Drug interactions
The interaction profile of 2C-H is shaped by its dual pharmacology: weak serotonin receptor activation combined with potent MAO-B inhibition. This combination creates interaction risks distinct from those of other 2C compounds.
Tramadol
The combination of 2C-H with tramadol is classified as dangerous. Tramadol increases serotonin levels through reuptake inhibitor and stimulation of serotonin release.[16][17] 2C-H compounds this risk through both weak serotonin receptor activation and potent MAO-B inhibition.[5] The monoamine oxidase inhibitor–tramadol combination is specifically identified as contraindicated in the pain management literature due to serotonin syndrome risk.[16]
safety citation needed No published case reports document the specific 2C-H + tramadol combination. The dangerous classification derives from mechanistic reasoning.
MAO inhibitors
2C-H's own MAO-B inhibitory activity creates a significant interaction with external MAO inhibitors.[5] Concurrent use could produce additive MAO inhibition with dangerously elevated monoamine levels.
A paradoxical activation risk also exists: MAO inhibitors could increase 2C-H's oral bioavailability by preventing the first-pass degradation that normally renders it inactive — potentially converting an inert oral dose into a psychoactive one. safety citation needed
Cannabis
No published data on the 2C-H–cannabis interaction exist. The interaction is classified as unknown.
Stimulants
Class-level concern exists for cardiovascular strain and serotonergic potentiation between 2C compounds and stimulants. 2C-H's MAO-B inhibition could theoretically potentiate stimulant effects by slowing dopamine breakdown, but this has not been studied. inferred
Contraindications
No substance-specific contraindication data for 2C-H exist. The following are inferred from the compound's pharmacological profile and class membership. inferred
- Concurrent MAO inhibitor use (absolute): 2C-H's own MAO-B activity creates risk of additive monoamine oxidase inhibition and potential serotonin syndrome.
- Concurrent tramadol use (absolute): dual serotonergic mechanism creates serotonin syndrome risk identified as contraindicated in clinical literature.
- History of serotonin syndrome (relative): any serotonergic compound may lower the threshold for recurrence.
- Heart conditions (relative, class-extrapolated): 2C compounds can produce elevated blood pressure and rapid heart rate, though 2C-H's weak activity makes this unlikely at oral doses.
- Seizure disorders (relative, class-extrapolated): 2C compounds have been associated with seizures in acute toxicity; relevance to 2C-H is unclear.
- Severe psychiatric disorders (relative, class-extrapolated): psychotic spectrum disorders and conditions worsened by serotonergic perturbation are standard contraindications for the 2C class.
Harm Reduction[edit]
Forms & Identification
2C-H is encountered almost exclusively in laboratory and research chemical contexts — it has no established recreational use pattern and no recognized active dose. The primary identification risk is confusion with pharmacologically active 2C-series compounds. Because 2C-H shares the same base scaffold as 2C-B, 2C-I, and 2C-E, mislabeled or contaminated material could deliver a potent psychedelic at doses assumed to be inert.
Reagent testing cannot reliably distinguish 2C-H from all 2C-series members; any material obtained outside regulated supply should be treated as unverified.
Guidelines
- Test all material. Reagent kits and, ideally, laboratory analysis (e.g., FTIR or GC-MS through drug checking services) are the only way to verify identity and rule out contamination with active 2C analogues.
- Do not assume inactivity. While 2C-H is considered orally inactive, material sold under this name may not be 2C-H. Treat any unverified powder as potentially active.
- Avoid combining with MAO inhibitors. 2C-H's potent MAO-B inhibition means co-administration with MAOIs could produce unpredictable monoamine elevation or even activate the compound itself.
- Start with the smallest possible amount if self-administration is undertaken despite the absence of established dosing. No safe dose has been determined.
- Have a sober companion present for any exposure scenario involving an uncharacterized substance.
