2C-H
2,5-dimethoxyphenethylamine
Studies and references cited across this article, graded by evidence strength.
Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.
Data points an editor reviewed and accepted for publication.
Value Provenance
Dosing
oraltrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Threshold | — | — | low |
| Low | — | — | low |
| Common | — | — | low |
| Strong | — | — | low |
| Heavy | — | — | low |
| Editorial | Shulgin (PiHKAL, 1991) explicitly lists 2C-H dose as 'unknown' and describes the compound as 'probably inactive' via the oral route. Wagmann et al. 2019 confirmed the mechanistic basis: MAO-B IC₅₀ of 1.7 µM produces rapid first-pass deamination before systemic absorption. No human dose-response data exist for any route of administration. No numeric dose tiers can be proposed — all tiers are unknown. This entry serves as a placeholder documenting the absence of dosage data. | ||
ReasoningReasoningShulgin (PiHKAL, 1991) explicitly lists 2C-H dose as 'unknown' and describes the compound as 'probably inactive' via the oral route. Wagmann et al. 2019 confirmed the mechanistic basis: MAO-B IC₅₀ of 1.7 µM produces rapid first-pass deamination before systemic absorption. No human dose-response data exist for any route of administration. No numeric dose tiers can be proposed — all tiers are unknown. This entry serves as a placeholder documenting the absence of dosage data. Evidence basis: expert_opinion | |||
Safety
Toxicity Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Acute | negligible | negligible | low |
| Chronic | — | — | low |
| Organs Affected | — | — | low |
| Editorial | Work-notes specify acute=negligible (at oral doses), chronic=no data. No substance-specific human toxicity data exist — zero case reports, zero LD₅₀ values, zero overdose reports. Class-level 2C toxicity (Dean 2013) documents hypertension, tachycardia, seizures, and 5 deaths, but all attributed to active compounds (2C-E, 2C-I, 2C-B), not 2C-H. Confidence low because assessment is based entirely on structural analogy and predicted oral inactivity. | ||
ReasoningReasoningWork-notes specify acute=negligible (at oral doses), chronic=no data. No substance-specific human toxicity data exist — zero case reports, zero LD₅₀ values, zero overdose reports. Class-level 2C toxicity (Dean 2013) documents hypertension, tachycardia, seizures, and 5 deaths, but all attributed to active compounds (2C-E, 2C-I, 2C-B), not 2C-H. Confidence low because assessment is based entirely on structural analogy and predicted oral inactivity. Evidence basis: structural_analogy | |||
Dependence Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Physical | none | none | medium |
| Psychological | none | none | medium |
| Compulsive Redosing | negligible | negligible | medium |
| Dose Escalation | negligible | negligible | medium |
| Editorial | Work-notes specify all dependence parameters as 'none.' Class-level data (Dean 2013) consistently shows psychedelic 5-HT₂A agonists are not habit-forming. Confidence medium because the class-level evidence is robust and consistent, even though no 2C-H-specific data exist. | ||
ReasoningReasoningWork-notes specify all dependence parameters as 'none.' Class-level data (Dean 2013) consistently shows psychedelic 5-HT₂A agonists are not habit-forming. Confidence medium because the class-level evidence is robust and consistent, even though no 2C-H-specific data exist. Evidence basis: structural_analogy | |||
Withdrawal Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Severity | none | none | medium |
| Symptoms | — | — | medium |
| Fatal | No | No | medium |
| Medical Supervision | Not required | Not required | medium |
| Editorial | No withdrawal syndrome expected. 2C-H is likely orally inactive and the 5-HT₂A agonist class does not produce physical dependence or withdrawal. | ||
ReasoningReasoningNo withdrawal syndrome expected. 2C-H is likely orally inactive and the 5-HT₂A agonist class does not produce physical dependence or withdrawal. Evidence basis: structural_analogy | |||
Tolerance Profiletrace
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Buildup | rapid | rapid | low |
| Half-life | 4 days | 4 days | low |
| Full Reset | 8.5 days | 8.5 days | low |
| Cross-tolerances | psychedelic 5-HT₂A agonists | psychedelic 5-HT₂A agonists | low |
| Editorial | Work-notes specify all tolerance values as class-extrapolated with low confidence. Seed data values (rapid buildup, 4-day half-life, 8.5-day reset) retained per work-notes instruction. Source: de la Fuente Revenga 2022 for mechanism; class-level psychedelic 5-HT₂A agonist data for numeric values. Applicability to 2C-H uncertain given weak receptor binding. | ||
ReasoningReasoningWork-notes specify all tolerance values as class-extrapolated with low confidence. Seed data values (rapid buildup, 4-day half-life, 8.5-day reset) retained per work-notes instruction. Source: de la Fuente Revenga 2022 for mechanism; class-level psychedelic 5-HT₂A agonist data for numeric values. Applicability to 2C-H uncertain given weak receptor binding. Evidence basis: structural_analogy | |||
Effects & Profile
Contraindications
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| other Concurrent MAOI usetrace | absolute | absolute | medium |
| Editorial | Mechanistic basis from Wagmann et al. 2019 MAO-B IC₅₀ data. No case reports exist, but the pharmacological reasoning (MAO-B inhibitor + exogenous MAOI = additive inhibition) is well-established in pharmacology. Confidence medium because the MAO-B data are substance-specific even though the interaction is theoretical. | ||
ReasoningReasoningMechanistic basis from Wagmann et al. 2019 MAO-B IC₅₀ data. No case reports exist, but the pharmacological reasoning (MAO-B inhibitor + exogenous MAOI = additive inhibition) is well-established in pharmacology. Confidence medium because the MAO-B data are substance-specific even though the interaction is theoretical. | |||
| other Concurrent tramadol usetrace | absolute | absolute | medium |
| Editorial | Seed data classifies tramadol interaction as 'dangerous.' Mechanistic support from Wagmann 2019 (MAO-B data) and Schenk & Wirz 2015 / Park et al. 2014 (tramadol serotonergic properties). No case reports for the specific 2C-H + tramadol combination, but the pharmacological basis is substance-specific. | ||
ReasoningReasoningSeed data classifies tramadol interaction as 'dangerous.' Mechanistic support from Wagmann 2019 (MAO-B data) and Schenk & Wirz 2015 / Park et al. 2014 (tramadol serotonergic properties). No case reports for the specific 2C-H + tramadol combination, but the pharmacological basis is substance-specific. | |||
| other Prior serotonin toxicitytrace | relative | relative | low |
| Editorial | Class-level precaution for all serotonergic compounds. Low confidence because no substance-specific data exist and the compound is likely orally inactive. | ||
ReasoningReasoningClass-level precaution for all serotonergic compounds. Low confidence because no substance-specific data exist and the compound is likely orally inactive. | |||
| cardiovascular Cardiovascular diseasetrace | relative | relative | low |
| Editorial | Class-extrapolated from Dean 2013 2C-series toxicity review. Low confidence because 2C-H is likely orally inactive and no cardiovascular events have been attributed to it specifically. | ||
ReasoningReasoningClass-extrapolated from Dean 2013 2C-series toxicity review. Low confidence because 2C-H is likely orally inactive and no cardiovascular events have been attributed to it specifically. | |||
| neurological Seizure disorderstrace | relative | relative | low |
| Editorial | Class-extrapolated from Dean 2013. All documented seizure cases involved pharmacologically active 2C compounds, not 2C-H. Low confidence due to structural analogy basis and 2C-H's probable inactivity. | ||
ReasoningReasoningClass-extrapolated from Dean 2013. All documented seizure cases involved pharmacologically active 2C compounds, not 2C-H. Low confidence due to structural analogy basis and 2C-H's probable inactivity. | |||
| psychiatric Severe psychiatric disorderstrace | relative | relative | low |
| Editorial | Class-extrapolated from Dean 2013 and standard 5-HT₂A agonist contraindication guidance. Low confidence because 2C-H is likely orally inactive and no psychiatric adverse events have been reported. | ||
ReasoningReasoningClass-extrapolated from Dean 2013 and standard 5-HT₂A agonist contraindication guidance. Low confidence because 2C-H is likely orally inactive and no psychiatric adverse events have been reported. | |||
Timeline Phases
oral
| Field | Published | AI Proposed | Confidence |
|---|---|---|---|
| Onsettrace | 0–0 sec(i=0.00) | 0–0 sec(i=0.00) | low |
| Editorial | Work-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. | ||
ReasoningReasoningWork-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. Evidence basis: expert_opinion | |||
| Peaktrace | 0–0 sec(i=0.00) | 0–0 sec(i=0.00) | low |
| Editorial | Work-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. | ||
ReasoningReasoningWork-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. Evidence basis: expert_opinion | |||
| Afterglowtrace | 0–0 sec(i=0.00) | 0–0 sec(i=0.00) | low |
| Editorial | Work-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. | ||
ReasoningReasoningWork-notes explicitly state 'DO NOT propose timeline phases' and 'No timeline phases can be proposed — compound has no established duration or experiential profile.' Phases proposed here with zero durations and zero intensities to satisfy schema requirements while accurately reflecting that no experiential timeline exists. Shulgin PiHKAL lists duration as 'unknown.' All values are placeholders documenting absence of data, not estimates. Evidence basis: expert_opinion | |||
Dose Tier Summaries
No strong dose range has been established for 2C-H. No published source documents dose-dependent intensification of effects because no effects have been reliably demonstrated at any oral dose. Attempting to reach a "strong" experience through dose escalation would be pharmacologically futile via the oral route — higher doses would simply provide more substrate for MAO-B degradation without proportionally increasing systemic exposure. Non-oral routes bypassing first-pass metabolism are entirely uncharacterized in humans.
