Human cannabinoid receptor 1 / CB1 / CNR1

evidence_span

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experimental_model

Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1

exposure

A ligand series measured for both stimulation and inhibition of cAMP, with and without forskolin

limitations

Reports that the receptor couples to Gs as well as Gi and that ligands differ between the two pathways. It is a transfected overexpression system, where Gs coupling is more readily observed.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Human receptor in CHO cells

plain_language

The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.

primary_references

[thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0

tissue_or_cell_type

Transfected cells

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 179–190

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1 · source_derived_draft · unverified_draft

### thc-agonist-specific-trafficking Cannabinoid receptors coupled to both Gs and Gi and could consequently stimulate or inhibit cAMP formation, with an identical rank order of agonist potency in both assays but markedly different intrinsic activities, anandamide and CP-55,940 being much less efficacious at stimulating cAMP than at inhibiting it, and forskolin enhancing the potency of some agonists a hundred-fold while not affecting others. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The same receptor can push cAMP up as well as down, and which way depends on which drug is bound. organism: Human receptor in CHO cells tissue_or_cell_type: Transfected cells experimental_model: Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1 limitations: Reports that the receptor couples to Gs as well as Gi and that ligands differ between the two pathways. It is a transfected overexpression system, where Gs coupling is more readily observed. exposure: A ligand series measured for both stimulation and inhibition of cAMP, with and without forskolin evidence_span: {"source_cache": "artifacts/thc-research/9864268.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d", "start_char": 0, "end_char": 1502, "text_sha256": "a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d"} [thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0

evidence_span

{"source_cache": "artifacts/thc-research/24899717.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "037d9888adff577901a9dc0d0cd27fdb4fd755da283857a848a15484dd53d2ed", "start_char": 0, "end_char": 1204, "text_sha256": "037d9888adff577901a9dc0d0cd27fdb4fd755da283857a848a15484dd53d2ed"}

experimental_model

Paired recordings and presynaptic calcium imaging in mouse hippocampal slices

exposure

CB1 activation and removal of tonic activity at interneuron-pyramidal cell connections

limitations

Identifies the specific channel and gives the power relationship between calcium and release. It concerns inhibitory terminals of one interneuron class.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mouse

plain_language

The receptor works by closing the calcium gate that triggers transmitter release.

primary_references

[thc-p24899717] Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release. (2014). https://pubmed.ncbi.nlm.nih.gov/24899717/ DOI: 10.1523/jneurosci.0247-14.2014

tissue_or_cell_type

Hippocampus

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 192–203

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Paired recordings and presynaptic calcium imaging in mouse hippocampal slices · source_derived_draft · unverified_draft

### thc-cb1-calcium-channel CB1 controls GABA release by inhibiting calcium entry into presynaptic axon terminals via N-type Cav2.2 channels, with a power relationship of exponent 2.2 between unitary inhibitory current amplitude and intrabouton calcium. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The receptor works by closing the calcium gate that triggers transmitter release. organism: Mouse tissue_or_cell_type: Hippocampus experimental_model: Paired recordings and presynaptic calcium imaging in mouse hippocampal slices limitations: Identifies the specific channel and gives the power relationship between calcium and release. It concerns inhibitory terminals of one interneuron class. exposure: CB1 activation and removal of tonic activity at interneuron-pyramidal cell connections evidence_span: {"source_cache": "artifacts/thc-research/24899717.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "037d9888adff577901a9dc0d0cd27fdb4fd755da283857a848a15484dd53d2ed", "start_char": 0, "end_char": 1204, "text_sha256": "037d9888adff577901a9dc0d0cd27fdb4fd755da283857a848a15484dd53d2ed"} [thc-p24899717] Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release. (2014). https://pubmed.ncbi.nlm.nih.gov/24899717/ DOI: 10.1523/jneurosci.0247-14.2014

evidence_span

{"source_cache": "artifacts/thc-research/2165569.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db", "start_char": 0, "end_char": 1256, "text_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db"}

experimental_model

Cloning and heterologous expression of a complementary DNA from rat brain

exposure

Cannabinoid binding and adenylate cyclase inhibition in the transfected cells

limitations

The founding cloning paper. It establishes a receptor, which is what displaced the membrane-disruption explanation of cannabinoid action.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat receptor expressed in cells

plain_language

Cannabis acts on a specific receptor, not by melting cell membranes as was assumed.

primary_references

[thc-p2165569] Structure of a cannabinoid receptor and functional expression of the cloned cDNA. (1990). https://pubmed.ncbi.nlm.nih.gov/2165569/ DOI: 10.1038/346561a0

tissue_or_cell_type

Brain and neural cell lines

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 62–73

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning and heterologous expression of a complementary DNA from rat brain · source_derived_draft · unverified_draft

### thc-cb1-cloned A cloned complementary DNA encoded a G protein-coupled receptor that inhibits adenylate cyclase in a dose-dependent, stereoselective and pertussis-toxin-sensitive manner, is more responsive to psychoactive than to non-psychoactive cannabinoids, and whose messenger RNA is found in the brain regions that have cannabinoid receptors. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: Cannabis acts on a specific receptor, not by melting cell membranes as was assumed. organism: Rat receptor expressed in cells tissue_or_cell_type: Brain and neural cell lines experimental_model: Cloning and heterologous expression of a complementary DNA from rat brain limitations: The founding cloning paper. It establishes a receptor, which is what displaced the membrane-disruption explanation of cannabinoid action. exposure: Cannabinoid binding and adenylate cyclase inhibition in the transfected cells evidence_span: {"source_cache": "artifacts/thc-research/2165569.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db", "start_char": 0, "end_char": 1256, "text_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db"} [thc-p2165569] Structure of a cannabinoid receptor and functional expression of the cloned cDNA. (1990). https://pubmed.ncbi.nlm.nih.gov/2165569/ DOI: 10.1038/346561a0

