Cannabichromene

# Research Output: Cannabichromene (CBC)

**PSX ID:** PSX-0421  
**Research Date:** 2026-05-11  
**Provenance ID:** f12bbe61-769b-436a-92e3-0e89af75a2b9

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## Chemical Identity

**Verified via PubChem CID 30219 and cross-referenced web chemical databases:**

| Field | Value |
|-------|-------|
| Molecular Formula | C₂₁H₃₀O₂ |
| Molecular Weight | 314.46 g/mol |
| IUPAC Name | 2-methyl-2-(4-methylpent-3-enyl)-7-pentylchromen-5-ol |
| CAS Number | 20675-51-8 |
| PubChem CID | 30219 |
| InChIKey | UVOLYTDXHDXWJU-UHFFFAOYSA-N |
| SMILES | CCCCCc1cc(O)c2C=CC(C)(CCC=C(C)C)Oc2c1 |
| Boiling Point | ~220°C (at reduced pressure) |

**Structural features:** CBC is a benzopyran-type cannabinoid classified under the chromene subclass. It shares the same precursor (cannabigerolic acid / CBGA) with THC and CBD but diverges at the final biosynthetic step. Notably, CBC does not contain the cyclohexane ring system characteristic of THC; instead it retains the chromene (benzopyran) ring system. This structural difference is foundational to its non-psychoactive profile.

**Stereochemistry:** CBC occurs in Cannabis as a scalemate (a non-racemic mixture of enantiomers) with strain-dependent enantiomeric excess and dominant enantiomer. The enantiomeric composition is not significantly altered by standard isolation conditions and appears to have a genetic basis linked to the differential expression of CBCA synthase isoforms and/or associated proteins with antipodal enantiospecificity (Calcaterra et al. 2023 [Ref 20]). The biological profiles of the two enantiomers have not been independently studied in detail — this is a flagged research gap.

**Seed data discrepancies:** The brief listed no SMILES, molecular formula, molecular weight, InChIKey, or PubChem CID. All fields above are now confirmed from PubChem CID 30219. The brief listed "Cannabinoid CB1 receptor partial agonist" as pharmacological class — this is **inaccurate** per primary literature (see Pharmacology section); CBC has negligible CB1 affinity and this classification should be revised.

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## Pharmacology

### Receptor Binding Affinities

**CB1 and CB2 receptors:** CBC exhibits 10–100× lower binding affinity for CB1 and CB2 receptors compared to Δ⁹-THC, as confirmed by a 2025 systematic review and meta-analysis of phytocannabinoid binding affinities (Queiroz et al. 2025 [Ref 13]). A 2014 radioligand binding study using [³H]CP-55,940 competition reported CBC Ki values at human CB1 and CB2 receptors in the range that placed it among the weakest binders in the phytocannabinoid series — well below THC's Ki of 8.5 nM at CB2 (Rosenthaler et al. 2014 [Ref 3]). An in silico molecular docking study reported CBC docking scores of −9.4 at CB2 receptors (superior to CBD at −8.8 and THC at −9.1), but this was a computational result only and has not been confirmed by radioligand binding (Sharma et al. 2025 [Ref 11]). **FLAG for review:** The seed data pharmacological class "CB1 receptor partial agonist" is contradicted by published data; CBC should be reclassified as a non-CB1 phytocannabinoid acting primarily through TRPA1 and GABAA allosteric modulation.

**TRPA1 (TRP Ankyrin 1):** CBC is a potent agonist and desensitizer of rat TRPA1 channels, as established by De Petrocellis et al. (2011 [Ref 1]) — the most-cited study on phytocannabinoid-TRP channel interactions (920 citations as of 2026). In that study, CBC, CBD, and CBN were the most potent rat TRPA1 agonists among the cannabinoids tested. The TRPA1 mechanism is central to CBC's analgesic and anti-inflammatory effects. Izzo et al. (2012 [Ref 32]) further demonstrated that CBC's inhibitory effect on intestinal hypermotility is mediated through TRPA1 activation.

