<table><tr><td></td><td>CA3 pyramidal cells (hippocampal slices)</td><td>SR144528 (2-5µM, 10 min)</td><td>∠ AP induced long lasting hyperpolarization</td><td></td><td>(Stempel et al., 2016)</td></tr><tr><td>Somatosensory cortex (Mouse)</td><td>Layer II/III RNSCP interneurons (somatosensory cortex slices)</td><td>HU-308 (1µM, 10 min)</td><td>Mimic AP-Driven long-lasting Hyperpolarization</td><td>Blocked by SR144528 (1 µM), no effect in KO mice (Zimmer strain)</td><td>(Stumpf et al., 2018)</td></tr><tr><td colspan="6"><b>DENDRITIC SPINES</b></td></tr><tr><td>Hippocampus (Rat)</td><td>CA1 pyramidal cells (hippocampal slices)</td><td>JWH-133 (200 nM), GP1a (10 nM, 7-10 days)</td><td>∠ dendritic spine density</td><td>Blocked by SR144528 (100 nM). No effect in KO mice (Deltagen strain)</td><td>(Kim and Li, 2015)</td></tr></table>

**Abbreviations:** 5-HT, 5-hydroxytryptamine receptor; AHP, afterhyperpolarization; AP, action potential; CA1 and 3, Cornu ammonis 1 and 3; CB2R, CGRP, calcitonin gene-related peptide; cKO, conditional knoc-out; DA, dopamine; dose-dep, dose dependent; DSI, depolarization-induced suppression of inhibition; EC, entorhinal cortex; eEPSC, evoked excitatory post-synaptic current; EPSP, excitatory post-synaptic potential; eIPSC, evoked IPSC; fEPSPs, field EPSP; GABA, gamma-aminobutyric acid; IPSC, inhibitory post-synaptic current; KO, knock-out; LPS, lipopolysaccharide; LTD, long term depression; mEPSC, miniature EPSP; mIPSC, miniature IPSC; mPFC, medial prefrontal cortex; Ref, reference; RNSCP, regular spiking non-pyramidal cells; sIPSC, spontaneous IPSC; SNc, substantia nigra compacta; RN, red nucleus; VTA, ventral tegmental area

<table><caption>**Supplementary Table 5. In vivo effect of CB2R agonists.** Outcome following CB2R activation is either enhanced (∝), decreased (\), or unchanged (=).</caption><thead><tr><th>CONDITION</th><th>TISSUE</th><th>NEURONAL SUBTYPE</th><th>TREATMENT</th><th>OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="7"><b>NEUROTRANSMITTERS RELEASE</b></td></tr><tr><td>Healthy (Mouse)</td><td>NAc</td><td>DA neurons</td><td>JWH-133 (3-20mg/Kg IP or 100µg/nostril IN or 1-1000 µM local intra NAc perfusion)</td><td>∠ extracellular DA (dose dep)</td><td>Blocked by AM630 (10 mg/kg IP). No effect in KO mice (Zimmer strain)</td><td>(Xi et al., 2011)</td></tr><tr><td>Healthy (Rat)</td><td>NAc</td><td>DA neurons</td><td>JWH-133 (10-20 mg/kg, IP)</td><td>= extracellular DA</td><td>-</td><td>(Zhang et al., 2017)</td></tr><tr><td>Cocaine self administration (Mouse)</td><td>NAc</td><td>DA neurons</td><td>JWH-133 (3-20mg/Kg IP, 30 prior to cocaine self admin)</td><td>∠ cocaine-enhanced extracellular DA (dose dep)</td><td>Blocked by AM630 (10 mg/kg IP). No effect in KO mice (Zimmer strain)</td><td>(Xi et al., 2011)</td></tr><tr><td>Ischemia (MCAO, rat)</td><td>Dorsal hippocampus</td><td>Glutamatergic neurons</td><td>JWH-133 (50-100 µM, intra-dorsal hippocampus infusion)</td><td>∠ ischemia-enhanced extracellular glutamate (dose-dep)</td><td>Blocked by AM630 (50µM)</td><td>(Zheng et al., 2015)</td></tr><tr><td>Morphine (Rat)</td><td>NAc</td><td>DA neurons</td><td>JWH-015 (1 mg/kg, IP, 1h before morphine injection)</td><td>∠ morphine-enhanced extracellular DA</td><td>-</td><td>(Grenald et al., 2017)</td></tr><tr><td>PD (MPTP, mouse)</td><td>Striatum</td><td>DA and serotonin neurons</td><td>AM1241 (0.75 to 12 mg/kg), IP, daily for 12 days starting 24 h after the last MPTP injection)</td><td>∠ DA and 5-HT levels (dose-dep)</td><td>-</td><td>(Shi et al., 2017)</td></tr><tr><td colspan="7"><b>IONIC CURRENTS</b></td></tr><tr><td>Spinal nerve ligation (Rat)</td><td>Spinal Cord</td><td>Deep convergent dorsal horn neurons</td><td>JWH-133 (8-486 ng/50 µL, local spinal administration)</td><td>∠ capsaicin evoked [Ca²⁺] increase</td><td>Blocked by SR144528 (1 ng/50 µL)</td><td>(Sagar et al., 2005)</td></tr><tr><td colspan="7"><b>MEMBRANE POTENTIAL</b></td></tr><tr><td>Physio (Mouse)</td><td>Hippocampus</td><td>CA3 pyramidal cells</td><td>HU-308 (10mg/kg, 1 injection after 1-hour baseline)</td><td>Hyperpolarization</td><td>No effect in KO mice (Zimmer strain) nor in Syn-CB2R custom cKO mice.</td><td>(Stempel et al., 2016)</td></tr><tr><td colspan="7"><b>EXCITABILITY</b></td></tr><tr><td rowspan="2">Healthy (Mouse)</td><td>Hippocampus</td><td>CA3 pyramidal cells</td><td>HU-308 (10mg/kg, 1 injection after 1-hour baseline)</td><td>∠ spike probability</td><td>No effect in KO mice (Zimmer strain) nor in Syn-CB2R custom cKO mice.</td><td>(Stempel et al., 2016)</td></tr><tr><td>VTA</td><td>DA neurons</td><td>JWH-133 (10-20 mg/kg IP)</td><td>∠ AP and burst firing rate (dose-dep)</td><td>Blocked by AM630 (10 mg/kg). No effect in KO mice (Zimmer strain)</td><td>(Zhang et al., 2014)</td></tr><tr><td>Healthy (Rat)</td><td>Spinal cord</td><td>Wide dynamic range neurons</td><td>AM1241 (0.3 mg/kg, IV)</td><td>= spontaneous firing, ∝ C-fiber-mediated activity (total suppression)</td><td>Blocked by SR144528 (1 mg/kg, IV)</td><td>(Nackley et al., 2004)</td></tr><tr><td rowspan="4">Spinal nerve ligation (Rat)</td><td rowspan="2">Thalamus</td><td rowspan="2">Ventral posterior nucleus neurons</td><td rowspan="2">JWH-133 (192 µM, 2 weeks post induction, local pressure ejection. Effect 30 min post admin)</td><td>∠ Spontaneous activity, ∝ mechanically evoked responses</td><td>Blocked with SR144528 (48 ng)</td><td>(Jhaveri et al., 2008)</td></tr><tr><td>= spontaneous