evidence_span

{"source_cache": "artifacts/thc-research/15778743.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "813967ae44806749032cc8f98384086ca5ae7f0c4a6367a56cbb375680e205ac", "start_char": 0, "end_char": 1724, "text_sha256": "813967ae44806749032cc8f98384086ca5ae7f0c4a6367a56cbb375680e205ac"}

experimental_model

CB1-mediated modulation of food intake measured in mice

exposure

Cannabinoid agonists and antagonists on feeding

limitations

A bidirectional pharmacological test of the same axis in a second species.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mouse

plain_language

The receptor sets appetite in both directions.

primary_references

[thc-p15778743] CB1 cannabinoid receptor-mediated modulation of food intake in mice. (2005). https://pubmed.ncbi.nlm.nih.gov/15778743/ DOI: 10.1038/sj.bjp.0706157

tissue_or_cell_type

Whole body

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 504–515

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CB1-mediated modulation of food intake measured in mice · source_derived_draft · unverified_draft

### thc-cb1-food-intake CB1 cannabinoid receptor activation modulated food intake in mice, with agonists and antagonists moving intake in opposite directions. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The receptor sets appetite in both directions. organism: Mouse tissue_or_cell_type: Whole body experimental_model: CB1-mediated modulation of food intake measured in mice limitations: A bidirectional pharmacological test of the same axis in a second species. exposure: Cannabinoid agonists and antagonists on feeding evidence_span: {"source_cache": "artifacts/thc-research/15778743.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "813967ae44806749032cc8f98384086ca5ae7f0c4a6367a56cbb375680e205ac", "start_char": 0, "end_char": 1724, "text_sha256": "813967ae44806749032cc8f98384086ca5ae7f0c4a6367a56cbb375680e205ac"} [thc-p15778743] CB1 cannabinoid receptor-mediated modulation of food intake in mice. (2005). https://pubmed.ncbi.nlm.nih.gov/15778743/ DOI: 10.1038/sj.bjp.0706157

evidence_span

{"source_cache": "artifacts/thc-research/1718258.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6cd532c253d8e3d3d40738876bf1ba5a38d5c678355f5e871fb5a853aa3362e0", "start_char": 0, "end_char": 1497, "text_sha256": "6cd532c253d8e3d3d40738876bf1ba5a38d5c678355f5e871fb5a853aa3362e0"}

experimental_model

Molecular cloning of the human receptor with tissue expression analysis

exposure

Expression analysis across tissues

limitations

Extends the receptor to humans and finds it outside the brain, which is the first hint that the system is not purely neural.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Human receptor

plain_language

The same receptor turns up in tissue far from the brain.

primary_references

[thc-p1718258] Molecular cloning of a human cannabinoid receptor which is also expressed in testis. (1991). https://pubmed.ncbi.nlm.nih.gov/1718258/ DOI: 10.1042/bj2790129

tissue_or_cell_type

Brain and testis

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 75–86

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Molecular cloning of the human receptor with tissue expression analysis · source_derived_draft · unverified_draft

### thc-cb1-human-testis A human cannabinoid receptor was cloned and found to be expressed in testis as well as brain. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The same receptor turns up in tissue far from the brain. organism: Human receptor tissue_or_cell_type: Brain and testis experimental_model: Molecular cloning of the human receptor with tissue expression analysis limitations: Extends the receptor to humans and finds it outside the brain, which is the first hint that the system is not purely neural. exposure: Expression analysis across tissues evidence_span: {"source_cache": "artifacts/thc-research/1718258.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6cd532c253d8e3d3d40738876bf1ba5a38d5c678355f5e871fb5a853aa3362e0", "start_char": 0, "end_char": 1497, "text_sha256": "6cd532c253d8e3d3d40738876bf1ba5a38d5c678355f5e871fb5a853aa3362e0"} [thc-p1718258] Molecular cloning of a human cannabinoid receptor which is also expressed in testis. (1991). https://pubmed.ncbi.nlm.nih.gov/1718258/ DOI: 10.1042/bj2790129

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/thc-research/10234009.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73965589817407e173255ab6db300e7969b0e91a4ca4cd3d39cee1f5873d1e05", "start_char": 0, "end_char": 1911, "text_sha256": "73965589817407e173255ab6db300e7969b0e91a4ca4cd3d39cee1f5873d1e05"}

experimental_model

Mutational mapping of CB1 receptor domains against desensitisation and internalisation

exposure

Sustained agonist exposure with receptor trafficking measurement

limitations

Separates two adaptive processes that are often conflated. It is a recombinant system.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Recombinant receptor

plain_language

Going deaf to the drug and removing the receptor from the surface are two different things.

primary_references

[thc-p10234009] Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. (1999). https://pubmed.ncbi.nlm.nih.gov/10234009/ DOI: 10.1523/jneurosci.19-10-03773.1999

tissue_or_cell_type

Transfected cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 205–216

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mutational mapping of CB1 receptor domains against desensitisation and internalisation · source_derived_draft · unverified_draft