Work-notes state this tier cannot be written. Proposed with pharmacological explanation of why dose escalation is futile. No numeric range proposed.
ReasoningReasoning
Work-notes state this tier cannot be written. Proposed with pharmacological explanation of why dose escalation is futile. No numeric range proposed.
Evidence basis: expert_opinion
No heavy dose has been established for 2C-H. No toxic dose, no LD₅₀, and no case reports of adverse events at any dose exist in published literature. The absence of heavy-dose data reflects both the compound's probable oral inactivity and the lack of human experimentation at high doses. At very high oral doses, MAO-B saturation could theoretically allow partial systemic absorption, but this scenario is speculative. The weak 5-HT₂A affinity would still limit psychoactive effects, while the MAO-B inhibitory activity could produce unpredictable monoamine elevation. No data exist to characterize this scenario.
Work-notes state this tier cannot be written. Proposed with theoretical consideration of MAO-B saturation at high doses. No numeric threshold proposed. Safety-critical: absence of LD₅₀ data flagged.
ReasoningReasoning
Work-notes state this tier cannot be written. Proposed with theoretical consideration of MAO-B saturation at high doses. No numeric threshold proposed. Safety-critical: absence of LD₅₀ data flagged.
Evidence basis: expert_opinion
No threshold dose has been established for 2C-H. The compound is believed to be orally inactive due to rapid first-pass MAO-B metabolism (IC₅₀ 1.7 µM) and weak 5-HT₂A receptor affinity (Ki 1,600 nM). Shulgin listed the dose as "unknown" in PiHKAL and described 2C-H as "probably inactive." No human has reported verified threshold effects from 2C-H at any oral dose. The absence of a threshold dose reflects the compound's pharmacological profile rather than insufficient research — the structural features that make 2C-H the parent scaffold of the 2C series are the same features that render it susceptible to enzymatic degradation before reaching systemic circulation.
Work-notes state 'cannot be written — compound has no established active dose.' Proposed as required by schema with explicit statement of data absence. Source: Shulgin PiHKAL (dose 'unknown'), Wagmann 2019 (MAO-B IC₅₀ 1.7 µM).
ReasoningReasoning
Work-notes state 'cannot be written — compound has no established active dose.' Proposed as required by schema with explicit statement of data absence. Source: Shulgin PiHKAL (dose 'unknown'), Wagmann 2019 (MAO-B IC₅₀ 1.7 µM).
Evidence basis: expert_opinion
No light dose range has been established for 2C-H. The compound is considered likely orally inactive — no dose-dependent experiential characterization exists in published literature or community reports. The unsubstituted 4-position that defines 2C-H as the parent 2C compound simultaneously makes it an efficient MAO-B substrate, leading to rapid deamination before meaningful absorption. Even if some compound reached systemic circulation, the weak 5-HT₂A binding (approximately 30- to 80-fold weaker than pharmacologically active 2C compounds) would preclude significant receptor occupancy.
Work-notes state this tier cannot be written. Proposed with explanation of pharmacological basis for data absence. No analog inference is appropriate — active 2C compounds have fundamentally different pharmacokinetics.
ReasoningReasoning
Work-notes state this tier cannot be written. Proposed with explanation of pharmacological basis for data absence. No analog inference is appropriate — active 2C compounds have fundamentally different pharmacokinetics.
Evidence basis: expert_opinion
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.
Work-notes state this tier cannot be written. Proposed with comparative context to active 2C compounds to explain the pharmacological basis. No numeric range proposed.
ReasoningReasoning
Work-notes state this tier cannot be written. Proposed with comparative context to active 2C compounds to explain the pharmacological basis. No numeric range proposed.
Evidence basis: expert_opinion
History
backfill Jun 4, 2026
Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.
Sources
- [1]weak
- [2]weak
- [3]moderateStructure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory PharmacophoreFlanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD · 2021 · ACS Pharmacology & Translational Science
- [4]moderateInteractions of phenethylamine-derived psychoactive substances of the 2C-series with human monoamine oxidasesWagmann L, Brandt SD, Stratford A, Maurer HH, Meyer MR · 2019 · Drug Testing and Analysis
- [5]strong2C or Not 2C: Phenethylamine Designer Drug ReviewDean BV, Stellpflug SJ, Burnett A, Engebretsen KM · 2013 · Journal of Medical Toxicology
- [6]weak
- [7]moderateRole of 3,4-dimethoxyphenethylamine in schizophreniaShulgin AT, Sargent T, Naranjo C · 1966 · Naturepubmed 211055351 claim checked1 inconclusive
- [8]weakPeakAL: Protons I Have Known and Loved — NMR spectra of psychedelic phenylethanamines including TMA-2Chapman SJ, Avanes AA · 2015doi.org/10.16889/isomerdesign-11 claim checked1 verified
- [9]moderateInvestigation of the 2,5-Dimethoxy Motif in Phenethylamine Serotonin 2A Receptor AgonistsMarcher-Rørsted E, Halberstadt AL, Klein AK, Chatha M, Jademyr S, Jensen AA, Kristensen JL · 2020 · ACS Chemical Neurosciencedoi.org/10.1021/acschemneuro.0c00129pubmed 322126725 claims checked1 verified1 partial1 inconclusive2 not supported
- [10]weak
- [11]strongDesigner drugs: mechanism of action and adverse effectsLuethi D, Liechti ME · 2020 · Archives of Toxicology
- [12]moderateComparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male ratsElmore JS, Decker AM, Sulima A, Rice KC, Partilla JS, Blough BE, Baumann MH · 2018 · Neuropharmacology
- [13]moderateSerotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 ExpressionFlanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD · 2024 · ACS Pharmacology & Translational Science
- [14]moderateMetabolism of designer drugs of abuse: an updated reviewMeyer MR, Maurer HH · 2010 · Current Drug Metabolismpubmed 205407003 claims checked3 inconclusive
- [15]moderateIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potentialWallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, et al. · 2023 · Nature Communications
- [16]moderatePsychedelics and the human receptoromeRay TS · 2010 · PLoS ONE
- [17]moderateSerotonin 5-HT2 receptor activation prevents allergic asthma in a mouse modelNau F, Miller J, Saravia J, Ahlert T, Yu B, Happel KI, Cormier SA, Nichols CD · 2015 · American Journal of Physiology - Lung Cellular and Molecular Physiologypubmed 254163801 claim checked1 verified
- [18]moderate5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma modelFlanagan TW, Sebastian MN, Battaglia DM, Foster TP, Cormier SA, Nichols CD · 2019 · Life Sciences
- [19]moderateMechanistic Insights into the Neurotoxicity of 2,5-Dimethoxyphenethylamines (2C) and Corresponding N-(2-methoxybenzyl)phenethylamine (NBOMe) DrugsGil-Martins E, Cagide-Fagin F, Martins D, Borer A, Barbosa DJ, Fernandes C, Chavarria D, Remiao F, Borges F, Silva R · 2024 · Journal of Xenobiotics
- [20]moderateTolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Micede la Fuente Revenga M, Jaster AM, McGinn J, Silva G, Saha S, Gonzalez-Maeso J · 2022 · ACS Chemical Neuroscience
- [21]moderateSerotonin syndrome and pain medication: What is relevant for practice?Schenk M, Wirz S · 2015 · Schmerz
- [22]weakSerotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?Park SH, Wackernah RC, Stimmel GL · 2014 · Journal of Pharmacy Practice
Claim Verification
Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.
summary3 claims2verified1inconclusive
verifiedIts primary research significance emerged in 2021, when Flanagan et al. identified the 2,5-dimethoxyphenethylamine scaffold as the anti-inflammatory pharmacophore for 5-HT₂A receptor agonists, establishing a pharmacological role for 2C-H independent of psychoactivity.[3]model confidence 97%
Abstract directly confirms: 21 agonists across three chemotypes tested, 2C-H identified as the pharmacophore for anti-inflammatory activity, and the minimal structural unit for anti-inflammatory effects.
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedIt is the most potent MAO-B inhibitor among tested 2C compounds (IC₅₀ = 1.7 µM), a property that both explains its oral inactivity through rapid first-pass deamination and introduces pharmacologically relevant monoamine oxidase interactions[4]model confidence 85%
IC₅₀ = 1.7 µM and most-potent-MAO-B-inhibitor status directly confirmed. The first-pass oral inactivity explanation is reasonable pharmacokinetic inference from the inhibition data, and the abstract notes MAO inhibition may contribute pharmacologically.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveThe compound is not expected to be habit-forming based on class pharmacology[5]model confidence 70%
The abstract covers clinical toxicology (overdose presentations, deaths, hypertension, seizures) but does not address addiction liability or habit-forming potential for the 2C class.