firing, ∝ C-fiber-mediated activity</td><td>Blocked by SR144528 (1 mg/kg, IV)</td><td>(Nackley et al., 2004)</td></tr><tr><td rowspan="2">Spinal cord</td><td rowspan="2">Wide dynamic range neurons</td><td rowspan="2">AM1241 (0.3 mg/kg, IV. just before insult)</td><td>∠ spontaneous firing</td><td>Blocked by SR144528 (1 mg/kg, IV)</td><td>(Nackley et al., 2004)</td></tr><tr><td>∠ C-fiber-mediated activity</td><td>Blocked by SR144528 (10 µg/50µL)</td><td>(Elmes et al., 2004)</td></tr><tr><td rowspan="2">Carrageenan induced inflammation (Rat)</td><td rowspan="2">Spinal cord</td><td rowspan="2">Wide dynamic range dorsal horn neurons</td><td rowspan="2">JWH-133 (10µg/50µL, intraplantar, 10 min before recording)</td><td>∠ mechanically evoked responses</td><td>Blocked by SR144528 (10 µg/50µL)</td><td>(Sokal et al., 2003)</td></tr><tr><td>∠ C-fiber-mediated activity</td><td>Blocked by SR144528 (10 µg/50µL)</td><td>(Sokal et al., 2003)</td></tr><tr><td rowspan="2">Spinal nerve ligation (Rat)</td><td rowspan="2">Spinal Cord</td><td rowspan="2">Deep convergent dorsal horn neurons</td><td rowspan="2">JWH-133 (8-486 ng/50 µL, local spinal administration)</td><td>∠ mechanically evoked responses</td><td>Blocked by SR144528 (0.001 µg/50µL, local)</td><td>(Sagar et al., 2005)</td></tr><tr><td>∠ C-fiber-mediated activity</td><td>Attenuated by SR144528 (10 µg/50µL)</td><td>(Elmes et al., 2004)</td></tr></tbody></table>
<table><thead><tr><th colspan="7">SYNAPTIC TRANSMISSION</th></tr></thead><tbody><tr><td>Alzheimer's Disease (APP/PS1, Mouse)</td><td>Hippocampus</td><td>CA1 Neurons</td><td>MDA7 (14 mg/kg, IP, ½ day, from 3-to 8-month-old)</td><td>↗ LTP</td><td>-</td><td>(Wu et al., 2017)</td></tr><tr><td>Alzheimer's Disease (intracerebral Aβ<sub>1-41</sub>, Rat)</td><td>Hippocampus</td><td>CA1 Neurons</td><td>MDA7 (1.5-15 mg/kg, IP, daily for 14 days)</td><td>↗ LTP, ↗ eEPSC amplitude</td><td>-</td><td>(Wu et al., 2013)</td></tr></tbody></table>

**Abbreviations**: 5-HT, 5-hydroxytryptamine receptor; Aβ, amyloid β; AP, action potential; APP, amyloid precursor protein; CA1 and 3, Cornu ammonis 1 and 3; DA, dopamine; dose-dep, dose-dependent; eEPSC, evoked excitatory post-synaptic current; IN, intranasal; IP, intra-peritoneal; KO, knock-out; LTP, long term potentiation; MCAO, middle cerebral artery occlusion; NAc, nucleus accumbens; PS1, presenilin 1; Ref, reference; VTA, ventral tegmental area.

**Supplementary Table 6. Feeding.** Behavioral outcome following CB2R activation or blockade is either enhanced (↗), decreased (↘) or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2<sup>tm1Dgen</sup>/), #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).

<table><thead><tr><th>MODEL</th><th>TREATMENT</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="5"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="5"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="2">Healthy (Mouse)</td><td>JWH-015 (10 mg/kg, IP)</td><td>↗ food intake</td><td>Blocked by AM630 (5 mg/kg, IP)</td><td>(Verty et al., 2015)</td></tr><tr><td>JWH-133 (10 mg/kg, IP, 1/day during CPP development, for 8 days)</td><td>= food intake</td><td>-</td><td>(Martin-Sánchez et al., 2019)</td></tr><tr><td rowspan="2">Diet-induced obesity (Mouse)</td><td rowspan="2">JWH-015 (10 mg/kg, IP, daily for 21 days)</td><td>↗ food intake (first 6 days)</td><td rowspan="2">-</td><td rowspan="2">(Verty et al., 2015)</td></tr><tr><td>↗ body weight (entire treatment duration), ↗ feed efficiency ratio</td></tr><tr><td>High fat diet (Rat)</td><td>β-caryophyllene (30 mg/kg, PO, daily for 4 weeks)</td><td>= weight gain. ↗ visceral fat index</td><td>Blocked by AM630 (1 mg/kg, IP)</td><td>(Youssef et al., 2019)</td></tr><tr><td>Parkinson's disease (MPTP, mouse)</td><td>AM1241 (0.75-12 mg/kg, IP, daily for 12 days starting 24 h after the last injection of MPTP)</td><td>Prevention of MPTP-induced weight loss</td><td>-</td><td>(Shi et al., 2017)</td></tr><tr><td colspan="5"><strong>Genetic overexpression</strong></td></tr><tr><td>CB2xP</td><td>-</td><td>= basal food intake. ↗ fasting-induced intake after 120 min. ↗ body weight (after 18-week-old, but not at 12)</td><td>-</td><td>(Romero-Zerbo et al., 2012)</td></tr><tr><td colspan="5"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="5"><strong>Pharmacological blockade</strong></td></tr><tr><td rowspan="2">Healthy (Mouse)</td><td>AM630 (10 mg/kg, IP, 24h before test)</td><td>↗ food intake</td><td>-</td><td>(Ishiguro et al., 2010)</td></tr><tr><td>AM630 (10 mg/kg, IP, 1h before test)</td><td>= food intake</td><td>-</td><td>(Martin-Sánchez et al., 2019)</td></tr><tr><td>Healthy (Rat)</td><td>SR144528 (0.1-1 mg/kg, IP, 45 min before test)</td><td>↗ food intake</td><td>-</td><td>(Adamczyk et al., 2012)</td></tr><tr><td>12h food deprivation (Mouse)</td><td>AM630 (10 mg/kg, IP, 24h before test)</td><td>↗ food intake</td><td>-</td><td>(Ishiguro et al., 2010)</td></tr><tr><td colspan="5"><strong>Genetic invalidation</strong></td></tr><tr><td>Healthy, CB2R KO (Zimmer strain)</td><td>-</td><td>↗ food intake</td><td>-</td><td>(Agudo et al., 2010)</td></tr><tr><td>Healthy, CB2R KO (Deltagen strain)</td><td>-</td><td>↗ visceral fat mass</td><td>-</td><td>(Schmitz et al., 2016)</td></tr></tbody></table>

**Abbreviations**: CB2xP, mice overexpressing CB2R; CPP, conditioned place preference; IP, intra-peritoneal; KO, knock-out; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PO, per os; Ref, reference.