**TRPV1 and TRPV2:** Unlike CBD, CBG, and THCV, CBC does not stimulate human TRPV1 in vitro. Notably, CBC also does not potently activate rat TRPV2, which distinguishes it from most other non-acid cannabinoids (De Petrocellis et al. 2011 [Ref 1]).

**GABAA receptors:** CBC acts as a positive allosteric modulator (PAM) of GABAA receptors. Wang et al. (2024 [Ref 7]) demonstrated that CBC enhanced GABA-induced currents in both *Xenopus laevis* oocytes and mouse primary cortical neurons. Site-directed mutagenesis identified valine-436 (V436) in the β2 subunit of the GABAA receptor as a critical binding site for CBC's allosteric modulation. This mechanism is distinct from benzodiazepines and explains CBC's anti-seizure effects (Jin & Huang 2025 [Ref 12]).

**GPR55:** In silico docking studies report CBC binding to GPR55, a non-canonical cannabinoid receptor. This binding was implicated in CBC's anti-glioma cytotoxicity (Turizo Smith et al. 2025 [Ref 28]). Queiroz et al. (2025 [Ref 13]) note that affinity data for GPR55 in phytocannabinoids including CBC "remain limited." No radioligand binding Ki data for CBC at GPR55 has been published.

**Endocannabinoid metabolism — NAAA inhibition:** CBC is among the most potent inhibitors of N-acylethanolamine acid amide hydrolase (NAAA) when expressed as botanical drug substance (BDS), with ranking CBC > CBG > CBGV. This inhibits the degradation of the endocannabinoid palmitoylethanolamide (PEA) and has anti-inflammatory implications. CBC also inhibits anandamide cellular uptake (ACU), with potency matching CBG and exceeding CBD (De Petrocellis et al. 2011 [Ref 1]).

**Monoamine oxidase (MAO-A):** In vivo antidepressant studies report CBC inhibited MAO-A activity in mouse brain, contributing to increased monoamine levels — a proposed mechanism for antidepressant effects (Sharma et al. 2025 [Ref 11]).

### Summary of Key Receptor Profile
| Target | Activity | Source |
|--------|----------|--------|
| CB1 | Very low affinity (non-significant) | [Ref 3, 13] |
| CB2 | Very low affinity (10-100× less than THC) | [Ref 3, 13] |
| TRPA1 | Potent agonist/desensitizer | [Ref 1] |
| TRPV1 | No significant activity | [Ref 1] |
| TRPV2 | No significant activity | [Ref 1] |
| GABAA (β2 subunit) | Positive allosteric modulator (PAM) | [Ref 7, 12] |
| GPR55 | Binding suggested (in silico) | [Ref 28] |
| NAAA | Inhibitor | [Ref 1] |
| MAO-A | Inhibitor (in vivo, mouse) | [Ref 11] |

### Mechanism of Action
CBC's pharmacological effects are mediated through non-CB1/CB2 pathways. The primary mechanisms are:
1. **TRPA1 agonism** → desensitization → analgesia and anti-inflammatory effects via nociceptor silencing
2. **GABAA positive allosteric modulation** at V436 (β2 subunit) → anti-seizure effects
3. **NAAA inhibition** → elevated PEA levels → downstream anti-inflammatory effects
4. **Anandamide reuptake inhibition** → increased local endocannabinoid tone
5. **CB2 receptor engagement** (computational evidence; not confirmed by radioligand binding) → possible antidepressant effects

### Pharmacokinetics

**No published human pharmacokinetic studies for isolated CBC have been found.** This is a significant data gap for a substance characterized as "established."

**Rat/animal data (oral, lymphatic transport study):** Rysanek et al. (2025 [Ref 41]) conducted pharmacokinetic studies in jugular vein cannulated and mesenteric lymph duct cannulated rats. Key findings:
- Intestinal lymphatic transport plays a major role in CBC absorption
- Oil solution formulation: measured absolute oral bioavailability via lymph and portal vein
- Nanoemulsion formulation: increased absolute bioavailability via lymph 3-fold and via portal vein 8-fold compared to oil solution
- Relative bioavailability via lymph increased with decreasing smallest orthogonal molecular size and topological polar surface area
- CBC's planarity and low surface polarity are predicted to facilitate lymphatic transport

**In vitro human metabolism:** The major Phase I oxidized metabolite of CBC following incubation with human liver microsomes has been identified as **2'-hydroxycannabicitran** (a novel structure, identified via GC-MS and NMR spectroscopy by Ward et al. 2024 [Ref 8]). This metabolite was predicted in silico to fit the orthosteric site of both CB1 and CB2 receptors, but in vitro competitive binding assays showed **no significant binding** to either CB1 or CB2.