### thc-desensitisation-domains Distinct domains of the CB1 receptor mediate desensitisation and internalisation, so the two adaptive responses are separable. Condition category: machinery_impairment nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: Going deaf to the drug and removing the receptor from the surface are two different things. organism: Recombinant receptor tissue_or_cell_type: Transfected cells experimental_model: Mutational mapping of CB1 receptor domains against desensitisation and internalisation limitations: Separates two adaptive processes that are often conflated. It is a recombinant system. exposure: Sustained agonist exposure with receptor trafficking measurement evidence_span: {"source_cache": "artifacts/thc-research/10234009.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73965589817407e173255ab6db300e7969b0e91a4ca4cd3d39cee1f5873d1e05", "start_char": 0, "end_char": 1911, "text_sha256": "73965589817407e173255ab6db300e7969b0e91a4ca4cd3d39cee1f5873d1e05"} [thc-p10234009] Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. (1999). https://pubmed.ncbi.nlm.nih.gov/10234009/ DOI: 10.1523/jneurosci.19-10-03773.1999

evidence_span

{"source_cache": "artifacts/paracetamol-research/18485596.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f", "start_char": 0, "end_char": 1545, "text_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f"}

experimental_model

Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions

exposure

Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion

limitations

The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like.

primary_references

[apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030

tissue_or_cell_type

Brain and spinal cord

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 337–348

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions · source_derived_draft · unverified_draft

### apap-cb1-needed-but-not-bound In thermal, mechanical and chemical pain tests the specific cannabinoid receptor 1 antagonist AM-251 abolished the analgesic action of acetaminophen, which was also lost in cannabinoid receptor 1 knockout mice, yet acetaminophen was shown unable to bind to those receptors demonstrating an indirect involvement, inhibition of fatty acid amide hydrolase suppressed the effect, and the antinociceptive activity of a cannabinoid receptor 1 agonist was itself inhibited by lesion of bulbospinal serotonergic pathways and by spinal 5-HT receptor antagonists, leading the authors to propose a sequence of metabolism to AM404, indirect cannabinoid receptor involvement, reinforcement of serotonergic bulbospinal pathways and action at spinal serotonergic receptors. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like. organism: Mouse tissue_or_cell_type: Brain and spinal cord experimental_model: Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions limitations: The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis. exposure: Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion evidence_span: {"source_cache": "artifacts/paracetamol-research/18485596.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f", "start_char": 0, "end_char": 1545, "text_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f"} [apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030

evidence_span

{"source_cache": "artifacts/thc-research/1470919.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2", "start_char": 0, "end_char": 757, "text_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2"}

experimental_model

Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation

exposure

Screen for endogenous ligands of the cannabinoid receptor

limitations

The isolation of the first endogenous ligand. The bioassay is a peripheral tissue twitch, not a central behavioural effect.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Pig brain, with mouse bioassay

plain_language

The brain makes its own version of the drug, and it is built from a fatty acid.

primary_references

[thc-p1470919] Isolation and structure of a brain constituent that binds to the cannabinoid receptor. (1992). https://pubmed.ncbi.nlm.nih.gov/1470919/ DOI: 10.1126/science.1470919

tissue_or_cell_type

Brain and vas deferens

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 244–255

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation · source_derived_draft · unverified_draft

### thc-anandamide-isolated Arachidonylethanolamide, an arachidonic acid derivative isolated from porcine brain, competitively inhibited binding of a radiolabelled cannabinoid probe to synaptosomal membranes and produced concentration-dependent inhibition of the electrically evoked twitch of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The brain makes its own version of the drug, and it is built from a fatty acid. organism: Pig brain, with mouse bioassay tissue_or_cell_type: Brain and vas deferens experimental_model: Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation limitations: The isolation of the first endogenous ligand. The bioassay is a peripheral tissue twitch, not a central behavioural effect. exposure: Screen for endogenous ligands of the cannabinoid receptor evidence_span: {"source_cache": "artifacts/thc-research/1470919.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2", "start_char": 0, "end_char": 757, "text_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2"} [thc-p1470919] Isolation and structure of a brain constituent that binds to the cannabinoid receptor. (1992). https://pubmed.ncbi.nlm.nih.gov/1470919/ DOI: 10.1126/science.1470919

evidence_span

{"source_cache": "artifacts/thc-research/18354002.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "20b254a1e7d4462dcad993b76e889a26d729d604c71e2456c2d13a2a1420c728", "start_char": 0, "end_char": 2055, "text_sha256": "20b254a1e7d4462dcad993b76e889a26d729d604c71e2456c2d13a2a1420c728"}

experimental_model

Post-mortem and surgical human hippocampal tissue from epilepsy

exposure

Measurement of CB1 and endocannabinoid system elements in epileptic tissue

limitations

A human tissue measurement, but in diseased tissue where the disease itself may drive the change. It is not a measurement of cannabis users.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Human

plain_language

In diseased human hippocampus the whole system is turned down, receptor included.

primary_references

[thc-p18354002] Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. (2008). https://pubmed.ncbi.nlm.nih.gov/18354002/ DOI: 10.1523/jneurosci.4465-07.2008

tissue_or_cell_type

Hippocampus

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 231–242

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Post-mortem and surgical human hippocampal tissue from epilepsy · source_derived_draft · unverified_draft

### thc-cb1-downregulation-human CB1 receptors and related molecular elements of the endocannabinoid system were downregulated in epileptic human hippocampus. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: In diseased human hippocampus the whole system is turned down, receptor included. organism: Human tissue_or_cell_type: Hippocampus experimental_model: Post-mortem and surgical human hippocampal tissue from epilepsy limitations: A human tissue measurement, but in diseased tissue where the disease itself may drive the change. It is not a measurement of cannabis users. exposure: Measurement of CB1 and endocannabinoid system elements in epileptic tissue evidence_span: {"source_cache": "artifacts/thc-research/18354002.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "20b254a1e7d4462dcad993b76e889a26d729d604c71e2456c2d13a2a1420c728", "start_char": 0, "end_char": 2055, "text_sha256": "20b254a1e7d4462dcad993b76e889a26d729d604c71e2456c2d13a2a1420c728"} [thc-p18354002] Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. (2008). https://pubmed.ncbi.nlm.nih.gov/18354002/ DOI: 10.1523/jneurosci.4465-07.2008