<table><caption>**Supplementary Table 7. Motor function.** Behavioral outcome following CB2R activation or blockade is either enhanced (▲), decreased (▼) or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2<sup>tm1Dgen</sup>/J, #005786), the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000), or the "Romero strain" generated with the cre-lox method (López et al., 2018)).</caption><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="5">Healthy (Mouse)</td><td>JWH-133 (20 mg/kg, IP)</td><td>Locomotor activity boxes, Ring test</td><td>▲ locomotor activity, catalepsy</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>β-caryophyllene (100 mg/kg, IP)</td><td>Open field, rotarod, forced swim test</td><td>= locomotor activity</td><td>-</td><td>(Oliveira et al., 2016)</td></tr><tr><td>JWH-015 (1-20 mg/kg, IP, 10 min pre-test)</td><td>Activity monitoring</td><td>▲ general locomotor activity (dose dep), ▲ stereotype behavior</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>JWH-133 (10-20 mg/kg, IP)</td><td>Open field</td><td>▲ basal and cocaine-enhanced locomotion (dose dep)</td><td>Blocked by AM630 (10 mg/kg, IP). No effect in KO mice (Zimmer strain)</td><td>(Xi et al., 2011)</td></tr><tr><td>HU-910 (30 mg/kg, IP, 30 pre-test)</td><td>Elevated Open Field</td><td>▲ Locomotion (total distance)</td><td>-</td><td>(Cortez et al., 2022)</td></tr><tr><td rowspan="3">Healthy (Rat)</td><td>GW833972A (100 nM, intranigral microinjection)</td><td>Observation chamber</td><td>Induction of contralateral turning (2-4 turns/min)</td><td>Blocked by AM630 (50 nM)</td><td>(Sánchez-Zavaleta et al., 2018)</td></tr><tr><td>JWH-133 (20 mg/kg, IP, 30 min pre-test)</td><td>Open Field</td><td>▲ Locomotion (total distance)</td><td>Attenuated by AM630 (3 mg/kg, IP)</td><td>(Spiller et al., 2019)</td></tr><tr><td>GW405833 (100 mg/kg, IP, 1 to 5h pre-test)</td><td>Rotarod, catalepsy assay</td><td>▲ motor performances + cataleptic effect + ataxia</td><td>No effect at 30 mg/kg</td><td>(Valenzano et al., 2005)</td></tr><tr><td>Amyotrophic lateral sclerosis (Mouse)</td><td>HU-308 (5mg/kg, IP, daily from 65 to 90 days old)</td><td>Rotarod</td><td>▲ locomotor activity</td><td>-</td><td>(Espejo-Porras et al., 2019)</td></tr><tr><td>Amphetamine-induced hyperlocomotion (Mouse)</td><td>HU-910 (3-60 mg/kg, IP, 60 min pre-injury, 70 min pre-test)</td><td>Elevated open field</td><td>No effect on hyperlocomotion</td><td>-</td><td>(Cortez et al., 2022)</td></tr><tr><td>Chronic Mild Stress (Mouse)</td><td>JWH-015 (1-20 mg/kg, IP, 10 min pre-test)</td><td>Activity monitoring (stereotypic counts like rearing behavior and other repetitive behaviors)</td><td>▲ stereotype behavior</td><td>-</td><td>(Onaivi, 2006)</td></tr><tr><td rowspan="3">High fat diet (Rat)</td><td>β-caryophyllene (30 mg/kg, PO, daily for 4 weeks)</td><td>Open field</td><td>▲ spontaneous locomotor activity and exploratory behavior</td><td>Blocked by AM630 (1 mg/kg, IP)</td><td>(Youssef et al., 2019)</td></tr><tr><td>JWH-133 (1.5 mg/kg, IP, 1h post-injury)</td><td>Modified Neurological Severity Score, forelimb placing test, corner turn test</td><td>▲ sensorymotor and balance function</td><td>Blocked by SR144528 (3 mg/kg IP, 3 min before agonist)</td><td>(Li et al., 2018)</td></tr><tr><td>JWH-133 (1.5 mg/kg, IP, 1h post-injury)</td><td>Modified Neurological Severity Score</td><td>▲ sensorymotor and balance function</td><td>Blocked by SR144528 (3 mg/kg IP, 3 min before agonist)</td><td>(Li et al., 2018)</td></tr><tr><td>LPS-induced sickness behavior (Mouse)</td><td>1-phenylisatin (20 mg/kg, PO, once daily for 7 days)</td><td>Open Field</td><td>▲ locomotor activity</td><td>LPS 1.5 mg/kg IP, 7th day of treatment</td><td>(Sahu et al., 2019)</td></tr><tr><td>MK801-induced hyperlocomotion (Mouse)</td><td>HU-910 (0.3-30 mg/kg, IP, 10 min pre-injury, 30 min pre-test)</td><td>Elevated open field</td><td>▲ hyperlocomotion</td><td>Blocked by AM630 (1 mg/kg, IP)</td><td>(Cortez et al., 2022)</td></tr><tr><td>Seizure (PTZ, Mouse)</td><td>β-caryophyllene (30-300 mg/kg, IP)</td><td>Rotarod</td><td>= locomotor activity</td><td>-</td><td>(Tchekarov et al., 2018)</td></tr><tr><td rowspan="2">Spinal cord injury (Mouse)</td><td>0-1966 (5 mg/kg, IP, 2 injections, 1h and 24h post-injury)</td><td>Open Field (Basso Mouse Scale (BMS), Basso Beattie-Bresnahan (BBB) locomotorscale)</td><td>▲ motor function</td><td>-</td><td>(Adhikary et al., 2011)</td></tr><tr><td>JWH-015 (3 mg/kg, IP, daily for 7 days post-injury)</td><td>Beam walking test, catwalk</td><td>▲ functional recovery</td><td>-</td><td>(Latini et al., 2014)</td></tr><tr><td>Stroke (MCAO, Rat)</td><td>AM1241 (2.5 mg/kg, IP, 5 min pre-injury. Test 2 days later)</td><td>Elevated bodyswing test, Bederson's score (postural reflex test)</td><td>▲ functional recovery</td><td>-</td><td>(Yu et al., 2015)</td></tr><tr><td>Surgery-induced cognitive impairment (Mouse)</td><td>JWH-133 (2 mg/kg, IP, immediately after recovery from anesthesia, and repeated 24h post-injury)</td><td>Open Field</td><td>= locomotor activity</td><td>-</td><td>(Sun et al., 2017)</td></tr><tr><td rowspan="2">Traumatic brain injury (CCI, Mouse)</td><td>GP1a (3 mg/kg, IP, 10 min post-injury)</td><td>Stationary beam walk and accelerating rotarod task</td><td>▲ motor coordination</td><td>-</td><td>(Braun et al., 2018)</td></tr><tr><td>0-1966 (5 mg/kg, IP, 1h and 24h post-injury)</td><td>Rotarod, glass cylinder test</td><td>▲ locomotor