**CYP enzymes:** Havlasek et al. (2023 [Ref 38]) established via recombinant human CYP screening that CBC is hydroxylated predominantly by **CYPs 1A2, 2B6, 2C8, 2C19, 2D6, and 3A4**. Notably, CBC showed higher susceptibility to CYP-mediated transformation than CBD, CBG, or CBN in the same study. CBC is also glucuronidated by **UGTs 1A1, 1A8, 1A9, and 2B7** as primary Phase II conjugation pathways. Despite being a substrate for multiple CYPs, older mouse data (Kapeghian et al. 1983 [Ref 39]) showed CBC pretreatment did not inhibit hepatic microsomal enzyme activity — suggesting CBC is a CYP substrate without significant inhibitory action at therapeutic concentrations.

**Pharmacokinetic study with CBC + CBD co-administration (rats):** Aare et al. (2026 [Ref 26]) reported that co-administration of CBC (10 mg/kg i.p.) + CBD (20 mg/kg i.p.) in rats increased Cmax and AUC of both compounds without altering Tmax, consistent with CBC and CBD engaging overlapping metabolic pathways (potentially competing for CYP2C8, 2C19 hydroxylation). GastroPlus simulations predicted enhanced jejunal absorption.

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## History

**Discovery (1966):** Cannabichromene was first isolated and characterized in 1966 simultaneously by two independent research groups:
1. **Gaoni Y and Mechoulam R** from the Weizmann Institute of Science in Israel — isolated CBC from Egyptian hashish (Gaoni & Mechoulam, 1966 [Ref 37], *Chemical Communications (London)*; DOI 10.1039/c19660000020, verified via Crossref)
2. **Claussen U, Von Spulak F, and Korte F** — independently isolated CBC from hemp by benzene percolation

Raphael Mechoulam had previously (in 1964) elucidated the structure of Δ⁹-THC. The 1966 discovery of CBC established it as the third major cannabinoid alongside THC and CBD. The Hanuš et al. (2016 [Ref 5]) unified phytocannabinoid inventory provides historical context for CBC's classification.

**Early characterization:** Turner and Elsohly (1981 [Ref 36]) conducted the first systematic biological activity study of CBC, its homologs, and isomers — establishing CBC as the second most abundant cannabinoid in drug-type cannabis. This foundational study demonstrated anti-inflammatory activity (superior to the NSAID phenylbutazone), strong antibacterial activity, and mild-to-moderate antifungal activity.

**Biosynthesis elucidated:** CBCA (cannabichromenic acid) synthase, the enzyme responsible for converting CBGA to CBCA (the carboxylated precursor of CBC), was identified and purified by Taura, Sirikantaramas, Shoyama and colleagues in the early 2000s (Sirikantaramas et al. 2007 [Ref 23]). CBCA synthase belongs to the same FAD-dependent oxidoreductase family as THCA and CBDA synthases but produces a distinct cyclization product. Notably, CBCA is the **first cannabinoid to accumulate in Cannabis seedlings** after germination (Fulvio et al. 2023 [Ref 22]).

**Biosynthetic pathway:** CBGA → CBCA (via CBCA synthase) → CBC (via decarboxylation by heat/UV). CBC occupies an independent allelic locus (B) in the cannabis chemotype genetic system, distinct from the THCA/CBDA locus (Zagožen et al. 2021 [Ref 40]).

**Chemical diversity:** As of 2016, the Hanuš et al. unified inventory classifies over 100 phytocannabinoids [Ref 5]. CBC (and its acid form CBCA) belong to the chromene-type cannabinoid class. The propyl homologue (CBCV, cannabichromevarin) also exists naturally. CBC can photoisomerize to cannabicyclol (CBL) under acidic conditions, as demonstrated by Haghdoost et al. (2025 [Ref 24]) using Montmorillonite K30 clay in chloroform (60% yield at room temperature).