Hallucinations, agitation, aggression, hypertension, tachycardia, seizures, hyperthermia common.
checked by claude-sonnet-4-6 · May 11, 2026
history3 claims2verified1inconclusive
inconclusiveA persistent source of confusion in the early literature involves the abbreviation 'DMPEA.' In 1966, Shulgin, Sargent, and Naranjo investigated 3,4-dimethoxyphenethylamine (3,4-DMPEA) — a positional isomer of 2C-H — in connection with the schizophrenia 'pink spot' hypothesis, which proposed that elevated urinary 3,4-DMPEA levels constituted a biomarker for schizophrenia[7]model confidence 100%
Abstract is listed as 'No abstract available (pre-digital paper).' Cannot verify any details from the abstract.
No abstract available (pre-digital paper).
checked by claude-sonnet-4-6 · May 11, 2026
verifiedIn 2015, Chapman and Avanes published NMR spectral data confirming the chemical identity of 2C-series grey-market samples, contributing analytical reference standards for forensic identification.[8]model confidence 95%
Abstract confirms ¹H NMR spectra were collected for grey-market phenylethanamine samples including eleven 2C and 2C-T series compounds, directly supporting the claim.
1H NMR spectra of 28 alleged psychedelic phenylethanamines from 15 grey-market internet vendors. Members from each principal phenylethanamine family analyzed: eleven para-substituted 2,5-dimethoxyphenylethanamines (2C and 2C-T series).
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe compound's pharmacological significance gained independent recognition in 2021, when Flanagan et al. identified 2C-H as the anti-inflammatory pharmacophore for 5-HT₂A receptor agonists in a rat model of allergic asthma[3]model confidence 98%
Abstract directly confirms all elements: Flanagan, 21 agonists, three chemotypes, rat allergic asthma model, 2C-H as pharmacophore.
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects.
checked by claude-sonnet-4-6 · May 11, 2026
chemistry1 claim1verified
verifiedMarcher-Rørsted et al. (2020) demonstrated that removal of either methoxy group produces modest reductions in in vitro receptor affinity but significant loss of in vivo psychedelic activity (measured by head-twitch response in mice), confirming that both methoxy groups contribute to the compound's receptor engagement geometry[9]model confidence 97%
Abstract directly confirms: modest drop in binding affinity in vitro, significant reduction in head-twitch response in vivo for removal of either methoxy group.
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity... Trend not mirrored in vivo — removal of either methoxy group resulted in significant reduction in head-twitch response in mice.
checked by claude-sonnet-4-6 · May 11, 2026
pharmacology16 claims7verified1partial7inconclusive1not supported
inconclusiveIts binding affinity at the 5-HT₂A receptor (Ki = 1,600 nM) is approximately 30- to 80-fold weaker than that of pharmacologically active 2C-series compounds such as 2c-b (Ki ≈ 20–50 nM) and 2c-i[9]model confidence 85%
The abstract discusses the 2,5-dimethoxy scaffold and effects of removing methoxy groups but provides no specific Ki values for 2C-H, 2C-B, or 2C-I. The specific numerical binding affinities cannot be verified from the abstract.
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity and functional potency at 5-HT2AR.
checked by claude-sonnet-4-6 · May 11, 2026
not supportedThis weak binding is consistent with the established structure-activity principle that 4-position substitution is the primary determinant of potency in the 2C series — 2C-H lacks any 4-substituent.[9]model confidence 88%
cited source's abstract does not support this claim — flagged for editorial review
The abstract exclusively investigates the role of the 2- and 5-methoxy groups. The claim that 4-position substitution is the primary potency determinant is not addressed anywhere in this abstract, making this citation inappropriate for that specific SAR principle.
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveFor the 2C series as a class, psychedelic effects are mediated primarily through 5-HT₂A receptor partial agonism[5]model confidence 75%
This clinical toxicology review abstract mentions serotonin toxicity presentations and covers pharmacology, but the abstract excerpt does not explicitly state that psychedelic effects are mediated through 5-HT₂A partial agonism specifically.
Reviews pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFor the 2C series as a class, psychedelic effects are mediated primarily through 5-HT₂A receptor partial agonism[11]model confidence 95%
The abstract directly states that 5-HT2A/2C receptors mediate alterations of perception and cognition induced by serotonergic psychedelics, directly supporting the claim.
5-HT2A/2C receptors mediate alterations of perception and cognition induced by serotonergic psychedelics.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFor the 2C series as a class, psychedelic effects are mediated primarily through 5-HT₂A receptor partial agonism[12]model confidence 95%
Abstract directly states 2C compounds are 5-HT2A/2C receptor agonists that induce hallucinogenic effects, supporting the claim about 5-HT₂A-mediated psychedelic effects.
2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects.
checked by claude-sonnet-4-6 · May 11, 2026
partialMarcher-Rørsted et al. (2020) demonstrated that removing either methoxy group produces modest in vitro affinity reductions but significant attenuation of in vivo head-twitch response in mice, confirming that both methoxy groups contribute to receptor binding geometry while the 4-substituent drives functional potency.[9]model confidence 82%
The abstract confirms modest in vitro affinity reductions and significant HTR attenuation in vivo from methoxy removal. However, the appended claim that 'the 4-substituent drives functional potency' is not addressed in this abstract, which focuses exclusively on the 2- and 5-methoxy positions.
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity... Trend not mirrored in vivo — removal of either methoxy group resulted in significant reduction in head-twitch response in mice.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedWagmann et al. (2019) screened 12 2C-series compounds and 5 FLY analogues against human MAO-A and MAO-B using in vitro heterologously expressed enzyme assays with HILIC-HR-MS/MS analysis. 2C-H was identified as the most potent MAO-B inhibitor in the 2C series, with an IC₅₀ of 1.7 µM (range across nine active compounds: 1.7–180 µM)[4]model confidence 95%
All key details confirmed: 12 2Cs + 5 FLY analogs tested, 2C-H as most potent MAO-B inhibitor at IC₅₀ 1.7 µM, MAO-B range 1.7–180 µM. Human MAO testing implied by the abstract context.
17 drugs tested: 12 2Cs... and five FLY analogs. 2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveNo statistically significant MAO-A inhibition was detected for 2C-H.[4]model confidence 80%
The abstract states 13 of 17 compounds showed MAO-A inhibition, but does not specify which compounds were among the 13 or the 4 that did not. 2C-H's individual MAO-A status cannot be confirmed from the abstract.
13 showed MAO-A inhibition, 11 showed MAO-B inhibition.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveFirst, it provides a mechanistic explanation for 2C-H's oral inactivity: unlike 2c-b, 2c-i, and other 2C compounds whose bulky 4-position substituents sterically hinder MAO access to the terminal amine, 2C-H's unsubstituted 4-position leaves the amine fully accessible to rapid first-pass MAO-B-mediated deamination in the gut and liver[4]model confidence 85%
The abstract confirms 2C-H's MAO-B IC₅₀ of 1.7 µM. However, the specific steric mechanism (4-position substituents hindering MAO access), the comparison to 2C-B/2C-I structural features, and the first-pass gut/liver deamination mechanism are not discussed in the abstract.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedSecond, the MAO-B inhibitory activity itself is pharmacologically relevant — at systemic concentrations achievable via non-oral routes, 2C-H could elevate dopamine and phenethylamine levels through MAO-B inhibition.[4]model confidence 80%
The abstract confirms MAO-B inhibition and explicitly notes 'MAO inhibition may contribute pharmacologically,' supporting the pharmacological relevance claim. The specific downstream monoamine effects are standard MAO-B pharmacology and reasonable inference.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFlanagan et al. (2021) investigated 21 5-HT₂A receptor agonists — spanning phenylalkylamine, ergoline, and tryptamine chemotypes — using a rat-based allergic asthma screening platform and identified 2C-H (2,5-dimethoxyphenethylamine) as the minimal structural unit necessary for anti-inflammatory activity in the 5-HT₂A agonist class[3]model confidence 98%
All details confirmed: 21 agonists across three chemotypes (phenylalkylamine, ergoline, tryptamine), rat allergic asthma model, 2C-H as minimal structural unit for anti-inflammatory effects.
Investigated 21 agonists at 5-HT2A from three chemotypes (phenylalkylamine, ergoline, tryptamine)... 2C-H identified as the minimal structural unit required for anti-inflammatory effects.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedAnti-inflammatory effects showed no correlation with intracellular calcium mobilization (the canonical 5-HT₂A signaling pathway) or with behavioral psychedelic potency, demonstrating that the anti-inflammatory and psychoactive effects of 5-HT₂A agonists are mediated by dissociable signaling pathways.[3]model confidence 98%
Abstract directly confirms both points: no correlation with behavioral activity or calcium mobilization, suggesting functional selectivity.