performance. ▲ usage of forelimb</td><td>-</td><td>(Elliott et al., 2011)</td></tr><tr><td rowspan="2">Traumatic brain injury (CHI, Mouse)</td><td>HU910 (10 mg/kg, IP, 1h post-injury)</td><td>Neurological severity score (evaluation of walk, balance, startle reflex, seeking behavior)</td><td>▲ locomotor performance</td><td>Blocked by SR144528 and AM630 (1 mg/kg, IP)</td><td>(Magid et al., 2019)</td></tr><tr><td>AM1241 (0.75-12 mg/kg, IP, daily for 12 days, 24h post-injury)</td><td>Rotarod, pole test (day 5 post MPTP)</td><td>▲ motor function</td><td>-</td><td>(Shi et al., 2017)</td></tr><tr><td>Parkinson's disease (MPTP, Mouse)</td><td>β-caryophyllene (10 mg/kg, IP, daily for 5 days, 24h pre-injury)</td><td>Pole test, gait lab, beam test</td><td>▲ MPTP-induced movement impairment, ▲ stride length impairment, ▲ balance impairment</td><td>Blocked by AM630 (3 mg/kg, IP), no effect in control mice</td><td>(Viveros-Paredes et al., 2017)</td></tr></tbody></table>
<table><tbody><tr><td></td><td>AM1241 (6 mg/kg, IP, 5 days post-injury, for 2 weeks)</td><td>Pole test</td><td>▲ motor function</td><td>No effect in KO mice (strain ?)</td><td>(He et al., 2020)</td></tr><tr><td>Parkinson's disease (6-OHDA, Mouse)</td><td>GW842166x (1 mg/kg, IP, daily for 3 weeks, post-injury)</td><td>Pole test, balance beam, grip strength, rotarod</td><td>▲ motor function</td><td>Blocked by AM630 (10 mg/kg, IP)</td><td>(Yu et al., 2021)</td></tr><tr><td>Parkinson's disease (LRRK2 transgenic mouse)</td><td>HU-308 (5 mg/kg, IP, daily, 12 to 18 months of age)</td><td>Rotarod, hanging wire test, pole test</td><td>▲ motor function (for hanging wire test only)</td><td>Blocked by SR144528 (1 mg/kg, IP)</td><td>(Palomo-Garo et al., 2016)</td></tr><tr><td colspan="6"><strong>Genetic overexpression</strong></td></tr><tr><td>CB2xP mouse</td><td>-</td><td>Open field</td><td>= basal motor activity</td><td>-</td><td>(Aracil-Fernández et al., 2012)</td></tr><tr><td>Cell-specific inducible overexpression (Camk2a-Cre, Gad2-Cre, Cx3cr1-Cre)</td><td>-</td><td>Open field</td><td>= basal motor activity</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td>Healthy (Rat)</td><td>SR144528 (0.1-1 mg/kg, IP)</td><td>Optomo-Varimex cages (horizontal activity + distance moved in cm)</td><td>= basal locomotor activity</td><td>-</td><td>(Adamczyk et al., 2012)</td></tr><tr><td rowspan="4">Healthy (Mouse)</td><td>AM630 (3 mg/kg, IP)</td><td>Open field</td><td>= motor activity</td><td>-</td><td>(Li and Kim, 2016b)</td></tr><tr><td>AM630 (10 mg/kg, IP, 1h pre-test)</td><td>IR motor activity monitor</td><td>= spontaneous locomotor activity</td><td>-</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td>SR144528 (1 mg/kg, IP)</td><td>Activity monitor</td><td>▲ General locomotor activity</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>AM630 (3 mg/kg, IP)</td><td>Pole test, gait lab, beam test</td><td>= locomotor activity, = stride length, = balance</td><td>-</td><td>(Viveros-Paredes et al., 2017)</td></tr><tr><td>Stroke (MCAO, Mouse)</td><td>SR144528 (5 mg/kg, IP, 2 days post-injury)</td><td>Staircase pellet-reaching test, open field</td><td>▲ spontaneous motor recovery</td><td>-</td><td>(Bravo-Ferrer et al., 2017)</td></tr><tr><td>Surgery-induced cognitive impairment (Mouse)</td><td>AM630 (3mg/kg, IP, immediately after recovery from anesthesia, and repeated 24h post-injury)</td><td>Open Field</td><td>= motor activity</td><td>-</td><td>(Sun et al., 2017)</td></tr><tr><td>Traumatic Brain Injury (Mouse, air blast injury)</td><td>SMM-189 (6 mg/kg, IP, 2h post-injury and daily for 14 days)</td><td>Rotarod, open field</td><td>▲ locomotor activity</td><td>-</td><td>(Reiner et al., 2014)</td></tr><tr><td colspan="6"><strong>Genetic invalidation</strong></td></tr><tr><td>CB2R KO (Zimmer strain)</td><td>-</td><td>Open field</td><td>▲ spontaneous locomotor activity</td><td>-</td><td>(Ortega-Alvaro et al., 2011)</td></tr><tr><td>Amyotrophic Lateral Sclerosis /CB2R KO (Romero strain)</td><td>-</td><td>Rotarod</td><td>▲ motor function</td><td>-</td><td>(Rodríguez-Cueto et al., 2021)</td></tr><tr><td>Cell-specific inducible deletion (Camk2a-Cas9, Gad2-Cas9, Cx3cr1-Ca9)</td><td>-</td><td>Open field</td><td>= basal motor activity</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td rowspan="2">DAT-CB2R cKO Mouse</td><td>-</td><td>IR photobeam-controlled open-field</td><td>▲ basal motor activity</td><td>-</td><td>(Canseco-Alba et al., 2019)</td></tr><tr><td>-</td><td>Open field and wheel running tests</td><td>▲ motor activity (distance moved + rearing)</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>Huntington's disease (R6/2) CB2R KO (Zimmer strain)</td><td>-</td><td>Rotarod</td><td>▲ motor function</td><td>-</td><td>(Palazuelos et al., 2009)</td></tr></tbody></table>

**Abbreviations**: 6-OHDA, 6-hydroxydopamine; Camk2a, Calcium/Calmodulin Dependent Protein Kinase II Alpha; CB2xP, mice overexpression CB2R; CCI, Controlled cortical impact; CHI, closed-head injury; cKO, conditional knock-out; Cre, Cre recombinase; CX3CR1, CX3C motif chemokine receptor 1; DAT, dopamine active transporter; dose-dep, dose-dependent; Gad2, glutamate decarboxylase 2; IP, intra-peritoneal; KO, knock-out; LPS, lipopolysaccharide; LRRK2, leucine-rich repeat kinase 2; MCAO, middle cerebral artery occlusion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PO, per os; PTZ, Pentylenetetrazol; Ref, reference; TBI, traumatic brain injury.