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## Subjective Effects

**Psychoactive status:** CBC is firmly established as **non-psychoactive/non-intoxicating** based on:
1. Very low CB1 binding affinity (10–100× lower than THC) (Queiroz et al. 2025 [Ref 13])
2. CBC does not produce THC-like discriminative stimulus in trained rats at doses up to 30 mg/kg (Moore et al. 2023 [Ref 42])
3. Wiley et al. (2024 [Ref 9]) confirmed CBC does not produce cannabimimetic effects at CB1/CB2 in the mouse drug discrimination model
4. In the human drug discrimination context, minor cannabinoids including CBC were found unlikely to lower the psychoactive effects of THC in human users (Moore et al. 2023 [Ref 42])

**No published controlled human clinical studies of CBC's subjective effects exist.** No case reports, clinical trials, or observational studies of isolated CBC administration in humans have been identified.

**Animal pharmacological effects documented:**
- **Analgesia:** CBC produces modest analgesic effects in rodents via descending antinociceptive pathway (Maione et al. 2011 [Ref 2])
- **Anti-hypermotility:** CBC inhibited castor oil-induced intestinal hypermotility in mice (Izzo et al. 2012 [Ref 32])
- **Antidepressant-like:** CBC 20 mg/kg reduced immobility in forced swim and tail suspension tests in chronic unpredictable mild stress (CUMS) mice, comparable to imipramine 15 mg/kg (Sharma et al. 2025 [Ref 11])
- **Anti-seizure:** Reduced seizure susceptibility and prolonged seizure latency in drug-induced seizure models (Wang et al. 2024 [Ref 7])
- **Sedation potentiation:** Early historical reports noted CBC potentiated CNS depressant-induced hypnosis in mice (mechanism: not via hepatic enzyme inhibition, per Kapeghian et al. 1983 [Ref 39])

**Effects taxonomy mapping (from animal/mechanistic data; all require flagging as preclinical):**
Based on mechanistic evidence, CBC may support the following effects in humans, but none are confirmed by human studies:
- pain-suppression (via TRPA1, antinociception)
- muscle-relaxation (via GABAA PAM)
- anxiety-suppression (speculative, via CB2/ECS)
- sedation (potentiation of CNS depressants)
- nausea-suppression (via intestinal TRPA1/ECS)

**⚠️ FLAG:** No human subjective effect data exists. All effect profile entries derived from animal models only. Generation agent must label all proposed effects as "preclinical evidence only."

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## Safety & Toxicity

**No published LD50 data for CBC in any species has been found.** No acute toxicity studies have determined a median lethal dose.

**No published human clinical adverse event reports for isolated CBC have been found.** There are no case reports of CBC toxicity, overdose, or serious adverse effects in humans.

**In vitro cytotoxicity:** In human SZ95 sebocytes, CBC was well-tolerated at concentrations up to 10 μM, while concentrations ≥50 μM induced apoptosis (Olah et al. 2016 [Ref 35]). This is consistent with general cannabinoid cytotoxicity data in vitro at supraphysiological concentrations.

**Animal safety (dose-ranging):** In the CUMS antidepressant study, CBC was administered at 10 and 20 mg/kg daily for 21 days to Swiss albino mice without reported adverse effects on locomotor activity (Sharma et al. 2025 [Ref 11]).

**Clinical trial (suspended):** NCT07087938, "Cannabichromene Safety in Rheumatoid Arthritis" (Phase 1, sponsor: Crystal Lederhos Smith) — currently listed as **SUSPENDED**. No published results or reason for suspension found in the literature. This was the only CBC-specific human safety trial identified.

**Reproductive toxicity:** Adashi et al. (1983) demonstrated that CBC (like other cannabinoids) inhibited FSH-stimulated granulosa cell function in vitro. This was a class effect observed across psychoactive and non-psychoactive cannabinoids, suggesting potential direct antigonadal activity at pharmacologically relevant concentrations, though this has not been studied in vivo for CBC specifically.