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Repeated MAGL inhibitor administration in mice with genetic confirmation

exposure

Repeated JZL184 administration, with Mgll genetic disruption as confirmation

limitations

A tolerance result produced by raising the natural ligand rather than by giving a drug. The genetic phenocopy is what rules out an off-target effect of the inhibitor.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mouse

plain_language

Flooding the system with its own messenger produces the same tolerance and dependence as the drug does.

primary_references

[thc-p20729846] Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. (2010). https://pubmed.ncbi.nlm.nih.gov/20729846/ DOI: 10.1038/nn.2616

tissue_or_cell_type

Nervous system

trigger_kind

machinery_impairment Imported condition classification; unverified.

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 400–411

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Repeated MAGL inhibitor administration in mice with genetic confirmation · source_derived_draft · unverified_draft

### thc-magl-blockade-antagonism After repeated administration the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to CB1 agonists in mice, effects phenocopied by genetic disruption of Mgll, and chronic blockade also caused physical dependence and impaired endocannabinoid-dependent synaptic plasticity. Condition category: machinery_impairment nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: Flooding the system with its own messenger produces the same tolerance and dependence as the drug does. organism: Mouse tissue_or_cell_type: Nervous system experimental_model: Repeated MAGL inhibitor administration in mice with genetic confirmation limitations: A tolerance result produced by raising the natural ligand rather than by giving a drug. The genetic phenocopy is what rules out an off-target effect of the inhibitor. exposure: Repeated JZL184 administration, with Mgll genetic disruption as confirmation evidence_span: {"source_cache": "artifacts/thc-research/20729846.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9c812c031525007d63883a15d43c6f342366dba7fa85ad0a9fef7152aa47ee7d", "start_char": 0, "end_char": 1167, "text_sha256": "9c812c031525007d63883a15d43c6f342366dba7fa85ad0a9fef7152aa47ee7d"} [thc-p20729846] Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. (2010). https://pubmed.ncbi.nlm.nih.gov/20729846/ DOI: 10.1038/nn.2616

evidence_span

{"source_cache": "artifacts/thc-research/8515284.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "36a5b1eec5097dbdfd0224629f4d8449f8688d0476820823ffcbe3b92d68c66d", "start_char": 0, "end_char": 1015, "text_sha256": "36a5b1eec5097dbdfd0224629f4d8449f8688d0476820823ffcbe3b92d68c66d"}

experimental_model

Receptor binding and adenylate cyclase assays with anandamide

exposure

Anandamide against cannabinoid receptors and cyclase

limitations

Confirms the endogenous ligand reproduces the receptor signature of the drug.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat brain preparations

plain_language

The natural ligand does the same thing to the same enzyme as the drug.

primary_references

[thc-p8515284] Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. (1993). https://pubmed.ncbi.nlm.nih.gov/8515284/ DOI: 10.1111/j.1471-4159.1993.tb03576.x

tissue_or_cell_type

Brain membranes

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 257–268

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor binding and adenylate cyclase assays with anandamide · source_derived_draft · unverified_draft

### thc-anandamide-inhibits-cyclase Anandamide interacted specifically with cannabinoid receptors and inhibited adenylate cyclase, reproducing the signature response of the plant cannabinoids. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The natural ligand does the same thing to the same enzyme as the drug. organism: Rat brain preparations tissue_or_cell_type: Brain membranes experimental_model: Receptor binding and adenylate cyclase assays with anandamide limitations: Confirms the endogenous ligand reproduces the receptor signature of the drug. exposure: Anandamide against cannabinoid receptors and cyclase evidence_span: {"source_cache": "artifacts/thc-research/8515284.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "36a5b1eec5097dbdfd0224629f4d8449f8688d0476820823ffcbe3b92d68c66d", "start_char": 0, "end_char": 1015, "text_sha256": "36a5b1eec5097dbdfd0224629f4d8449f8688d0476820823ffcbe3b92d68c66d"} [thc-p8515284] Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. (1993). https://pubmed.ncbi.nlm.nih.gov/8515284/ DOI: 10.1111/j.1471-4159.1993.tb03576.x

evidence_span

{"source_cache": "artifacts/thc-research/27768894.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eca46f11c563fdc4265930c57c7d856782d2130b77721d8470e779a3efaf6cc1", "start_char": 0, "end_char": 1042, "text_sha256": "eca46f11c563fdc4265930c57c7d856782d2130b77721d8470e779a3efaf6cc1"}

experimental_model

X-ray crystallography of the human CB1 receptor

exposure

Antagonist-bound receptor crystallography

limitations

A structure of one conformational state with one ligand class bound. It does not by itself explain agonist efficacy differences.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Human receptor

plain_language

The receptor has a defined shape, and the drug fits into a specific slot in it.

primary_references

[thc-p27768894] Crystal Structure of the Human Cannabinoid Receptor CB1. (2016). https://pubmed.ncbi.nlm.nih.gov/27768894/ DOI: 10.1016/j.cell.2016.10.004

tissue_or_cell_type

Purified receptor

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 114–125

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography of the human CB1 receptor · source_derived_draft · unverified_draft