<table><caption>**Supplementary Table 8. Learning and memory.** Behavioral outcome following CB2R activation or blockade is either enhanced (✓), decreased (\), or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2tm1Dgen/J, #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).</caption><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="6">Healthy (Mouse)</td><td>β-caryophyllene (100 mg/kg, IP)</td><td>NOR</td><td>✓ recognition index</td><td>-</td><td>(Oliveira et al., 2016)</td></tr><tr><td>β-caryophyllene (10-50 mg/kg, IP)</td><td>MWM</td><td>✓ Spatial learning (dose dep)</td><td>-</td><td>(Tchekalarova et al., 2018)</td></tr><tr><td>JWH-133 (0.5-2 mg/kg, IP)</td><td>Step down inhibitory avoidance test</td><td>✓ aversive memory performance</td><td>No effect in KO mice (Zimmer strain)</td><td>(García-Gutiérrez et al., 2013)</td></tr><tr><td>JWH-133 (0.25-1 mg/kg, IP)</td><td>Passive avoidance test</td><td>= acquisition, ✓ consolidation of long-term memory</td><td>-</td><td>(Kruk-Slomka et al., 2022)</td></tr><tr><td>JWH-133 (2 mg/kg, IP)</td><td>Passive avoidance test</td><td>✓ acquisition and consolidation of memory</td><td>-</td><td>(Kruk-Slomka et al., 2016)</td></tr><tr><td>GP1a (1-100 µg, intra-CA1, post-training)</td><td>Passive avoidance test</td><td>✓ memory consolidation</td><td>-</td><td>(Nasehi et al., 2018)</td></tr><tr><td>Healthy (Rat)</td><td>GP1a (150 ng, Intra-CA1 microinjection)</td><td>Step-through task</td><td>✓ memory consolidation</td><td>-</td><td>(Nasehi et al., 2017)</td></tr><tr><td>Alzheimer's disease (AlCl3 + D-Gal, Mouse)</td><td>1-Phenylisatin (10-20 mg/kg, 31 days after first injection of AlCl3+D-Gal)</td><td>MWM, Attentional set shifting test</td><td>✓ memory performance (MWM: acquisition + retrieval. ASST: reversal learning)</td><td>-</td><td>(Jayant et al., 2016)</td></tr><tr><td rowspan="4">Alzheimer's disease (APP/PS1, Mouse)</td><td>JWH-133 (0.2 mg/kg, IP, daily for 5 weeks at 3 months old (pre-symptomatic phase))</td><td>Two-object recognition test, active avoidance test</td><td>✓ memory performance (✓ recognition index)</td><td>-</td><td>(Aso et al., 2013)</td></tr><tr><td>JWH-133 (0.2 mg/kg, IP, daily for 5 weeks at 6 months old (early-symptomatic phase))</td><td>Two-object recognition test, active avoidance test</td><td>✓ memory performance (✓ recognition index)</td><td>-</td><td>(Aso et al., 2013)</td></tr><tr><td>JWH-015 (0.5 mg/kg, IP, daily for 8 weeks, start at 8-month-old)</td><td>NOR, MWM</td><td>✓ NOR memory. No effect on MWM performance</td><td>-</td><td>(Li et al., 2019)</td></tr><tr><td>MDA7 (14 mg/kg, IP, ½ day, from 3- to 8-month-old)</td><td>MWM</td><td>✓ memory performance</td><td>-</td><td>(Wu et al., 2017)</td></tr><tr><td>Alzheimer's disease (STZ, Mouse)</td><td>1-Phenylisatin (10-20 mg/kg, PO, once daily for 30 days, 4 days after first injection of STZ</td><td>MWM: D16-19. Attentional set shifting test: testing session on D30</td><td>✓ memory performance (MWM: acquisition + retrieval. ASST: reversal learning)</td><td>-</td><td>(Jayant et al., 2016)</td></tr><tr><td>Alzheimer's disease (Tg APP 2576, Mouse)</td><td>JWH-133 (0.2 mg/kg, PO, 1/day in the drinking water for 4 months, start at 7 months (before Aβ deposition))</td><td>NOR</td><td>✓ recognition memory</td><td>-</td><td>(Martín-Moreno et al., 2012)</td></tr><tr><td>Alzheimer's disease (intrahippocampal Aβ<sub>1-42</sub>, Rat)</td><td>WIN55,212 (10 µg, intra hippocampal, 1h post Aβ<sub>1-42</sub> and repeated day 3, 5 and 7)</td><td>MWM</td><td>✓ Spatial learning</td><td>Partially blocked by SR144528 (70 µg, intra-hippocampal)</td><td>(Fakhfouri et al., 2012)</td></tr><tr><td>Alzheimer's disease (intracerebral Aβ<sub>1-41</sub>, Rat)</td><td>MDA7 (1.5-15 mg/kg, IP, daily for 14 days)</td><td>MWM</td><td>✓ Spatial learning (dose dep)</td><td>Blocked by AM630 (5 mg/kg, IP)</td><td>(Wu et al., 2013)</td></tr><tr><td>Age-related cognitive decline (Mouse)</td><td>β-caryophyllene (100-300 mg/kg, IP, 3/week for 1 week)</td><td>Y-maze</td><td>✓ memory performance</td><td>-</td><td>(Lindsey et al., 2019)</td></tr><tr><td>D-AP5-induced memory impairment (Rat)</td><td>GP1a (50 ng, Intra-CA1 microinjection, post training)</td><td>Step-through task</td><td>✓ memory consolidation</td><td>-</td><td>(Nasehi et al., 2017)</td></tr><tr><td>High fat diet (Rat)</td><td>β-caryophyllene (30 mg/kg, PO, daily for 4 weeks)</td><td>Y-maze</td><td>✓ memory performance</td><td>Blocked by AM630 (1 mg/kg, IP)</td><td>(Youssef et al., 2019)</td></tr><tr><td>HIV-1 glycoprotein 120 induced neural injury (Rat)</td><td>Win55,212-2 (3 mg/kg/d, IP, for 3 days before injury)</td><td>MWM</td><td>✓ learning and memory performance</td><td>Blocked by AM630 (1.5 mg/kg/d, IP)</td><td>(Wang et al., 2022)</td></tr><tr><td>MK-801-induced cognitive impairment (Schizophrenia, Mouse)</td><td>HU-910 (3-30 mg/kg, IP, once a day, for 7 days, 24h after the end of MK-801 administration)</td><td>NOR</td><td>✓ memory performance</td><td>-</td><td>(Cortez et al., 2022)</td></tr><tr><td>Okadaic acid-induced neurodegeneration (Rat)</td><td>JWH-133 (0.2 mg/kg, IP, for 13 days)</td><td>MWM</td><td>✓ spatial memory performance</td><td>-</td><td>(Cakir et al., 2019)</td></tr><tr><td>Sepsis-induced encephalopathy (Mouse)</td><td>HU-308 (2.5 mg/kg, IP, 30 post injury and 1/day for 3 days)</td><td>NOR, MWM</td><td>✓ recognition and spatial memory</td><td>-</td><td>(Yang et al., 2022)</td></tr><tr><td>Surgery-induced cognitive impairment (Mouse)</td><td>JWH-133 (2 mg/kg, IP, immediately after recovery from anesthesia, and repeated 24h post-injury)</td><td>Fear conditioning (context and cue)</td><td>✓ contextual fear (hippocampal-dep) memory. = tone fear (hippocampal-indep) memory</td><td>-</td><td>(Sun et al., 2017)</td></tr><tr><td>Stroke (Mouse)</td><td>O-1966 (5 mg/kg, IP, 1h prior to and 2- and 5-days post injury)</td><td>NOR, food motivated operant procedure</td><td>✓ memory performance</td><td>-</td><td>(Ronca et al., 2015)</td></tr><tr><td rowspan="2">Vascular dementia (Rat)</td><td>Paeoniflorin (40 mg/kg, IP, daily for 28 days one week post injury)</td><td>MWM</td><td>✓ spatial memory</td><td>Blocked by AM630 (3 mg/kg, IP)</td><td>(Luo et al., 2018)</td></tr><tr><td>HU-308 (3 mg/kg, IP, daily for 28 days one week post injury)</td><td>MWM</td><td>✓ spatial memory</td><td>-</td><td>(Luo et al., 2018)</td></tr></tbody></table>