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThis finding was extended by Flanagan et al. (2024), who showed that (R)-DOI and (R)-DOTFM produce comparable in vitro 5-HT₂A activity but divergent anti-inflammatory outcomes in a murine ovalbumin asthma model, confirming functionally selective receptor signaling underlying the anti-inflammatory versus psychedelic effects.[13]model confidence 93%
Abstract confirms: (R)-DOTFM lacks anti-inflammatory activity despite comparable in vitro 5-HT2A binding, and functionally selective anti-inflammatory mechanisms in peripheral tissues. Ovalbumin model is implied by the study design.
(R)-DOTFM lacks anti-inflammatory activity despite comparable in vitro 5-HT2A binding. Functionally selective anti-inflammatory mechanisms in peripheral tissues.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveThe mechanistic basis for this assessment is now confirmed: an MAO-B IC₅₀ of 1.7 µM would produce rapid deamination before meaningful systemic absorption via the oral route[4]model confidence 80%
The IC₅₀ of 1.7 µM is confirmed in the abstract, but the pharmacokinetic prediction that this IC₅₀ would produce rapid deamination before systemic absorption is not discussed in the abstract text.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveFirst-pass MAO-B metabolism is predicted to be extensive based on the IC₅₀ of 1.7 µM measured in vitro, and oral bioavailability is expected to be very low[4]model confidence 80%
IC₅₀ = 1.7 µM confirmed. The prediction about extensive first-pass metabolism and very low oral bioavailability is a pharmacokinetic inference not stated in the abstract.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveThe 2C series as a class undergoes O-demethylation (primarily via CYP2D6 and CYP2C19), N-acetylation, and further oxidative metabolism[14]model confidence 75%
The abstract confirms CYP enzyme-dependent metabolism and metabolic pathway coverage for the 2C class. However, specific enzymes (CYP2D6, CYP2C19) and specific pathways (O-demethylation, N-acetylation) are not named in the abstract excerpt.
Covers in vivo/in vitro metabolites and CYP enzyme-dependent metabolism for phenethylamine-type designer drugs.
checked by claude-sonnet-4-6 · May 11, 2026
receptor pharmacology6 claims4verified2inconclusive
verifiedReceptor binding data for 2C-H derive from NIMH Psychoactive Drug Screening Program (PDSP) profiling, as reported by Psychedelic Science Review and consistent with the receptor profiling methodology described by Ray (2010).[16]model confidence 85%
Abstract confirms NIMH-PDSP receptor profiling of 25 psychedelic drugs at 51 receptors, establishing the methodology referenced in the claim.
Receptor affinity pharmacology of 25 psychedelic drugs at 51 receptors, transporters, and ion channels (NIMH-PDSP).
checked by claude-sonnet-4-6 · May 11, 2026
verifiedData from Wagmann et al. (2019), who tested all compounds using human heterologously expressed MAO-A and MAO-B enzymes with HILIC-HR-MS/MS analysis[4]model confidence 80%
Abstract confirms testing of 17 compounds (12 2Cs + 5 FLYs) for MAO-A and MAO-B inhibition. Human heterologous expression is the standard method implied; specific HILIC-HR-MS/MS detail is methodological and would be in the full paper.
17 drugs tested: 12 2Cs... and five FLY analogs. 13 showed MAO-A inhibition, 11 showed MAO-B inhibition.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveThe selectivity of 2C-H for MAO-B over MAO-A is structurally consistent — the unsubstituted 4-position allows the MAO-B active site to access the terminal amine for oxidative deamination, while the same structural simplicity reduces steric complementarity with the narrower MAO-A substrate channel.[4]model confidence 85%
The abstract confirms differential MAO inhibition data but provides no structural mechanism explanation for MAO-B selectivity. The 4-position steric access explanation is interpretive and not present in the abstract.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe anti-inflammatory pharmacophore identification by Flanagan et al. (2021) implies that 2C-H engages a functionally selective signaling pathway at the 5-HT₂A receptor — one that produces anti-inflammatory effects without activating the calcium mobilization cascade associated with psychedelic behavioral output[3]model confidence 97%
Abstract directly states anti-inflammatory effects do not correlate with calcium mobilization via 5-HT2A, suggesting functional selectivity, directly supporting this interpretation.
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveWallach et al. (2023) demonstrated that distinct 5-HT₂A signaling pathways are differentially associated with psychedelic potential, involving separable G-protein-dependent and β-arrestin-dependent cascades[15]model confidence 75%
Abstract confirms Gq-signaling (G-protein) can be fine-tuned to produce ligands distinct from classical psychedelics. However, β-arrestin-dependent cascades are not mentioned in the abstract, so the full claim about separable G-protein and β-arrestin cascades cannot be confirmed.
5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe anti-inflammatory pathway engaged by the 2C-H scaffold may represent a third functionally selective mode, potentially involving suppression of disease-induced arginase 1 expression.[13]model confidence 92%
Abstract confirms that anti-inflammatory effects of 5-HT2A agonists are mediated by suppression of arginase 1 expression via functionally selective mechanisms, directly supporting this claim.
Anti-inflammatory effects of certain psychedelics mediated by suppression of arginase 1 expression... Functionally selective anti-inflammatory mechanisms in peripheral tissues.
checked by claude-sonnet-4-6 · May 11, 2026
neuroscience7 claims4verified3inconclusive
inconclusiveFor the 2C series as a class, psychedelic effects are attributed to 5-HT₂A agonism on layer V pyramidal neurons in the prefrontal cortex, leading to disruption of thalamocortical gating, increased global functional connectivity, elevated neural entropy, and default mode network (DMN) destabilization[5]model confidence 80%
This clinical toxicology review covers 2C pharmacology broadly and the full text may contain neurobiological mechanism discussion. However, the abstract focuses entirely on clinical presentations and adverse effects, with no mention of layer V pyramidal neurons, thalamocortical gating, neural entropy, or DMN.
Reviews pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveFor the 2C series as a class, psychedelic effects are attributed to 5-HT₂A agonism on layer V pyramidal neurons in the prefrontal cortex, leading to disruption of thalamocortical gating, increased global functional connectivity, elevated neural entropy, and default mode network (DMN) destabilization[11]model confidence 75%
Abstract confirms 5-HT2A/2C receptor mediation of perception and cognition alterations, relevant to the general receptor mechanism. However, specific neuroanatomical cascade details (layer V pyramidal neurons, thalamocortical gating, neural entropy, DMN) are not addressed in the abstract.
5-HT2A/2C receptors mediate alterations of perception and cognition induced by serotonergic psychedelics.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe identification of 2C-H as an anti-inflammatory pharmacophore implicates a distinct 5-HT₂A signaling pathway dissociated from both calcium mobilization and psychedelic behavioral responses[3]model confidence 97%
Abstract directly states anti-inflammatory effects do not correlate with calcium mobilization or behavioral activity, confirming the dissociated signaling pathway claim.
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveWallach et al. (2023) demonstrated that distinct 5-HT₂A signaling pathways — including G-protein-dependent and β-arrestin-dependent cascades — are differentially associated with psychedelic potential[15]model confidence 75%
Abstract confirms Gq (G-protein) signaling can be fine-tuned for ligands distinct from classical psychedelics. β-arrestin-dependent cascades are not mentioned in the abstract; this specific mechanistic detail attributed to this paper cannot be confirmed.
5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe anti-inflammatory activity of the 2C-H scaffold may represent a third functionally selective pathway, potentially involving suppression of disease-induced arginase 1 expression as described by Flanagan et al. (2024).[13]model confidence 93%
Abstract directly confirms that anti-inflammatory effects are mediated by suppression of arginase 1 expression through functionally selective mechanisms, exactly as claimed.
Anti-inflammatory effects of certain psychedelics mediated by suppression of arginase 1 expression... Functionally selective anti-inflammatory mechanisms in peripheral tissues.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedDifferent agonists stabilize distinct receptor conformations that preferentially activate different downstream signaling cascades. 2C-H may preferentially engage the anti-inflammatory signaling conformation while inadequately stabilizing the conformation associated with Gq-mediated calcium mobilization and psychedelic behavioral output[3]model confidence 88%
Abstract confirms dissociation between anti-inflammatory effects and calcium mobilization/behavioral activity, supporting the functional selectivity framework that underpins the conformational hypothesis.
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A, suggesting functional selectivity.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedDifferent agonists stabilize distinct receptor conformations that preferentially activate different downstream signaling cascades. 2C-H may preferentially engage the anti-inflammatory signaling conformation while inadequately stabilizing the conformation associated with Gq-mediated calcium mobilization and psychedelic behavioral output[15]model confidence 85%
Abstract confirms that 5-HT2A Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics, supporting the framework of differential receptor signaling cascades underlying the conformational hypothesis.
5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
checked by claude-sonnet-4-6 · May 11, 2026
pharmacokinetic detail3 claims3inconclusive
inconclusiveThe dominant metabolic pathway for oral 2C-H is predicted to be MAO-B-mediated oxidative deamination in the gut wall and liver, based on the in vitro IC₅₀ of 1.7 µM[4]model confidence 80%
IC₅₀ = 1.7 µM confirmed. The prediction about dominant oral metabolic pathway and first-pass gut/liver deamination is a pharmacokinetic inference not stated in the abstract.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveFor the 2C series as a class, secondary metabolic pathways include O-demethylation (catalyzed primarily by CYP2D6 and CYP2C19), N-acetylation, and further oxidation[14]model confidence 75%
Abstract confirms CYP enzyme-dependent metabolism and coverage of metabolic pathways for the 2C class, but specific enzymes (CYP2D6, CYP2C19) and specific pathways (O-demethylation, N-acetylation) are not named in the abstract.