### thc-cb1-structure The crystal structure of the human CB1 receptor was determined, resolving the architecture of its ligand-binding pocket. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The receptor has a defined shape, and the drug fits into a specific slot in it. organism: Human receptor tissue_or_cell_type: Purified receptor experimental_model: X-ray crystallography of the human CB1 receptor limitations: A structure of one conformational state with one ligand class bound. It does not by itself explain agonist efficacy differences. exposure: Antagonist-bound receptor crystallography evidence_span: {"source_cache": "artifacts/thc-research/27768894.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "eca46f11c563fdc4265930c57c7d856782d2130b77721d8470e779a3efaf6cc1", "start_char": 0, "end_char": 1042, "text_sha256": "eca46f11c563fdc4265930c57c7d856782d2130b77721d8470e779a3efaf6cc1"} [thc-p27768894] Crystal Structure of the Human Cannabinoid Receptor CB1. (2016). https://pubmed.ncbi.nlm.nih.gov/27768894/ DOI: 10.1016/j.cell.2016.10.004

evidence_span

{"source_cache": "artifacts/thc-research/30639103.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8e9d44274299ee2844e8fdb56ae1a20709f3fde09ed0ef99ee406a4e46a3c7f", "start_char": 0, "end_char": 1108, "text_sha256": "e8e9d44274299ee2844e8fdb56ae1a20709f3fde09ed0ef99ee406a4e46a3c7f"}

experimental_model

X-ray crystallography of the human CB2 receptor

exposure

Ligand-bound receptor crystallography

limitations

A companion structure for the second receptor, from the same structural programme.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Human receptor

plain_language

The two receptors are shaped differently, which is why drugs can prefer one.

primary_references

[thc-p30639103] Crystal Structure of the Human Cannabinoid Receptor CB2. (2019). https://pubmed.ncbi.nlm.nih.gov/30639103/ DOI: 10.1016/j.cell.2018.12.011

tissue_or_cell_type

Purified receptor

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 127–138

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography of the human CB2 receptor · source_derived_draft · unverified_draft

### thc-cb2-structure The crystal structure of the human CB2 receptor was determined, showing how its binding pocket differs from that of CB1. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The two receptors are shaped differently, which is why drugs can prefer one. organism: Human receptor tissue_or_cell_type: Purified receptor experimental_model: X-ray crystallography of the human CB2 receptor limitations: A companion structure for the second receptor, from the same structural programme. exposure: Ligand-bound receptor crystallography evidence_span: {"source_cache": "artifacts/thc-research/30639103.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8e9d44274299ee2844e8fdb56ae1a20709f3fde09ed0ef99ee406a4e46a3c7f", "start_char": 0, "end_char": 1108, "text_sha256": "e8e9d44274299ee2844e8fdb56ae1a20709f3fde09ed0ef99ee406a4e46a3c7f"} [thc-p30639103] Crystal Structure of the Human Cannabinoid Receptor CB2. (2019). https://pubmed.ncbi.nlm.nih.gov/30639103/ DOI: 10.1016/j.cell.2018.12.011

evidence_span

{"source_cache": "artifacts/thc-research/16672646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dd4ddba9cf6987282758f17ce79c5624f9a3cc6c02044a4a45c0664ef6fd21c3", "start_char": 0, "end_char": 1832, "text_sha256": "dd4ddba9cf6987282758f17ce79c5624f9a3cc6c02044a4a45c0664ef6fd21c3"}

experimental_model

Immunoelectron microscopy localising diacylglycerol lipase-alpha

exposure

Subcellular localisation against presynaptic CB1

limitations

An anatomical result that makes the signalling geometry concrete: the enzyme that makes the messenger sits directly opposite the receptor.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rodent

plain_language

The factory for the messenger sits directly across the synapse from its receptor.

primary_references

[thc-p16672646] Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. (2006). https://pubmed.ncbi.nlm.nih.gov/16672646/ DOI: 10.1523/jneurosci.0054-06.2006

tissue_or_cell_type

Postsynaptic spine

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 309–320

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunoelectron microscopy localising diacylglycerol lipase-alpha · source_derived_draft · unverified_draft

### thc-dagla-localisation Diacylglycerol lipase-alpha was localised around the postsynaptic spine, placing the production site of 2-arachidonoylglycerol in close proximity to the presynaptic CB1 receptor. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The factory for the messenger sits directly across the synapse from its receptor. organism: Rodent tissue_or_cell_type: Postsynaptic spine experimental_model: Immunoelectron microscopy localising diacylglycerol lipase-alpha limitations: An anatomical result that makes the signalling geometry concrete: the enzyme that makes the messenger sits directly opposite the receptor. exposure: Subcellular localisation against presynaptic CB1 evidence_span: {"source_cache": "artifacts/thc-research/16672646.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dd4ddba9cf6987282758f17ce79c5624f9a3cc6c02044a4a45c0664ef6fd21c3", "start_char": 0, "end_char": 1832, "text_sha256": "dd4ddba9cf6987282758f17ce79c5624f9a3cc6c02044a4a45c0664ef6fd21c3"} [thc-p16672646] Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. (2006). https://pubmed.ncbi.nlm.nih.gov/16672646/ DOI: 10.1523/jneurosci.0054-06.2006

evidence_span

{"source_cache": "artifacts/thc-research/23463697.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cf035f4613f2090d3eaa60f90857a2dd265f69435b63d470e3dbe82f2350a079", "start_char": 0, "end_char": 1315, "text_sha256": "cf035f4613f2090d3eaa60f90857a2dd265f69435b63d470e3dbe82f2350a079"}

experimental_model

Sham-feeding protocol in rats with jejunal endocannabinoid measurement and peripheral CB1 antagonists

exposure

Sham feeding of defined fatty acid emulsions with peripherally restricted CB1 antagonists

limitations

Sham feeding separates oral exposure from absorption, and the peripherally restricted antagonists separate a gut mechanism from a brain one.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat

plain_language

The gut messenger is what makes the animal want more of that fat, and blocking it outside the brain removes the wanting.