<table><thead><tr><th></th><th></th><th></th><th></th><th></th><th></th></tr></thead><tbody><tr><td></td><td>β-caryophyllene (30-144 mg/kg, IP, administered as a HPβCD/BCP complex, 1/day for 4 weeks, starting 4 weeks post injury)</td><td>MWM</td><td>✓ spatial memory</td><td>-</td><td>(Lou et al., 2017)</td></tr><tr><td colspan="6"><strong>Genetic overexpression</strong></td></tr><tr><td>Cell-specific inducible overexpression (Camk2a-Cre, Gad2-Cre)</td><td>-</td><td>Fear memory test, Y-maze, NOR</td><td>= cued and contextual fear response.<br>= novelty memory, = spatial working memory</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>Microglia-specific inducible overexpression (Cx3cr1-Cre)</td><td>-</td><td>Fear memory test, Y-maze, NOR</td><td>= cued fear memory. ✓ contextual fear memory.<br>= novelty memory, = spatial working memory</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td rowspan="4">Healthy (Mouse)</td><td>AM630 (1-3 mg/kg, IP, immediately after foot shock (pretraining session))</td><td>Step down inhibitory avoidance test</td><td>✓ short (1h) and long (24h) term aversive memory</td><td>No effect in KO mice (Zimmer strain)</td><td>(García-Gutiérrez et al., 2013)</td></tr><tr><td>AM630 (3 mg/kg, IP)</td><td>Cued fear conditioning (tone), Contextual fear conditioning</td><td>= cued and contextual fear memory, = spatial working memory.</td><td>-</td><td>(Li and Kim, 2016b)</td></tr><tr><td>AM630 (0.5-3 mg/kg, IP, 30 min before the first trial or post training)</td><td>Passive avoidance test</td><td>✓ acquisition and consolidation of long-term memory</td><td>-</td><td>(Kruk-Slomka et al., 2016)</td></tr><tr><td>AM630 (0.25-1 mg/kg, IP, 30 min before the first trial and 24h after)</td><td>Passive avoidance test</td><td>✓ acquisition and consolidation of long-term memory</td><td>-</td><td>(Kruk-Slomka et al., 2022)</td></tr><tr><td>Healthy (Rat)</td><td>AM630 (50-100 ng, Intra-CA1 microinjection, post-training)</td><td>Step-through task</td><td>✓ memory consolidation</td><td>-</td><td>(Nasehi et al., 2017)</td></tr><tr><td>Surgery-induced cognitive impairment (Mouse)</td><td>AM630 (3mg/kg, IP, immediately after recovery from anesthesia, and repeated 24h post-injury)</td><td>Fear conditioning (sound + electrical footshock or context)</td><td>✓ contextual fear memory. = tone fear memory</td><td>-</td><td>(Sun et al., 2017)</td></tr><tr><td>D-AP5-induced memory impairment (Rat)</td><td>AM630 (50 ng, Intra-CA1 microinjection, post-training)</td><td>Step-through task, Isobologram analysis</td><td>✓ memory consolidation (D-AP5>0.5µg) or ✓ (D-AP5<0.5µg)</td><td>Synergic effect between, D-AP5 and AM630</td><td>(Nasehi et al., 2017)</td></tr><tr><td>Vascular dementia (Rat)</td><td>AM630 (3 mg/kg, IP, daily for 28 days one-week post-injury)</td><td>MWM</td><td>✓ spatial memory</td><td>-</td><td>(Luo et al., 2018)</td></tr><tr><td colspan="6"><strong>Genetic deletion</strong></td></tr><tr><td rowspan="4">Healthy, CB2R KO (Zimmer strain)</td><td>-</td><td>Step down inhibitory avoidance test</td><td>✓ short (1h) and long (24h) term aversive memory</td><td>-</td><td>(García-Gutiérrez et al., 2013)</td></tr><tr><td>-</td><td>Step down inhibitory avoidance</td><td>✓ short (1-3h) and long (24h) term memory</td><td>-</td><td>(Ortega-Alvaro et al., 2011)</td></tr><tr><td>-</td><td>MWM</td><td>✓ spatial memory at 6 months (no difference at 9 and 14 months)</td><td>-</td><td>(Schmöle et al., 2015)</td></tr><tr><td>-</td><td>MWM, Contextual fear conditioning</td><td>✓ spatial learning and memory, ✓ hippocampus-dependent contextual memory</td><td>-</td><td>(L. Wang et al., 2018)</td></tr><tr><td>Healthy, CB2R KO (Deltagen strain)</td><td>-</td><td>Cued fear conditioning, Contextual fear conditioning, Y-maze</td><td>✓ contextual fear memory (but not cued), ✓ spatial working memory.</td><td>-</td><td>(Li and Kim, 2016b)</td></tr><tr><td>-</td><td>NOR</td><td>= recognition memory</td><td>-</td><td>(Galán-Ganga et al., 2021)</td></tr><tr><td>Pyramidal cells-specific inducible deletion (Camk2a-Cas9)</td><td>-</td><td>Fear memory test, Y-maze, NOR</td><td>= cued and contextual fear response, = novelty memory. ✓ spatial working memory</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>Interneuron-specific inducible deletion (Gad2-Cas9)</td><td>-</td><td>Fear memory test, Y-maze, NOR</td><td>= cued and contextual fear response, = novelty memory, = spatial working memory</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>Microglia-specific inducible deletion (Cx3cr1-Cas9)</td><td>-</td><td>Fear memory test, Y-maze, NOR</td><td>= cued fear memory. ✓ contextual fear memory. ✓ novelty memory. = spatial working memory</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>Alzheimer's disease APP/PS1*CB2R KO (Zimmer strain)</td><td>-</td><td>MWM</td><td>✓ spatial memory at 6 months (No difference at 9 and 14 months)</td><td>-</td><td>(Schmöle et al., 2015)</td></tr><tr><td>-</td><td>9 and 14 months</td><td>MWM</td><td>✓ spatial memory</td><td>-</td><td>(Schmöle et al., 2018)</td></tr><tr><td>Aging, CB2KO (Zimmer strain)</td><td>3, 12 and 18 months</td><td>Partner recognition, MWM</td><td>✓ social memory, = spatial learning and memory</td><td>-</td><td>(Komorowska-Müller et al., 2021b)</td></tr><tr><td>Isoflurane-induced spatial cognitive impairment, CB2R KO (Deltagen strain)</td><td>-</td><td>MWM</td><td>✓ spatial learning and memory</td><td>-</td><td>(Li et al., 2021)</td></tr><tr><td>Tau induced neurodegeneration, CB2R KO (Deltagen strain)</td><td>-</td><td>NOR</td><td>✓ recognition memory</td><td>-</td><td>(Galán-Ganga et al., 2021)</td></tr></tbody></table>

**Abbreviations:** Aβ, amyloid β; APP, amyloid protein precursor; ASST, attentional set shifting test; CA1, Cornu ammonis 1; Camk2a, Calcium/Calmodulin Dependent Protein Kinase II Alpha; Cre, Cre recombinase; CX3CR1, CX3C motif chemokine receptor 1; D-AP5, D-2-amino-5-phosphonopentanoate; D-Gal, D-galactose; Gad2, glutamate decarboxylase 2; HIV, human immunodeficiency virus; IP, intra-peritoneal; KO, knock-out; MWM, Morris water maze; NOR, novel object recognition test; Physio, physiological state; PO, per os; PS1, presenilin 1; Ref, reference; STZ, streptozotocin.