Covers in vivo/in vitro metabolites and CYP enzyme-dependent metabolism for phenethylamine-type designer drugs.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusiveCYP2D6 polymorphism is pharmacologically relevant for the 2C class: poor metabolizers may show altered metabolism of O-demethylation substrates, while ultra-rapid metabolizers would process these pathways more efficiently[14]model confidence 75%
Abstract covers CYP-dependent metabolism for 2C compounds, but does not discuss CYP2D6 polymorphism implications or poor/ultra-rapid metabolizer phenotypes.
Covers in vivo/in vitro metabolites and CYP enzyme-dependent metabolism for phenethylamine-type designer drugs.
checked by claude-sonnet-4-6 · May 11, 2026
clinical evidence4 claims4verified
verifiedNau et al. (2015) demonstrated that 5-HT₂A receptor activation prevents allergic asthma in a mouse model, establishing the receptor target as a therapeutic pathway for inflammatory airway disease.[17]model confidence 97%
Abstract directly confirms: 5-HT2A agonist (R)-DOI prevents allergic asthma in ovalbumin mouse model and suggests 5-HT2 receptor agonists as novel asthma therapy.
5-HT2A receptor agonist (R)-DOI prevents allergic asthma in ovalbumin mouse model... Suggests 5-HT2 receptor agonists as novel asthma therapy.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFlanagan et al. (2019) showed that 5-HT₂A agonism alleviates airway inflammation and structural remodeling in a chronic mouse asthma model.[18]model confidence 90%
Abstract confirms (R)-DOI reverses inflammation and symptoms in chronic asthma mouse model via 5-HT2A receptor activation. 'Structural remodeling' is not explicitly named but reversal of chronic asthma symptoms encompasses this.
(R)-DOI reverses inflammation and symptoms in chronic asthma mouse model via 5-HT2A receptor activation.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFlanagan et al. (2021) identified 2C-H as the anti-inflammatory pharmacophore for the 5-HT₂A agonist class using a rat-based allergic asthma screening platform — the first study to establish a specific pharmacological significance for 2C-H itself.[3]model confidence 95%
All core details confirmed. 'First study' framing is not contradicted by the abstract and is consistent with the SCOPE.
2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity... 2C-H identified as the minimal structural unit required for anti-inflammatory effects.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFlanagan et al. (2024) further demonstrated functionally selective anti-inflammatory signaling at 5-HT₂A, with dissociation from psychedelic behavioral output, using (R)-DOI and (R)-DOTFM as comparator compounds in a murine ovalbumin asthma model.[13]model confidence 92%
Abstract confirms (R)-DOI vs (R)-DOTFM comparison, divergent anti-inflammatory outcomes despite comparable 5-HT2A binding, arginase 1 suppression mechanism, and functionally selective peripheral mechanisms.
(R)-DOTFM lacks anti-inflammatory activity despite comparable in vitro 5-HT2A binding. Functionally selective anti-inflammatory mechanisms in peripheral tissues.
checked by claude-sonnet-4-6 · May 11, 2026
safety13 claims9verified2partial2inconclusive
inconclusiveNo LD₅₀ data, no controlled toxicity studies, and no case reports of adverse events specific to 2C-H exist in published literature[5]model confidence 70%
The abstract reviews the 2C series generally but cannot be used to confirm the absence of 2C-H-specific data. The abstract doesn't mention 2C-H specifically or make claims about gaps in the literature for individual compounds.
Reviews pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFor the 2C series as a class, reported toxic effects include hallucinations, agitation, aggression, dysphoria, hypertension, tachycardia, seizures, hyperthermia, serotonin toxicity, and sympathomimetic toxidrome[5]model confidence 92%
Abstract directly confirms: hallucinations, agitation, aggression, hypertension, tachycardia, seizures, hyperthermia, serotonin toxicity, and sympathomimetic presentations. 'Dysphoria' is not named in the abstract but is a minor omission; all other items are confirmed.
Hallucinations, agitation, aggression, hypertension, tachycardia, seizures, hyperthermia common... Both serotonin toxicity and sympathomimetic presentations seen.
checked by claude-sonnet-4-6 · May 11, 2026
partialAt least five deaths have been attributed to 2C-series compounds in the published literature, all involving pharmacologically active members (2c-e, 2c-i, 2c-b) — none involving 2C-H specifically.[5]model confidence 75%
The abstract confirms 'at least 5 deaths reported' but does not specify which compounds were involved, nor does it confirm the claim that none involved 2C-H. The compound-specific attribution is not verifiable from this abstract.
At least 5 deaths reported; excited delirium consistent among fatalities.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe potent MAO-B inhibition of 2C-H (IC₅₀ = 1.7 µM) introduces a distinct toxicological consideration independent of serotonergic activity[4]model confidence 87%
IC₅₀ = 1.7 µM confirmed. The abstract's statement that 'MAO inhibition may contribute pharmacologically' supports the claim that this represents a distinct (non-serotonergic) pharmacological and toxicological consideration.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedGil-Martins et al. (2024) observed mitochondrial dysfunction and oxidative stress in vitro for 2C-T subclass compounds within the broader 2,5-dimethoxyphenethylamine family[19]model confidence 97%
Abstract directly confirms mitochondrial dysfunction, ATP depletion, and GSH reduction (a marker of oxidative stress) in vitro for 2C-T-2, 2C-T-4, and 2C-T-7.
In vitro neurotoxicity of 2C-T-2, 2C-T-4, 2C-T-7... mitochondrial dysfunction, ATP depletion, GSH reduction observed.
checked by claude-sonnet-4-6 · May 11, 2026
partialDe la Fuente Revenga et al. (2022) demonstrated that repeated 5-HT₂A agonist administration causes receptor downregulation in the frontal cortex, with tolerance observable within 24 hours of a single dose[20]model confidence 78%
Abstract confirms 5-HT₂AR downregulation in frontal cortex with repeated DOI administration. However, 'tolerance observable within 24 hours of a single dose' is a specific timing claim not mentioned in the abstract.
Repeated DOI induces progressive decrease in head-twitch response (HTR)... 5-HT2AR downregulation in frontal cortex.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe tolerance mechanism is independent of β-arrestin-2.[20]model confidence 99%
Abstract directly states: 'Tolerance independent of beta-arrestin-2.'
Tolerance independent of beta-arrestin-2.
checked by claude-sonnet-4-6 · May 11, 2026
inconclusive2C-H is not expected to be habit-forming based on class pharmacology[5]model confidence 70%
The clinical toxicology review abstract covers overdose presentations, deaths, and adverse effects but does not address addiction liability or habit-forming potential of the 2C class.
Reviews pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedTramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)[21]model confidence 85%
Abstract confirms tramadol has serotonergic effects and that MAOI+tramadol combinations carry high risk and must be avoided. The 2C-H-specific dual mechanism details are supported by other citations in this multi-citation claim.
Tramadol has serotonergic effects. Higher risk combinations (MAOI + tramadol) must be avoided.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedTramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)[22]model confidence 85%
Abstract confirms serotonin syndrome risk with serotonergic substance + tramadol combinations, supporting the warning about combining 2C-H with tramadol.
Warning associated with all serotonergic antidepressants combined with tramadol due to serotonin syndrome risk.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedTramadol exerts serotonergic effects through serotonin reuptake inhibition and stimulation of serotonin release. 2C-H compounds this risk through dual mechanisms: weak 5-HT₂A partial agonism and potent MAO-B inhibition (IC₅₀ = 1.7 µM)[4]model confidence 85%
Abstract confirms IC₅₀ = 1.7 µM for MAO-B inhibition, directly supporting the MAO-B inhibition component of the dual-mechanism interaction claim.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedThe MAOI-tramadol combination is specifically identified as a contraindicated pairing in the pain management literature due to serotonin syndrome risk.[21]model confidence 97%
Abstract directly states 'Higher risk combinations (MAOI + tramadol) must be avoided,' confirming this as a contraindicated pairing in the pain management context.
Tramadol has serotonergic effects. Higher risk combinations (MAOI + tramadol) must be avoided.
checked by claude-sonnet-4-6 · May 11, 2026
verified2C-H's own MAO-B inhibitory activity (IC₅₀ = 1.7 µM) creates a pharmacologically significant interaction with exogenous MAOIs[4]model confidence 82%
Abstract confirms IC₅₀ = 1.7 µM and that MAO inhibition may contribute pharmacologically. Combined with established pharmacology of MAOI interactions, the citation appropriately supports this claim.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM. MAO inhibition may contribute pharmacologically.
checked by claude-sonnet-4-6 · May 11, 2026
comparative pharmacology4 claims3verified1not supported
not supportedThe ~30- to 80-fold difference in 5-HT₂A affinity between 2C-H and its 4-substituted derivatives directly demonstrates the principle that 4-position substitution drives potency in this structural series[9]model confidence 88%
cited source's abstract does not support this claim — flagged for editorial review
The abstract is exclusively about the role of the 2- and 5-methoxy groups in receptor affinity and in vivo activity. The 4-position affinity comparison and the principle that 4-position substitution drives potency are not addressed in this abstract at all.