Set & Setting
Because 2C-H has no established psychoactive dose or confirmed subjective effects, conventional set-and-setting guidance does not apply in the usual sense. If exposure occurs — whether intentional or through mislabeled material — the standard principles hold: a calm, familiar environment with a sober companion reduces risk from unexpected effects.
The compound's unknown pharmacological profile at any achievable dose means there is no reliable basis for predicting what the experience would involve.
Aftercare & integration. If unexpected psychoactive effects occur following exposure to material labeled as 2C-H, standard psychedelic aftercare applies. Rest, hydration, and light nutrition support physical recovery. A quiet environment without demanding tasks or social obligations is appropriate for 24–48 hours following any psychoactive experience.
If distressing psychological effects persist beyond 48 hours — anxiety, perceptual disturbances, depersonalization — professional consultation is warranted. A therapist experienced with substance-related distress can help contextualize the experience. Journaling the timeline of effects, including onset, peak, and resolution, provides useful information for any future clinical encounter.
Recovery & Support
2C-H is not expected to produce dependence or compulsive use patterns. If problematic use of 2C-series compounds or research chemicals more broadly is a concern, the following resources offer support:
- SAMHSA National Helpline (US): 1-800-662-4357 — free, confidential, 24/7 referral service
- Talk to Frank (UK): 0300 123 6600
- Global Drug Survey — anonymous self-assessment tools for substance use patterns
- Local harm reduction organizations often provide non-judgmental support and referrals regardless of the specific substance involved
Recovery resources, crisis lines, and support pathways → View all
Emergency Response
Because 2C-H has no established effect profile, any unexpected reaction after ingestion of material believed to be 2C-H should be treated as a potential medical emergency — the substance may be mislabeled.
Recognizing an emergency:
- Rapid heart rate, chest pain, or difficulty breathing
- Seizures or loss of consciousness
- Severe agitation, confusion, or inability to communicate
- Body temperature that feels elevated through clothing
- Signs of serotonin syndrome: muscle rigidity, rapid eye movements, extreme agitation, high fever
Immediate steps:
- Call emergency services immediately if any of the above are present.
- Place an unconscious person in the recovery position (on their side, airway clear).
- Do not induce vomiting.
- Do not restrain a conscious person unless they are in immediate physical danger.
- Keep the environment quiet and reduce stimulation.
What to tell the dispatcher:
- What was taken (or what it was sold as), how much, and when
- Current symptoms
- Any other substances consumed
- Good Samaritan laws in many jurisdictions protect callers from prosecution for drug-related offenses
Legal Status[edit]
2C-H is controlled in multiple jurisdictions under provisions targeting the 2C phenethylamine structural class rather than evidence of 2C-H-specific harm or abuse. Its scheduling reflects blanket regulatory control applied to structural families following the emergence of pharmacologically active members — principally 2C-B and 2C-I — as substances of misuse.
| Jurisdiction | Classification | Key provisions |
|---|---|---|
| United States | Schedule I (Controlled Substances Act) | Classified under the Synthetic Drug Abuse Prevention Act of 2012, effective July 9, 2012[7] |
| United Kingdom | Class A (Misuse of Drugs Act 1971) | Covered under catch-all phenethylamine provisions; also subject to the Psychoactive Substances Act 2016[7] |
| Canada | Schedule III (CDSA) | Scheduled October 31, 2016 under the Controlled Drugs and Substances Act[7] |
| Germany | Anlage I (BtMG) | Controlled under the Narcotics Act; 2C-x class covered[7] |
| Australia | Likely Schedule 9 (prohibited) | Blanket coverage of substituted phenethylamines; explicit 2C-H entry not confirmed in SUSMPcitation needed |
Analogue act considerations
In jurisdictions with structural analog legislation, 2C-H's status as a directly scheduled substance renders analogue prosecution unnecessary. Its classification despite probable pharmacological inactivity illustrates the regulatory approach of structural-class scheduling, where legal status derives from molecular similarity to active compounds rather than from demonstrated risk of the individual substance.
references
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