<table><caption>**Supplementary Table 9. Mood disorder.** Behavioral outcome following CB2R activation or blockade is either enhanced (>) or decreased (\) or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2 um1dgen /J, #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).</caption><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL<br>OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="4">Healthy (Mouse)</td><td>JWH-015 (1-20 mg/kg, IP, daily)</td><td>Sucrose consumption</td><td>&gt; depression</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>JWH-015 (1-20 mg/kg, IP)</td><td>Light/dark box</td><td>&gt; anxiety</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>JWH-015 (10 mg/kg, IP, daily for 21 days)</td><td>Forced swim test, elevated plus maze</td><td>= depressive-like<br>behavior, &gt; anxiety</td><td>-</td><td>(Verty et al., 2015)</td></tr><tr><td>JWH-133 (0.5-2 mg/kg, IP, twice a day for 7 days)</td><td>Light/dark box, elevated plus maze</td><td>&gt; anxiety</td><td>-</td><td>(García-Gutiérrez et al., 2012)</td></tr><tr><td>Healthy (Rat)</td><td>GW405833 (30 mg/kg, IP)</td><td>Marble-burying behavior test</td><td>= anxiety</td><td>-</td><td>(Valenzano et al., 2005)</td></tr><tr><td>Anxiety (S1<br>mouse)</td><td>JWH-133 (IP, 5 mg/kg)</td><td>Elevated Plus Maze</td><td>= anxiety</td><td>-</td><td>(Ten-Blanco et al., 2022b)</td></tr><tr><td>Chronic Mild<br>Stress (Mouse)</td><td>JWH-015 (1-20 mg/kg, IP, daily)</td><td>Sucrose consumption, light/dark box</td><td>= CMS-induced anxiety<br>and anhedonia</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>Chronic restraint<br>stress (Rat)</td><td>β-caryophyllene (25-100 mg/kg, IP, daily for 28 days)</td><td>Tail suspension test, forced swim test,</td><td>&gt; depression</td><td>-</td><td>(Hwang et al., 2020)</td></tr><tr><td>High fat diet (Rat)</td><td>β-caryophyllene (30 mg/kg, PO, daily for 4 weeks)</td><td>Open-field, elevated plus maze, and<br>light/dark box, forced-swim test</td><td>&gt; high fat diet-induced<br>anxiety and depression</td><td>Blocked by<br>AM630 (1<br>mg/kg, IP)</td><td>(Youssef et al., 2019)</td></tr><tr><td>LPS-induced<br>sickness behavior<br>(Mouse)</td><td>1-phenylisatin (20 mg/kg, PO, once daily for 7-days)</td><td>Open field test, forced swim test, tail suspension test</td><td>&gt; anxiety, depression</td><td>-</td><td>(Sahu et al., 2019)</td></tr><tr><td>Sepsis-induced<br>encephalopathy<br>(Mouse)</td><td>HU-308 (2.5 mg/kg, IP, 30 post injury and 1/day for 3 days)</td><td>Open field</td><td>&gt; anxiety</td><td>-</td><td>(Yang et al., 2022)</td></tr><tr><td>Neuropathic pain<br>(PSN, Mouse)</td><td>JWH-133 (0.3 mg/kg/inf, IV self administration)</td><td>Elevated-plus maze</td><td>&gt; anxiety</td><td>-</td><td>(Cabañero et al., 2020)</td></tr><tr><td>Traumatic brain<br>injury (Mouse)</td><td>GP1a (3 mg/kg, IP, 10 min post injury)</td><td>Open field</td><td>&gt; anxiety</td><td>-</td><td>(Braun et al., 2018)</td></tr><tr><td colspan="6"><strong>Genetic overexpression</strong></td></tr><tr><td rowspan="3">Healthy, CB2xP</td><td>-</td><td>Open field, light-dark box, elevated plus maze</td><td>&gt; anxiety</td><td>-</td><td>(García-Gutiérrez and Manzanares, 2011)</td></tr><tr><td>-</td><td>Tail suspension test, novelty-suppressed feeding test, unpredictable chronic mild stress tests, Forced swimming test, sucrose intake</td><td>&gt; acute and chronic<br>depression</td><td>-</td><td>(García-Gutiérrez et al., 2010)</td></tr><tr><td>-</td><td>Light/dark box, open field, elevated plus maze, tail suspension test, novelty suppressed feeding, chronic mild stress, sucrose consumption</td><td>&gt; depression and<br>anxiogenic-like<br>behavior</td><td>-</td><td>(Romero-Zerbo et al., 2012)</td></tr><tr><td>Cell-specific<br>inducible<br>overexpression<br>(Cx3cr1-Cre,<br>Gad2-Cre)</td><td>-</td><td>Elevated O-maze, tail suspension test, Open field</td><td>=anxiety, depression</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>Cell-specific<br>inducible<br>overexpression<br>(Camk2a-Cre)</td><td>-</td><td>Elevated O-maze, tail suspension test, Open field</td><td>&gt; anxiety (open field only), = depression</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td rowspan="4">Healthy (Mouse)</td><td>AM630 (1-3 mg/kg, IP, 30 min<br>before test for acute, twice a day<br>for 7 days for chronic)</td><td>Light/dark box, elevated plus maze</td><td>&gt; anxiety (for both<br>acute and chronic<br>treatment)</td><td>Blocked by<br>JWH-133 (2<br>mg/kg, IP)</td><td>(García-Gutiérrez and Manzanares, 2011)</td></tr><tr><td>AM630 (1-3 mg/kg, IP, 30 min<br>before test for acute, twice a day<br>for 4 weeks for chronic)</td><td>Forced swimming test (acute stress),<br>Unpredictable chronic mild stress tests<br>(chronic stress)</td><td>&gt; depression (acute and<br>chronic)</td><td>No effect in<br>CB2xP mice</td><td>(García-Gutiérrez et al., 2010)</td></tr><tr><td>AM630 (3 mg/kg, IP)</td><td>Elevated O-Maze, open field</td><td>= anxiety</td><td>-</td><td>(Li and Kim, 2016b)</td></tr><tr><td>AM630 (1 mg/kg, IP, daily)</td><td>Sucrose consumption</td><td>= depression</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>Anxiety (DBA/2<br>Mouse)</td><td>AM630 (IP, twice a day for 7 days<br>(chronic). Test 15h after the last<br>injection)</td><td>Light/dark