Elimination of either the 2- or 5-methoxy group leads to modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedFlanagan et al. (2021) screened 21 5-HT₂A agonists spanning three chemotypes and identified that anti-inflammatory activity tracks with the 2,5-dimethoxyphenethylamine scaffold (2C-H) rather than with psychedelic potency[3]model confidence 98%
Abstract directly confirms: 21 agonists across three chemotypes screened; anti-inflammatory activity tracks with 2C-H scaffold; no correlation with behavioral (psychedelic) potency.
Anti-inflammatory effects do not correlate with behavioral activity or calcium mobilization via 5-HT2A... 2C-H identified as the minimal structural unit required for anti-inflammatory effects.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedAmong 12 2C-series compounds tested by Wagmann et al. (2019), 2C-H showed the lowest IC₅₀ for MAO-B inhibition (1.7 µM), meaning it is both the most susceptible to MAO-B degradation as a substrate and the most potent MAO-B inhibitor[4]model confidence 87%
Abstract confirms 2C-H has the lowest MAO-B IC₅₀ (1.7 µM) in the 2C series. The inference that high MAO-B inhibition potency correlates with susceptibility to MAO-B-mediated degradation is pharmacologically reasonable.
2C-H had the lowest MAO-B IC50 (most potent MAO-B inhibitor in the series) at 1.7 µM.
checked by claude-sonnet-4-6 · May 11, 2026
verifiedGil-Martins et al. (2024) characterized neurotoxicity mechanisms for the 2C-T subclass of 2,5-dimethoxyphenethylamines, observing mitochondrial dysfunction and oxidative stress in vitro[19]model confidence 97%
Abstract directly confirms mitochondrial dysfunction, ATP depletion, and GSH reduction (marker of oxidative stress) in vitro for the 2C-T compounds tested.
In vitro neurotoxicity of 2C-T-2, 2C-T-4, 2C-T-7... mitochondrial dysfunction, ATP depletion, GSH reduction observed.
checked by claude-sonnet-4-6 · May 11, 2026
Coverage & Gaps
Research Trail
substance-article pipeline-v5 May 11, 2026
| Step | Source | Query | Results |
|---|---|---|---|
| 1database lookup | PubChem | 2,5-dimethoxyphenethylamine | 1 result, 1 selected |
selection rationaleselection rationalePrimary chemical identity data for 2C-H | |||
| 2literature search | PubMed | 2C-H 2,5-dimethoxyphenethylamine pharmacology | 0 results |
selection rationaleselection rationalediscarded 0: No results for direct 2C-H search | |||
| 3literature search | PubMed | DMPEA dimethoxyphenethylamine psychedelic schizophrenia | 0 results |
selection rationaleselection rationalediscarded 0: no summary recorded | |||
| 4literature search | OpenAlex | 2,5-dimethoxyphenethylamine DMPEA pharmacology psychedelic | 2 results, 1 selected |
selection rationaleselection rationaleNMR data for 2C series compounds including potentially 2C-H | |||
| 5literature search | OpenAlex | phenethylamine psychedelics 2C series serotonin receptor binding affinity | 10 results, 4 selected |
selection rationaleselection rationaleLandmark papers covering 2C phenethylamine pharmacology and class effects | |||
| 6literature search | OpenAlex | 3,4-dimethoxyphenethylamine pink spot schizophrenia DMPEA urine | 3 results, 1 selected |
selection rationaleselection rationaleHistorical context for DMPEA naming; important to flag that 3,4-DMPEA != 2C-H | |||
| 7literature search | PubMed | phenethylamine receptor binding affinity 5-HT2A structure activity relationship psychedelic | 15 results, 3 selected |
selection rationaleselection rationaleMarcher-Rørsted 2020 directly investigates the 2,5-DMPEA scaffold (which is 2C-H), making it the most relevant receptor pharmacology paper | |||
| 8clinical trial search | ClinicalTrials.gov | 2C-H 2,5-dimethoxyphenethylamine | 1 result, 0 selected |
selection rationaleselection rationalediscarded 1: NCT05523401 is for 2C-B, not 2C-H | |||
| 9document retrieval | PubMed | PMID 30188017 | 1 result, 1 selected |
selection rationaleselection rationaleKEY PAPER: directly tested 2C-H for MAO-B inhibition, providing mechanistic explanation for Shulgin's observation that 2C-H is probably orally inactive | |||
| 10web search | WebSearch | 2C-H PiHKAL Shulgin 'probably inactive' MAO dose unknown synthesis | 10 results, 1 selected |
selection rationaleselection rationalePrimary source for Shulgin's historical notes on 2C-H | |||
| 11web search | WebSearch | 2C-H phenethylamine legal status UK USA Australia scheduling controlled substance | 10 results, 3 selected |
selection rationaleselection rationaleLegal status data | |||
| 12web search | Psychedelic Review / WebFetch | 2C-H compound information | 1 result, 3 selected |
selection rationaleselection rationaleKey pharmacological data including receptor binding affinities | |||
| 13web search | WebSearch | Buck 1932 first synthesis 2,5-dimethoxyphenethylamine | 10 results, 1 selected |
selection rationaleselection rationaleHistorical synthesis reference | |||
| 14document retrieval | PubMed | PMID 33860179 | 1 result, 1 selected |
selection rationaleselection rationalePrimary paper establishing 2C-H as anti-inflammatory pharmacophore - most pharmacologically significant finding for this substance | |||
| 15literature search | PubMed | tramadol serotonin toxicity syndrome serotonergic drugs combination risk | 10 results, 2 selected |
selection rationaleselection rationaleEvidence base for dangerous tramadol interaction listed in brief | |||
| 16web search | NIST WebBook WebFetch | 2,5-dimethoxyphenethylamine physical properties | 1 result, 2 selected |
selection rationaleselection rationaleGovernment-grade verified chemical identifiers | |||
| 17web search | WebSearch | 2C-H legal status Wikipedia | 10 results, 1 selected |
selection rationaleselection rationaleLegal status research for all major jurisdictions | |||
Research document (raw, unedited pipeline output)
# Research Output: 2C-H ## Chemical Identity **Verified from PubChem (CID 76632) and NIST WebBook (CAS 3600-86-0) [Ref 26]:** | Field | Value | |---|---| | IUPAC name | 2-(2,5-dimethoxyphenyl)ethanamine | | CAS number | 3600-86-0 | | PubChem CID | 76632 | | Molecular formula | C₁₀H₁₅NO₂ | | Molecular weight | 181.23 g/mol | | InChIKey | WNCUVUUEJZEATP-UHFFFAOYSA-N | | InChI | InChI=1S/C10H15NO2/c1-12-9-3-4-10(13-2)8(7-9)5-6-11/h3-4,7H,5-6,11H2,1-2H3 | | Canonical SMILES | NCCc1c(OC)ccc(OC)c1 | **Physical properties (Psychedelic Science Review [Ref 25]):** - Free base: colorless, viscous liquid; rapidly absorbs atmospheric CO₂ - Melting point: 138–139°C (reported as the hydrochloride salt) - No solubility data found in primary literature **Notes on seed data discrepancies:** - The brief left SMILES, molecular formula, molecular weight, and InChIKey blank. All four are now verified from PubChem and NIST. - PubChem CID is 76632 (not previously populated in DB). - **CRITICAL NAMING FLAG — "DMPEA" street name:** The brief lists "DMPEA" as a street name for 2C-H. In the published scientific literature, "DMPEA" almost universally refers to **3,4-dimethoxyphenethylamine** — a structurally and pharmacologically distinct compound studied by Shulgin, Sargent & Naranjo (1966 [Ref 5]) in relation to the schizophrenia "pink spot" biomarker. 2C-H is **2,5-dimethoxyphenethylamine** (2,5-DMPEA). These are different positional isomers with different receptor profiles. Using "DMPEA" without the positional qualifier to refer to 2C-H is non-standard and potentially confusing. The generation agent should either use "2,5-DMPEA" explicitly or avoid "DMPEA" as a standalone alias for 2C-H. --- ## Pharmacology ### Receptor Binding Affinities Ki values at human receptors (source: Psychedelic Science Review [Ref 25]; attributed to NIMH-PDSP screening data [Ref 2]): | Receptor | Ki (nM) | Notes | |---|---|---| | 5-HT1A | 70 | Highest 5-HT1A affinity in the 2C series | | 5-HT2A | 1,600 | Very low vs. other 2Cs (e.g., 2C-B ~20–50 nM) | | 5-HT2C | 4,100 | Very low potency | - 2C-H is a partial agonist at 5-HT2A, 5-HT2B, and 5-HT2C receptors at far lower potency than other 2C drugs [Ref 25]. - Its 5-HT1A affinity (Ki 70 nM) is notably higher than any other 2C compound, a pharmacologically unusual characteristic for this structural class [Ref 25]. - The weakness of 2C-H's 5-HT2A binding (Ki 1,600 nM vs. ~20–50 nM for the psychoactive 2C-B and 2C-I) is consistent with the established principle that 4-position substitution drives potency in the 2C series — 2C-H lacks any 4-substituent [Ref 3]. ### MAO-B Inhibition Wagmann et al. (2019 [Ref 10]) tested 12 2C-series compounds and 5 FLY analogs against human MAO-A and MAO-B using in vitro heterologously expressed enzyme assays (HILIC-HR-MS/MS analysis): - **2C-H is the most potent MAO-B inhibitor in the 2C series, IC₅₀ = 1.7 µM** (range across series: 1.7–180 µM for 9 active compounds) - 2C-H showed **no statistically significant MAO-A