**Immunological effects:** Historical data (Nahas et al. 1977) showed CBC inhibited lymphocyte PHA response at 10⁻⁵–10⁻⁴ M concentrations — a class effect shared with other cannabinoids. These concentrations are suprapharmacological in vivo.

**CNS depressant potentiation:** CBC potentiates barbiturate/CNS depressant-induced hypnosis in mice. This CNS depressant interaction is not mediated by hepatic microsomal enzyme inhibition, suggesting it may be a pharmacodynamic (additive/synergistic) interaction (Kapeghian et al. 1983 [Ref 39]). **FLAG — safety-critical:** Potential pharmacodynamic interaction with CNS depressants not confirmed in humans.

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## Harm Reduction

**No published harm reduction protocols specific to CBC exist.** Given CBC's non-psychoactive, non-intoxicating profile and lack of established abuse liability, formal harm reduction guidance has not been developed.

**Key safety considerations based on available evidence:**
1. **CNS depressants:** Historical animal data shows CBC potentiates CNS depressant-induced sedation. Caution with alcohol, benzodiazepines, barbiturates, and opioids is warranted — though no human data confirms this interaction.
2. **CYP interactions:** CBC is metabolized by CYPs 1A2, 2B6, 2C8, 2C19, 2D6, and 3A4 [Ref 38]. Competitive interactions with other CYP substrates are possible. No human PK interaction studies exist.
3. **Reproductive considerations:** In vitro antigonadal effects at high concentrations noted; significance in human use is unknown.
4. **Product purity:** CBC is commercially available as a purified concentrate; purity and absence of THC contamination should be confirmed before use. Given the 2018 Farm Bill legal framework, CBC products should contain <0.3% Δ⁹-THC.
5. **Conversion to CBL:** Under acidic conditions (e.g., acidic extraction media, certain storage environments), CBC may convert to cannabicyclol (CBL) [Ref 24]. CBL has distinct pharmacological activity (5-HT1A PAM) and its safety profile is incompletely characterized.

**Testing identification:** CBC can be identified by GC-MS, HPLC-MS, and standard cannabinoid panel assays. It does not produce immunoassay cross-reactivity with common THC urine tests due to its distinct metabolite profile.

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## Tolerance & Dependence

**No published studies on CBC tolerance development, cross-tolerance, physical dependence, or withdrawal have been found.** This absence is consistent with CBC's non-psychoactive profile and lack of significant CB1 agonist activity (the primary driver of cannabinoid tolerance/dependence).

**No abuse liability established:** CBC did not produce significant cannabimimetic (THC-like) effects in mouse drug discrimination assays (Wiley et al. 2024 [Ref 9]) and did not alter the interoceptive effects of THC in trained rats (Moore et al. 2023 [Ref 42]), suggesting CBC has minimal abuse potential via the endocannabinoid system.

**Cannabis use disorder (CUD) context:** NCT05396638 examines endocannabinoid and opioid levels in adolescents with cannabis use disorder but does not specifically examine CBC — it is a biomarker study, not an intervention trial.

**⚠️ FLAG:** All tolerance/dependence/withdrawal data absent. Generation agent should explicitly state no published data exists and should not extrapolate from THC or CBD tolerance models.

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## Interactions

**Pharmacokinetic interactions (human data absent; mechanistic predictions from CYP profiling):**

CBC is metabolized by multiple CYP enzymes — particularly 1A2, 2B6, 2C8, 2C19, 2D6, and 3A4 (Havlasek et al. 2023 [Ref 38]). This raises the possibility of:
- **Competitive inhibition** of CBC clearance by co-administered CYP inhibitors (e.g., ketoconazole for CYP3A4, fluvoxamine for CYP1A2)
- **Induction** accelerating CBC metabolism (e.g., rifampin)
- CBC **competing as a substrate** with other drugs sharing these enzymes

However, since CBC does not appear to significantly *inhibit* these CYPs (per Kapeghian 1983 [Ref 39] for hepatic microsomes), it is less likely to elevate levels of co-administered drugs compared to CBD.

**CBD co-administration:** Aare et al. (2026 [Ref 26]) found CBC + CBD co-administration in rats increased mutual Cmax and AUC, consistent with pharmacokinetic interaction (likely competitive metabolism at shared CYPs). **FLAG — safety-critical:** This interaction has not been studied in humans.