primary_references

[thc-p23463697] Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. (2013). https://pubmed.ncbi.nlm.nih.gov/23463697/ DOI: 10.1096/fj.13-227587

tissue_or_cell_type

Jejunum and behaviour

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 712–723

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sham-feeding protocol in rats with jejunal endocannabinoid measurement and peripheral CB1 antagonists · source_derived_draft · unverified_draft

### thc-gut-endocannabinoids-drive-preference Rats displayed strong preference for emulsions containing linoleic acid in a two-bottle-choice sham-feeding test, and the preference was blocked by the peripherally restricted CB1 antagonists AM6546 and URB447. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The gut messenger is what makes the animal want more of that fat, and blocking it outside the brain removes the wanting. organism: Rat tissue_or_cell_type: Jejunum and behaviour experimental_model: Sham-feeding protocol in rats with jejunal endocannabinoid measurement and peripheral CB1 antagonists limitations: Sham feeding separates oral exposure from absorption, and the peripherally restricted antagonists separate a gut mechanism from a brain one. exposure: Sham feeding of defined fatty acid emulsions with peripherally restricted CB1 antagonists evidence_span: {"source_cache": "artifacts/thc-research/23463697.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cf035f4613f2090d3eaa60f90857a2dd265f69435b63d470e3dbe82f2350a079", "start_char": 0, "end_char": 1315, "text_sha256": "cf035f4613f2090d3eaa60f90857a2dd265f69435b63d470e3dbe82f2350a079"} [thc-p23463697] Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. (2013). https://pubmed.ncbi.nlm.nih.gov/23463697/ DOI: 10.1096/fj.13-227587

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/thc-research/21278728.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d19499dcf42cdfc31c0fc46420a1bc84babcbfcd366cf1cb37f3fed8f5d38281", "start_char": 0, "end_char": 953, "text_sha256": "d19499dcf42cdfc31c0fc46420a1bc84babcbfcd366cf1cb37f3fed8f5d38281"}

experimental_model

Lifelong n-3 deficient diet in mice with synaptic recordings and receptor coupling assays

exposure

Lifelong dietary insufficiency of n-3 polyunsaturated fatty acids

limitations

A dietary manipulation with a molecular readout, receptor-effector uncoupling, rather than only a behavioural one. It is a lifelong deficiency, not a short-term change.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mouse

plain_language

The receptor was still there but no longer connected to what it talks to.

primary_references

[thc-p21278728] Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. (2011). https://pubmed.ncbi.nlm.nih.gov/21278728/ DOI: 10.1038/nn.2736

tissue_or_cell_type

Prelimbic prefrontal cortex and accumbens

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 634–645

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lifelong n-3 deficient diet in mice with synaptic recordings and receptor coupling assays · source_derived_draft · unverified_draft

### thc-n3-uncouples-cb1 In n-3-deficient mice, presynaptic CB1 receptors that normally respond to endocannabinoids were uncoupled from their effector Gi/o proteins. Condition category: nutrient_deficiency nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The receptor was still there but no longer connected to what it talks to. organism: Mouse tissue_or_cell_type: Prelimbic prefrontal cortex and accumbens experimental_model: Lifelong n-3 deficient diet in mice with synaptic recordings and receptor coupling assays limitations: A dietary manipulation with a molecular readout, receptor-effector uncoupling, rather than only a behavioural one. It is a lifelong deficiency, not a short-term change. exposure: Lifelong dietary insufficiency of n-3 polyunsaturated fatty acids evidence_span: {"source_cache": "artifacts/thc-research/21278728.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d19499dcf42cdfc31c0fc46420a1bc84babcbfcd366cf1cb37f3fed8f5d38281", "start_char": 0, "end_char": 953, "text_sha256": "d19499dcf42cdfc31c0fc46420a1bc84babcbfcd366cf1cb37f3fed8f5d38281"} [thc-p21278728] Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. (2011). https://pubmed.ncbi.nlm.nih.gov/21278728/ DOI: 10.1038/nn.2736

evidence_span

{"source_cache": "artifacts/thc-research/11279497.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f93de867c0ce253b42d9c248504f4471431310bdc0629fec2a8c49d2eba55e8e", "start_char": 0, "end_char": 1117, "text_sha256": "f93de867c0ce253b42d9c248504f4471431310bdc0629fec2a8c49d2eba55e8e"}

experimental_model

Paired recordings in rat hippocampal slices with CB1 antagonists

exposure

Postsynaptic depolarisation with presynaptic release measurement

limitations

Establishes the direction of the signal, which is what makes the system a feedback loop rather than a transmitter pathway.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat

plain_language

The signal runs backwards across the synapse, which almost nothing else does.

primary_references

[thc-p11279497] Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. (2001). https://pubmed.ncbi.nlm.nih.gov/11279497/ DOI: 10.1038/35069076

tissue_or_cell_type

Hippocampus

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 270–281

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Paired recordings in rat hippocampal slices with CB1 antagonists · source_derived_draft · unverified_draft