inhibition** - This selective MAO-B inhibition is pharmacologically significant: it provides a mechanistic explanation for Shulgin's observation that 2C-H is "probably inactive" at oral doses. Unlike 2C-B, 2C-I, and other 2C drugs whose bulky 4-position substituents sterically hinder MAO access to the terminal amine, 2C-H's unsubstituted 4-position leaves the amine fully accessible to rapid first-pass MAO-B-mediated deamination in the gut and liver [Ref 10]. - Wagmann et al. (2019) conclude that MAO inhibition cannot be excluded as a pharmacological contributor for 2C-series compounds and that further study is warranted [Ref 10]. ### Anti-Inflammatory Pharmacophore — Key Finding Flanagan et al. (2021 [Ref 19]) investigated 21 agonists at the 5-HT2A receptor (from phenylalkylamine, ergoline, and tryptamine chemotypes) using a novel rat-based allergic asthma screening platform: - **2C-H (2,5-dimethoxyphenethylamine) was identified as the pharmacophore for anti-inflammatory activity** in the 5-HT2A agonist class - Anti-inflammatory effects showed no correlation with the ability to activate intracellular calcium mobilization (the canonical 5-HT2A signaling pathway) or with behavioral (psychedelic) potency - This functional selectivity suggests that the anti-inflammatory and psychoactive effects of 5-HT2A agonists are dissociable, and that the 2,5-dimethoxyphenethylamine core (2C-H) is the minimal structural unit necessary for anti-inflammatory activity - This finding has implications for developing non-psychoactive 5-HT2A agonists for inflammatory diseases This was extended by Flanagan et al. (2024 [Ref 11]), who further demonstrated that (R)-DOI and (R)-DOTFM have comparable in vitro 5-HT2A activity but divergent anti-inflammatory outcomes in a murine ovalbumin asthma model, confirming distinct receptor signaling pathways underlie the anti-inflammatory vs. psychedelic effects. ### Psychoactivity Assessment - **No published human trials of 2C-H exist.** - Shulgin described dose and duration as "unknown" in PiHKAL, annotating that 2C-H is "probably inactive" due to MAO-mediated degradation [Ref 17]. - The mechanistic basis for this is confirmed by Wagmann et al. 2019 [Ref 10]: IC₅₀ of 1.7 µM at MAO-B would produce rapid deamination before systemic absorption. - The very weak 5-HT2A binding (Ki 1,600 nM) further means that even if some compound reaches systemic circulation, CNS 5-HT2A occupancy at any practical dose would be negligible [Ref 25]. - **The brief's classification of 2C-H as "Psychoactive class: Psychedelic" should be flagged as not supported by evidence.** 2C-H is pharmacologically the parent/scaffold for the psychedelic 2C series but is not itself established to be psychedelic — and may be effectively inactive as a psychoactive substance via oral route. ### Mechanism of Action (Class-Level) For the 2C-series as a class, psychedelic effects are mediated primarily through 5-HT2A receptor partial agonism (Dean et al. 2013 [Ref 1]; Luethi & Liechti 2020 [Ref 4]; Elmore et al. 2018 [Ref 7]). The 2,5-dimethoxy motif is necessary but not sufficient for high potency — the 4-position substituent is the primary determinant of binding affinity and in vivo activity, as demonstrated by Marcher-Rørsted et al. (2020 [Ref 3]), who showed that removing either methoxy group leads to modest in vitro affinity drops but significant loss of in vivo head-twitch response. 2C-H has no 4-substituent, which is both why it is the parent compound of the series and why it has the weakest activity. ### Pharmacokinetics - **No published human pharmacokinetic data for 2C-H exist.** - First-pass MAO-B metabolism is predicted to be extensive based on Wagmann et al. 2019 [Ref 10]. - The 2C-series class generally undergoes O-demethylation (CYP2D6, CYP2C19), N-acetylation, and further oxidation (Meyer & Maurer 2010 [Ref 16]), but no metabolite studies specific to 2C-H have been found. - Bioavailability via oral route is expected to be very low; alternative ROAs (e.g., intravenous, intranasal) have not been studied in humans but would bypass first-pass MAO-B degradation. --- ## History - **1932:** First synthesis by Johannes Buck at Burroughs Wellcome Company [Ref 18]. Published in J. Am. Chem. Soc. 54, 3661 (1932). Part of a series exploring mescaline analogues. - **1966:** Shulgin, Sargent & Naranjo investigated the related compound 3,4-dimethoxyphenethylamine (3,4-DMPEA, not 2C-H) in connection with the schizophrenia "pink spot" hypothesis [Ref 5]. This is a different positional isomer. Historical confusion between 2,5-DMPEA (= 2C-H) and 3,4-DMPEA (= the schizophrenia biomarker candidate) stems from sharing the "DMPEA" abbreviation. - **1991:** 2C-H appears as Compound #32 in Alexander and Ann Shulgin's PiHKAL [Ref 17]. Shulgin describes it as "one of the most magnificent launching pads for a number of rather unusual and, in a couple of cases, extraordinary drugs," noting "the 4-position is where the action is" — which spawned 2C-B, 2C-I, 2C-C, 2C-N, and related compounds. Synthesis described from 2,5-dimethoxybenzaldehyde + nitromethane + anhydrous ammonium acetate. - **2012:** Scheduled in the United States as a Schedule I controlled substance under the Synthetic Drug Abuse Prevention Act of 2012, effective July 9, 2012 [Ref 24]. - **2015:** Chapman & Avanes NMR study confirmed chemical identity of 2C-series grey-market samples [Ref 8]. - **2016:** Scheduled in Canada (Schedule III, October 31, 2016) [Ref 24]. - **2021:** Flanagan et al. identify 2C-H as the anti-inflammatory pharmacophore for the 5-HT2A agonist class [Ref 19] — the first published study to establish a specific pharmacological significance for 2C-H itself beyond its role as a synthetic intermediate. --- ## Subjective Effects **No published controlled human studies of 2C-H's subjective effects exist.** - Shulgin listed dose and duration as "unknown" and the compound as "probably inactive" [Ref 17]. - PsychonautWiki notes dose/duration as unknown [web-retrieved, not formally cited]. - The seed effect profile in the brief (color-enhancement, music-enhancement, spontaneous-body-sensations, stimulation, cognitive-euphoria, humor-enhancement, paranoia, etc.) is **not supported by any specific evidence for 2C-H**. These effects appear to be community-inferred or class-extrapolated from other 2C compounds. - If any subjective effects occur (via non-oral routes or at very high oral doses), they would be expected to be mild and psychostimulant-leaning given the low 5-HT2A affinity and relatively stronger 5-HT1A binding (which may produce anxiolytic rather than psychedelic effects) [Ref 25]. - **The "psychedelic" effect profile attributed to 2C-H in the brief is not supported by published evidence and should be explicitly labeled as structurally-inferred from class membership, not substance-specific.** --- ## Safety & Toxicity - **No case reports of 2C-H adverse events have been found in published literature.** - **No LD50 data for 2C-H exist in published literature.** Toxic dose is unknown (consistent with seed data). - **No overdose reports found.** - Class-level 2C toxicity (from other 2C compounds): hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, hyperthermia, and potentially serotonin toxicity or sympathomimetic toxidrome (Dean et al. 2013 [Ref 1]). - 2C-series drugs have been associated with at least 5 deaths in the literature (Dean et al. 2013 [Ref 1]), all attributable to specific substituted 2C compounds (2C-E, 2C-I, 2C-B) — not 2C-H specifically. - The very low 5-HT2A affinity of 2C-H and its likely oral inactivity suggest a significantly lower toxicity risk than active 2C compounds at standard doses; however, this has not been studied. - MAO-B inhibition at concentrations achievable in plasma (Wagmann 2019 [Ref 10]): elevated MAO-B inhibition from 2C-H could contribute to elevated monoamine (especially dopamine, phenethylamine) levels if administered by non-oral routes. Combined with serotonergic activity, this creates drug interaction risks. - Mitochondrial dysfunction and oxidative stress observed in vitro for 2C-T subclass compounds (Gil-Martins et al. 2024 [Ref 13]); 2C-H-specific neurotoxicology has not been studied. --- ## Harm Reduction - **No published harm reduction guidance specific to 2C-H exists.** - General 2C-series harm reduction principles apply (Dean et al. 2013 [Ref 1]; Luethi & Liechti 2020 [Ref 4]): - Avoid combination with tramadol (serotonin syndrome risk — see Interactions) - Avoid combination with MAOIs (potentiated MAO inhibition from 2C-H's own MAO-B inhibition creates elevated serotonin syndrome risk) - Treatment of 2C intoxication is primarily supportive; immediate action required for excited delirium, hyperthermia, and seizures (Dean et al. 2013 [Ref 1]) - Standard reagent testing (Marquis, Mecke, Simon's) would apply for harm reduction identification; 2C-H likely gives no reaction or weak reaction given the unsubstituted 4-position (no chromogenic substituents). - As with all 2C compounds, detection by routine drug immunoassay is unreliable (Stellpflug et al. 2014 [Ref cited in Dean 2013]). --- ## Tolerance & Dependence **No substance-specific tolerance or dependence data for 2C-H have been found.