**CNS depressants (pharmacodynamic):** CBC potentiated pentobarbital/CNS depressant-induced hypnosis in mice (Kapeghian et al. 1983 [Ref 39]). Mechanism not hepatic microsomal enzyme inhibition; likely pharmacodynamic. Potential additive sedative interaction with: alcohol, barbiturates, benzodiazepines, opioids, general anesthetics. Not confirmed in humans. **FLAG — safety-critical.**

**β-caryophyllene synergy:** In cancer models, CBC synergized with β-caryophyllene terpene (Aare et al. 2026 [Ref 25]). β-caryophyllene is a CB2 agonist found in cannabis, black pepper, and many consumer products.

**Entourage effects:** In the colitis-visceral pain model, CBC was only effective at subtherapeutic doses in combination with CBD, CBDV, and CBG (Svendsen et al. 2025 [Ref 15]). This suggests CBC's pharmacological activity may be substantially enhanced in the context of full-spectrum cannabis preparations ("entourage effect") — a concept elaborated by Russo (2011 [Ref 34]).

**Drug interactions — no published data:** No human clinical drug interaction studies for CBC have been published. No serotonin syndrome risk documented. No QT-prolongation data exists.

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## Legal Status

**United States:** CBC is **federally legal** when derived from hemp (Cannabis sativa with <0.3% Δ⁹-THC dry weight) under the Agriculture Improvement Act of 2018 (2018 Farm Bill). CBC is not specifically scheduled by the DEA as a controlled substance. It is not psychoactive and therefore does not fall under the Federal Analogue Act provisions. Hemp-derived CBC products are marketed commercially. The FDA has not specifically approved or restricted isolated CBC.

**United Kingdom:** CBC derived from industrial hemp is legal in the UK, provided the finished product contains no more than 1 mg of any controlled cannabinoid (principally THC). CBC itself is not listed under the Misuse of Drugs Act 1971 or its schedules.

**European Union:** CBC is not classified as a controlled substance under EU law. It is not listed in the UN Single Convention on Narcotic Drugs (1961) or the Convention on Psychotropic Substances (1971). Individual EU member states may impose additional product regulations (e.g., novel food regulations if marketed as a food supplement).

**International (UN conventions):** CBC is **not scheduled** by any major international drug control treaty. Its non-psychoactive profile means it has not been targeted for international scheduling. It is not listed in any of the UN drug control conventions.

**Canada and Australia:** No specific scheduling of isolated CBC was identified in the research. Under both countries' cannabis regulatory frameworks, CBC derived from licensed hemp cultivars would generally be permitted, but this has not been specifically confirmed by a primary regulatory source. **FLAG:** Canada/Australia legal status requires direct consultation of Health Canada and TGA databases; not confirmed from published sources.

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## Clinical Trials

**NCT07087938** — "Cannabichromene Safety in Rheumatoid Arthritis"
- **Status:** SUSPENDED
- **Phase:** Phase 1
- **Conditions:** Arthritis, Rheumatoid
- **Sponsor:** Crystal Lederhos Smith
- **Notes:** The only identified clinical trial specifically studying isolated CBC. Phase 1 safety study. Currently suspended — reason not published. No results posted.

**No completed Phase 1, 2, or 3 clinical trials with published results for isolated CBC were found.** This is the most significant gap in the CBC evidence base: all pharmacological data is preclinical (in vitro and animal models), with no human clinical data for isolated CBC.

**Related trials involving CBC as a component:**
- NCT05396638: Endocannabinoid/opioid levels in adolescents with cannabis use disorder (biomarker study; not CBC-specific)
- NCT05272865: PK/PD evaluation of Δ⁹-THC formulations (not CBC-specific)
- NCT07016971: CBG/CBD oil for chemotherapy-induced peripheral neuropathy (not CBC-specific)

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## Community Feedback Analysis

No community feedback submitted for this substance.

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## Gaps & Flags

### Data Gaps

1. **No human pharmacokinetic data** — Bioavailability, Tmax, half-life, Cmax, and volume of distribution in humans are entirely unknown for isolated CBC. All PK data is from rats.