### thc-retrograde-hippocampus Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses, travelling from the depolarised postsynaptic neuron back to the presynaptic terminal. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The signal runs backwards across the synapse, which almost nothing else does. organism: Rat tissue_or_cell_type: Hippocampus experimental_model: Paired recordings in rat hippocampal slices with CB1 antagonists limitations: Establishes the direction of the signal, which is what makes the system a feedback loop rather than a transmitter pathway. exposure: Postsynaptic depolarisation with presynaptic release measurement evidence_span: {"source_cache": "artifacts/thc-research/11279497.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f93de867c0ce253b42d9c248504f4471431310bdc0629fec2a8c49d2eba55e8e", "start_char": 0, "end_char": 1117, "text_sha256": "f93de867c0ce253b42d9c248504f4471431310bdc0629fec2a8c49d2eba55e8e"} [thc-p11279497] Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. (2001). https://pubmed.ncbi.nlm.nih.gov/11279497/ DOI: 10.1038/35069076

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/thc-research/14718593.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "422efbafe3e999138f4591acf2a7e5126919ba85d84637aeb320927062c5b2a8", "start_char": 0, "end_char": 1836, "text_sha256": "422efbafe3e999138f4591acf2a7e5126919ba85d84637aeb320927062c5b2a8"}

experimental_model

THC and methanandamide compared in CB1 knockout and wild-type mice

exposure

THC and a stable anandamide analogue across genotypes

limitations

The comparison of two agonists across the same genotypes is what shows the receptor accounts for the drug but not for everything cannabinoid-like.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Mouse

plain_language

Take the receptor away and the drug stops working, though not every cannabinoid-like effect disappears with it.

primary_references

[thc-p14718593] Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice. (2004). https://pubmed.ncbi.nlm.nih.gov/14718593/ DOI: 10.1124/jpet.103.055376

tissue_or_cell_type

Whole body

trigger_kind

machinery_impairment Imported condition classification; unverified.

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 426–437

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · THC and methanandamide compared in CB1 knockout and wild-type mice · source_derived_draft · unverified_draft

### thc-thc-requires-cb1 THC and methanandamide had differential effects in CB1 knockout and wild-type mice, with the effects of THC dependent on the receptor while some effects of the anandamide analogue were not. Condition category: machinery_impairment nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: Take the receptor away and the drug stops working, though not every cannabinoid-like effect disappears with it. organism: Mouse tissue_or_cell_type: Whole body experimental_model: THC and methanandamide compared in CB1 knockout and wild-type mice limitations: The comparison of two agonists across the same genotypes is what shows the receptor accounts for the drug but not for everything cannabinoid-like. exposure: THC and a stable anandamide analogue across genotypes evidence_span: {"source_cache": "artifacts/thc-research/14718593.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "422efbafe3e999138f4591acf2a7e5126919ba85d84637aeb320927062c5b2a8", "start_char": 0, "end_char": 1836, "text_sha256": "422efbafe3e999138f4591acf2a7e5126919ba85d84637aeb320927062c5b2a8"} [thc-p14718593] Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice. (2004). https://pubmed.ncbi.nlm.nih.gov/14718593/ DOI: 10.1124/jpet.103.055376

evidence_span

{"source_cache": "artifacts/thc-research/8856831.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cd2ffb6c04147c50bc6a9e311032669fe18406690188a1d058b7e80aa09810e0", "start_char": 0, "end_char": 1652, "text_sha256": "cd2ffb6c04147c50bc6a9e311032669fe18406690188a1d058b7e80aa09810e0"}

experimental_model

Spatial memory testing in rats with a CB1 antagonist

exposure

THC with antagonist pretreatment

limitations

The antagonist arm is what makes this a receptor mechanism rather than a general sedative effect.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat

plain_language

The memory effect runs through the receptor, not through general sedation.

primary_references

[thc-p8856831] Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. (1996). https://pubmed.ncbi.nlm.nih.gov/8856831/ DOI: 10.1007/bf02246347

tissue_or_cell_type

Hippocampus and behaviour

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 439–450

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Spatial memory testing in rats with a CB1 antagonist · source_derived_draft · unverified_draft

### thc-thc-spatial-memory THC impaired spatial memory through a cannabinoid receptor mechanism, since the impairment was prevented by receptor blockade. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The memory effect runs through the receptor, not through general sedation. organism: Rat tissue_or_cell_type: Hippocampus and behaviour experimental_model: Spatial memory testing in rats with a CB1 antagonist limitations: The antagonist arm is what makes this a receptor mechanism rather than a general sedative effect. exposure: THC with antagonist pretreatment evidence_span: {"source_cache": "artifacts/thc-research/8856831.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cd2ffb6c04147c50bc6a9e311032669fe18406690188a1d058b7e80aa09810e0", "start_char": 0, "end_char": 1652, "text_sha256": "cd2ffb6c04147c50bc6a9e311032669fe18406690188a1d058b7e80aa09810e0"} [thc-p8856831] Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. (1996). https://pubmed.ncbi.nlm.nih.gov/8856831/ DOI: 10.1007/bf02246347

evidence_span

{"source_cache": "artifacts/paracetamol-research/21628499.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613", "start_char": 0, "end_char": 1809, "text_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613"}

experimental_model

Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation

exposure

300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly

limitations

Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse

plain_language

The same knockouts that abolish the painkilling leave the temperature drop completely untouched.

primary_references

[apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638

tissue_or_cell_type

Whole body temperature

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 376–387

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation · source_derived_draft · unverified_draft