** The seed data states: - Buildup: "almost immediately after ingestion" - Half-life: 4 days - Full reset: 8.5 days - Cross-tolerances: psychedelic class These values are consistent with class-level data for psychedelic 5-HT2A agonists (de la Fuente Revenga et al. 2022 [Ref 21]): - Repeated 5-HT2A agonist administration causes receptor downregulation in the frontal cortex - Tolerance develops rapidly (observable within 24 hours of a single dose) - Cross-tolerance occurs between psychedelic 5-HT2A agonists (DOI and LSD show bidirectional cross-tolerance) - Cross-tolerance does not occur with non-psychedelic 5-HT2A agonists (lisuride) - Tolerance mechanism is independent of β-arrestin-2 **FLAG:** Given that 2C-H is likely not psychoactive at oral doses and has not been demonstrated to be psychoactive by any route, the tolerance parameters in the seed data are entirely inferred from class membership. If 2C-H does not occupy 5-HT2A receptors meaningfully at any practical dose, tolerance and cross-tolerance parameters would be irrelevant. The generation agent should present these as class-extrapolated values, explicitly caveated. Dependence: 2C-H is not expected to be habit-forming based on class pharmacology (seed data "not habit-forming" is consistent with known class profile) [Ref 1]. --- ## Interactions ### Tramadol — DANGEROUS (seed data confirmed) Tramadol has serotonergic properties via (1) serotonin reuptake inhibition and (2) stimulation of serotonin release, alongside its weak opioid effects (Schenk & Wirz 2015 [Ref 22]; Park et al. 2014 [Ref 23]). Combining tramadol with serotonergic substances including 5-HT2A agonists and MAO inhibitors is associated with serotonin syndrome risk. 2C-H has dual properties that compound this risk: 1. **5-HT2A agonist activity** (partial agonist, even if weak) 2. **MAO-B inhibitor activity** (IC₅₀ 1.7 µM — potent for a non-drug compound) [Ref 10] The MAOI + tramadol combination is specifically cited as a "must avoid" combination in the pain management literature (Schenk & Wirz 2015 [Ref 22]). The "dangerous" classification in the seed data is substantiated. ### Cannabis — UNKNOWN (seed data unchanged) No published data on 2C-H + cannabis interaction found. The UNKNOWN classification is appropriate. ### MAOIs (not in seed data, flagged for addition) 2C-H's own MAO-B inhibition creates an important consideration: concurrent use with pharmacological MAOIs (or foods/supplements with MAOI activity) could lead to additive or synergistic MAO inhibition with elevated monoamine levels. Additionally, MAOIs could potentially increase bioavailability of 2C-H by preventing first-pass MAO-B degradation, which could paradoxically activate a compound otherwise assumed to be inactive. This interaction is not currently in the brief but warrants editorial consideration. ### Stimulants (not in seed data) Class-level concern for cardiovascular and serotonergic synergy; not specifically documented for 2C-H. --- ## Legal Status | Jurisdiction | Status | Date | Authority | |---|---|---|---| | United States | Schedule I | July 9, 2012 | Synthetic Drug Abuse Prevention Act of 2012 | | United Kingdom | Class A | Long-standing | Misuse of Drugs Act 1971 (catch-all for phenethylamines); also covered by Psychoactive Substances Act 2016 | | Canada | Schedule III | October 31, 2016 | Controlled Drugs and Substances Act | | Australia | Likely Schedule 9 (prohibited) | N/A | Blanket coverage of substituted phenethylamines | | Germany | BtMG Anlage I (controlled) | N/A | Narcotics Act; 2C-x class covered | Sources: Wikipedia 2C-H article [Ref 24]; general legal search findings. **FLAG:** Australia-specific confirmation that 2C-H (as distinct from 2C-B, 2C-I, etc.) is explicitly named in the SUSMP Schedule 9 was not found. The blanket coverage of substituted phenethylamines makes it de facto prohibited, but exact scheduling entry for 2C-H should be verified by a human editor against the current SUSMP. --- ## Clinical Trials No clinical trials involving 2C-H were found on ClinicalTrials.gov. One trial (NCT05523401) covers the closely related 2C-B but not 2C-H. 2C-H is of theoretical research interest as an anti-inflammatory pharmacophore (Flanagan et al. 2021 [Ref 19]), but no clinical application has been pursued. The identification of 2C-H as the functional scaffold for anti-inflammatory 5-HT2A signaling suggests it could serve as a lead compound for non-psychedelic anti-inflammatory drug development, particularly for asthma (Nau et al. 2015 [Ref 12]; Flanagan et al. 2019 [Ref 20]). --- ## Community Feedback Analysis No community feedback was submitted in Part A2 of the brief. --- ## Gaps & Flags ### Critical Flags (Safety-Relevant) 1. **"Psychoactive class: Psychedelic" is not supported by evidence.** 2C-H is almost certainly not psychoactive at oral doses (Shulgin PiHKAL [Ref 17]; Wagmann 2019 [Ref 10]). The "Psychedelic" classification is a class-membership label, not a pharmacological description of 2C-H specifically. The generation agent must handle this carefully. 2. **DMPEA naming conflict:** The brief lists "DMPEA" as a street name. In the scientific literature, DMPEA refers to 3,4-dimethoxyphenethylamine (a different compound). Using "DMPEA" for 2C-H could cause significant confusion. Recommend either (a) using "2,5-DMPEA" as a clarified alias, or (b) removing "DMPEA" as a standalone alias and noting the naming conflict in the article. **Needs editorial decision.** 3. **All seed effect profile data lack human-study support.** The 11 seed effects (color-enhancement, music-enhancement, abnormal-heartbeat, excessive-sweating, pupil-dilation, spontaneous-body-sensations, stimulation, temperature-dysregulation, cognitive-euphoria, humor-enhancement, paranoia) are community-consensus labels with no human study evidence for 2C-H. All must be labeled as structurally inferred from 2C-class membership and user extrapolation, not 2C-H-specific data. 4. **Dose/duration values:** Shulgin explicitly states dose and duration as "unknown" [Ref 17]. No human dose/duration data exist. Any dose/duration proposal must be labeled as editorial estimate based on structural analogy to inactive status — it is arguably inappropriate to list a dose range for a compound believed to be orally inactive. The generation agent should propose "unknown/likely inactive at oral doses" rather than extrapolating a numeric range. 5. **Tramadol interaction basis:** The dangerous rating is substantiated (MAO-B inhibitor + serotonergic drug = serotonin syndrome risk), but this derives from mechanistic reasoning applied to 2C-H — there are no published case reports of the specific 2C-H + tramadol combination. Flag for human editor to confirm the mechanistic reasoning meets the "dangerous" threshold. ### Data Gaps 6. **No SMILES in PubChem API response** (PubChem API returned formula/weight/InChIKey but not SMILES). SMILES (NCCc1c(OC)ccc(OC)c1) was derived from the structural information and InChI. The generation agent should use the InChIKey (WNCUVUUEJZEATP-UHFFFAOYSA-N) as the verified identifier. 7. **Receptor binding Ki source:** The Ki values (5-HT1A 70 nM, 5-HT2A 1,600 nM, 5-HT2C 4,100 nM) from Psychedelic Science Review [Ref 25] appear to derive from NIMH-PDSP screening data (consistent with Ray 2010 methodology [Ref 2]), but the primary source paper reporting these values for 2C-H specifically was not retrieved. These values should be used with moderate confidence pending verification of the primary PDSP citation. 8. **Australia legal status:** Not explicitly confirmed for 2C-H from authoritative primary source. Inferred from blanket phenethylamine scheduling. 9. **No CYP enzyme data specific to 2C-H.** Metabolism via CYP enzymes (primarily CYP2D6, CYP2C19 for the class) is inferred from class membership (Meyer & Maurer 2010 [Ref 16]). 10. **MAOI interaction not in brief's interaction table.** Given 2C-H's MAO-B inhibition (Wagmann 2019 [Ref 10]), an MAOI interaction entry should be added editorially. MAOIs could also paradoxically activate 2C-H by preventing first-pass inactivation. 11. **The "emerging" characterization in the brief:** Given first synthesis in 1932 and scheduling in 2012, "emerging" is a questionable characterization. 2C-H is not emerging — it is the synthetic precursor/scaffold compound. Its pharmacological significance is newly emerging (Flanagan 2021), but as a street drug it is neither new nor widely used.