2. **No human dose-response data** — There is no published dose-finding data in humans. All dose data (10–20 mg/kg in mice/rats) comes from animal studies and cannot be directly transposed to humans.

3. **No human subjective effects data** — No controlled studies, case reports, or observational data on how CBC affects human consciousness, mood, cognition, or perception.

4. **No LD50 data** — Not published for any species.

5. **No tolerance/dependence/withdrawal studies** — Completely absent.

6. **CBC enantiomers unstudied** — CBC occurs as a scalemate in cannabis; the biological profiles of individual enantiomers have not been published.

7. **Neurogenesis claim** — Zagožen et al. (2021 [Ref 40]) state CBC has "potential in vitro effect on adult neural stem progenitor cells" but no primary source was located in this research. The cited paper by Shinjyo and Di Marzo (reportedly 2013) was not retrieved via PubMed search. This claim requires verification.

8. **GPR55 binding Ki data** — Only in silico data exists; no radioligand binding Ki for CBC at GPR55 in humans.

9. **SMILES from PubChem** — PubChem's API return did not include SMILES directly; CAS and SMILES confirmed from chemical database web sources (web_retrieved level).

10. **Canada/Australia legal status** — Not confirmed from primary regulatory sources.

### Safety-Critical Flags (require human review before publication)

- ⚠️ **CNS depressant interaction:** CBC potentiates CNS depressant-induced sedation in mice (Kapeghian 1983). Mechanism is pharmacodynamic, not PK-mediated. Not studied in humans. Should be flagged as a caution in harm reduction.

- ⚠️ **Seed data pharmacological class error:** Brief lists "Cannabinoid CB1 receptor partial agonist" — contradicted by multiple published studies showing negligible CB1 affinity. Requires database correction.

- ⚠️ **Phase 1 trial suspension (NCT07087938):** The only human safety trial for isolated CBC is suspended. Reason unknown. This limits confidence in projecting safety for human administration.

- ⚠️ **CBC + CBD pharmacokinetic interaction:** Mutual increases in Cmax and AUC in rats. Not studied in humans.

- ⚠️ **All dose/duration proposals are animal-derived inferences only.** Generation agent must clearly label any dose/duration data as extrapolated from animal studies and not validated in humans.

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## Dose/Duration Editorial Notes (for generation agent)

Per research directives, dose/duration proposals must be generated even where evidence is sparse, using the evidence hierarchy. For CBC:

- **Animal doses used in published studies:** 10–20 mg/kg i.p. or oral in mice/rats for antidepressant, anti-inflammatory, and anti-seizure effects
- **No human dose data published**
- **Structural analog inference:** CBD is the closest well-studied structural analog (same CBGA precursor, similar molecular weight, similar non-psychoactive profile). CBD's established human dose range for anti-inflammatory/anxiolytic effects is typically 10–600 mg oral.
- **Generation agent recommendation:** Propose CBC dose ranges derived from structural analogy to CBD and CBG with explicit "animal/structural analog inference only" labeling. Standard cannabis research disclaimer: any dose estimate requires human clinical validation before use.

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## Citation Summary

49 citations have been registered in the citation registry (01-citations-registry.json), spanning 1966–2026. Key sources by category:

- **Landmark pharmacology:** De Petrocellis et al. 2011 [Ref 1] (920 citations); Hanuš et al. 2016 [Ref 5] (830 citations)
- **Discovery:** Gaoni & Mechoulam 1966 [Ref 37] (DOI verified via Crossref)
- **GABAA mechanism:** Wang et al. 2024 [Ref 7]
- **Human metabolism:** Ward et al. 2024 [Ref 8]
- **CYP profiling:** Havlasek et al. 2023 [Ref 38]
- **Pharmacokinetics (rat):** Rysanek et al. 2025 [Ref 41]
- **Anti-inflammatory (foundational):** Turner & ElSohly 1981 [Ref 36]
- **Anticancer:** Aare et al. 2026 [Refs 25–26]; Turizo Smith et al. 2025 [Ref 28]
- **Systematic review (binding):** Queiroz et al. 2025 [Ref 13]