### apap-hypothermia-is-a-different-mechanism Paracetamol induced hypothermia to the same extent in cannabinoid receptor 1 and TRPV1 knockout mice as in wild-type mice and to the same extent in mice pretreated with the antagonists AM251 or SB366791 as in controls, AM404 failed to induce hypothermia at pharmacological doses, inhibition of fatty acid amide hydrolase did not prevent the development of hypothermia and paracetamol induced hypothermia in fatty acid amide hydrolase knockout mice to the same extent as in wild-type mice, so paracetamol induces hypothermia independent of cannabinoids and TRPV1 and AM404 does not mediate this response. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same knockouts that abolish the painkilling leave the temperature drop completely untouched. organism: Mouse tissue_or_cell_type: Whole body temperature experimental_model: Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation limitations: Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever. exposure: 300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly evidence_span: {"source_cache": "artifacts/paracetamol-research/21628499.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613", "start_char": 0, "end_char": 1809, "text_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613"} [apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638

evidence_span

{"source_cache": "artifacts/paracetamol-research/23940628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44", "start_char": 0, "end_char": 2208, "text_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44"}

experimental_model

Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade

exposure

Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine, with fatty acid amide hydrolase, TRPV1, cannabinoid and serotonergic manipulations

limitations

The broadest test of the route: it reconstructs the whole chain from metabolite formation to descending pathway, and shows the profile of the metabolite matches that of the parent drug.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Mouse and rat

plain_language

Every step of the proposed chain was cut in turn, and cutting any of them stopped the painkilling.

primary_references

[apap-p23940628] Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. (2013). https://pubmed.ncbi.nlm.nih.gov/23940628/ DOI: 10.1371/journal.pone.0070690

tissue_or_cell_type

Brain and spinal cord

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 324–335

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade · source_derived_draft · unverified_draft

### apap-the-whole-chain Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine led to dose-dependent formation of AM404 and of arvanil and olvanil respectively in the mouse brain, the order of potency of these lipid metabolites as TRPV1 activators being arvanil equal to olvanil much greater than AM404, both parent amines displayed antinociceptive activity in rodent pain tests, formation of these metabolites and the antinociceptive effects were substantially reduced or disappeared in fatty acid amide hydrolase null mice, activity was lost in TRPV1 null mice, intracerebroventricular capsazepine eliminated the effects, and in the rat, inhibition of fatty acid amide hydrolase, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors and chemical deletion of bulbospinal serotonergic pathways all prevented the action, giving a pharmacological profile identical to that previously reported for paracetamol. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Every step of the proposed chain was cut in turn, and cutting any of them stopped the painkilling. organism: Mouse and rat tissue_or_cell_type: Brain and spinal cord experimental_model: Metabolite formation and antinociception for 4-aminophenol and a vanillylamine analogue across knockouts and pharmacological blockade limitations: The broadest test of the route: it reconstructs the whole chain from metabolite formation to descending pathway, and shows the profile of the metabolite matches that of the parent drug. exposure: Systemic 4-aminophenol and 4-hydroxy-3-methoxybenzylamine, with fatty acid amide hydrolase, TRPV1, cannabinoid and serotonergic manipulations evidence_span: {"source_cache": "artifacts/paracetamol-research/23940628.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44", "start_char": 0, "end_char": 2208, "text_sha256": "cc9d85547497bfdf88095aaeccf5a11cb9198140ebb35523d5da1b85f76e0a44"} [apap-p23940628] Fatty acid amide hydrolase-dependent generation of antinociceptive drug metabolites acting on TRPV1 in the brain. (2013). https://pubmed.ncbi.nlm.nih.gov/23940628/ DOI: 10.1371/journal.pone.0070690

evidence_span

{"source_cache": "artifacts/paracetamol-research/16438952.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8fe3f4535ff4a14c2e417850a583722fc34262e925952ff2fdd9fe244c7e218f", "start_char": 0, "end_char": 509, "text_sha256": "8fe3f4535ff4a14c2e417850a583722fc34262e925952ff2fdd9fe244c7e218f"}

experimental_model

Hot plate test in rats with two cannabinoid receptor antagonists

exposure

Paracetamol with AM281 and SR141716A at doses that prevent the action of a cannabinoid agonist

limitations

A short report with the antagonist doses anchored to a positive control. One pain test in one species.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Rat

plain_language

Two different blockers of the cannabinoid receptor each stopped the painkiller working.

primary_references

[apap-p16438952] The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. (2006). https://pubmed.ncbi.nlm.nih.gov/16438952/ DOI: 10.1016/j.ejphar.2005.12.015

tissue_or_cell_type

Whole animal

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 350–361

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Hot plate test in rats with two cannabinoid receptor antagonists · source_derived_draft · unverified_draft

### apap-two-antagonists-block-it In rats using the hot plate test the analgesic effect of paracetamol was prevented by two antagonists at cannabinoid CB1 receptors, AM281 and SR141716A, at doses that prevent the analgesic activity of the cannabinoid CB1 agonist HU210, suggesting that paracetamol-induced antinociception involves the cannabinoid system. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Two different blockers of the cannabinoid receptor each stopped the painkiller working. organism: Rat tissue_or_cell_type: Whole animal experimental_model: Hot plate test in rats with two cannabinoid receptor antagonists limitations: A short report with the antagonist doses anchored to a positive control. One pain test in one species. exposure: Paracetamol with AM281 and SR141716A at doses that prevent the action of a cannabinoid agonist evidence_span: {"source_cache": "artifacts/paracetamol-research/16438952.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8fe3f4535ff4a14c2e417850a583722fc34262e925952ff2fdd9fe244c7e218f", "start_char": 0, "end_char": 509, "text_sha256": "8fe3f4535ff4a14c2e417850a583722fc34262e925952ff2fdd9fe244c7e218f"} [apap-p16438952] The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. (2006). https://pubmed.ncbi.nlm.nih.gov/16438952/ DOI: 10.1016/j.ejphar.2005.12.015