box</td><td>&gt; anxiety</td><td>-</td><td>(García-Gutiérrez and Manzanares, 2011)</td></tr><tr><td>Anxiety (S1<br>mouse)</td><td>SR144528 (3 mg/kg, IP)</td><td>Elevated Plus Maze</td><td>&gt; anxiety</td><td>-</td><td>(Ten-Blanco et al., 2022b)</td></tr><tr><td>Orexin-induced<br>fear extinction<br>deficit (mouse)</td><td>AM630 (3 mg/kg, IP, immediately<br>after the extinction session)</td><td>Fear extinction</td><td>&gt; fear extinction</td><td>-</td><td>(Ten-Blanco et al., 2022a)</td></tr><tr><td>Traumatic Brain<br>Injury (Mouse, air<br>blast injury)</td><td>SMM-189 (6 mg/kg, IP, 2h post-injury and daily for 14 days)</td><td>Tail suspension test, fear extinction</td><td>&gt; depression, &gt; fear<br>extinction, &lt; fear</td><td>-</td><td>(Reiner et al., 2014)</td></tr><tr><td colspan="6"><strong>Genetic deletion</strong></td></tr><tr><td>CB2R KO (Deltagen<br>strain)</td><td>-</td><td>Elevated O-Maze, open field</td><td>= anxiety</td><td>-</td><td>(Li and Kim, 2016b)</td></tr><tr><td>CB2R KO (Zimmer<br>strain)</td><td>-</td><td>Light-dark box test, Elevated +-maze,<br>Tail suspension test</td><td>&gt; anxiety, &gt; despair<br>behavior</td><td>-</td><td>(Ortega-Alvaro et al., 2011)</td></tr></tbody></table>
<table><tr><td>Cell-specific inducible deletion (Camk2a-Cas9, Gad2-Cas9, Cx3cr1-Cas9)</td><td>-</td><td>Elevated O-maze, tail suspension test, Open field</td><td>= anxiety, depression</td><td>-</td><td>(Li and Kim, 2017)</td></tr><tr><td>DAT-CB2R cKO</td><td>-</td><td>Forced swim and tail-suspension test, black and white box, elevated plus-maze tests</td><td>✓ depression</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>Aging, CB2R KO (Zimmer strain)</td><td>3, 12 and 18 months</td><td>O-maze</td><td>✓ anxiety</td><td>-</td><td>(Komorowska-Müller et al., 2021b)</td></tr><tr><td>Chronic Mild Stress, DAT-CB2R cKO</td><td>-</td><td>Sucrose intake</td><td>✓ stress-induced anhedonia</td><td>-</td><td>(Liu et al., 2017)</td></tr></table>

**Abbreviations** : Camk2a, Calcium/Calmodulin Dependent Protein Kinase II Alpha ; CB2xP, mice overexpression CB2R ; cKO, conditional knock-out ; CMS, chronic mild stress ; Cre, Cre recombinase ; CX3CR1, CX3C motif chemokine receptor 1 ; DAT, dopamine active transporter ; Gad2, glutamate decarboxylase 2 ; IP, intra-peritoneal ; IV, intra-veinous ; KO, knock-out ; LPS, lipopolysaccharide ; PO, per os ; PSN, partial sciatic nerve ligation model ; Ref, reference.

**Supplementary Table 10. Reward and addiction.** Behavioral outcome following CB2R activation or blockade is either enhanced (✓), decreased (✓) or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2tm1Dgen/J, #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).

<table><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="3">Alcohol (Mouse)</td><td>β-caryophyllene (25-100 mg/kg, IP, daily)</td><td>Two-bottle choice, EtOH conditioning</td><td>✓ EtOH consumption and preference. ✓ EtOH elicited conditioning</td><td>Blocked by AM630 (3 mg/kg, IP)</td><td>(Al Mansouri et al., 2014)</td></tr><tr><td>JWH-133 (10 mg/kg, IP, 1/D during CPP development, 1h before conditioning session (8 days))</td><td>Conditioned place preference</td><td>✓ EtOH-induced CPP</td><td>EtOH: 10%, 12.6 mL/kg, IP</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td>JWH-133 (10-20 mg/kg, IP 30 minutes before behavioral testing)</td><td>Conditioned place preference</td><td>= EtOH intake, = EtOH-induced CPP expression</td><td>EtOH: 20%, 2g/kg, IP</td><td>(Powers et al., 2015)</td></tr><tr><td rowspan="5">Alcohol, Chronic Mild Stress (Mouse)</td><td>JWH-015 (20 mg/kg, IP, chronic (daily))</td><td>EtOH consumption monitoring</td><td>✓ EtOH intake</td><td>No effect in non-stressed animals. EtOH: 4%, PO</td><td>(Ishiguro et al., 2007; Onaivi et al., 2008)</td></tr><tr><td>JWH-133 (3 mg/kg, IP, pre-treatment)</td><td>Conditioned place preference</td><td>✓ cocaine induced CPP</td><td>Cocaine: 7.5 mg/kg, IP</td><td>(Canseco-Alba et al., 2019)</td></tr><tr><td>JWH-133 (1-10 mg/kg, IP, 30 min before cocaine)</td><td>Conditioned place preference</td><td>✓ cocaine induced-sensitization. ✓ cocaine-induced CPP</td><td>Cocaine: 20 mg/kg, IP</td><td>(Lopes et al., 2020)</td></tr><tr><td>JWH-133 (10-20 mg/kg, IP; 1-1000 µM, intra NAc)</td><td>Cocaine self-administration</td><td>✓ cocaine self-administration (dose-dep), ✓ cocaine's rewarding efficacy.</td><td>Cocaine: 10mg/kg, IP. Blocked by AM630 (10 mg/kg, IP). No effect in KO mice (Zimmer strain)</td><td>(Xi et al., 2011)</td></tr><tr><td>GW405833 (3-10 mg/kg, IP)</td><td>Cocaine self-administration</td><td>✓ cocaine self-administration (dose-dep)</td><td>Cocaine: 10, 20 mg/kg, IP</td><td>(Xi et al., 2011)</td></tr><tr><td rowspan="4">Cocaine (Mouse)</td><td>JWH-133 (10-20 mg/kg, IP or 10-20 µg, intranasal, 30min before testing)</td><td>Cocaine self-administration</td><td>✓ cocaine self-administration</td><td>Cocaine: 0.5 mg/kg/injection, IV. No effect in KO mice (Zimmer strain)</td><td>(Zhang et al., 2015)</td></tr><tr><td>JWH-133 (1-3 µg/side, Intra VTA microinjection, 30 min before testing)</td><td>Cocaine self-administration</td><td>✓ cocaine self-administration</td><td>Cocaine: 0.5 mg/kg/injection, IV. Blocked by AM630 (3µg/side). No effect in KO mice (Zimmer strain)</td><td>(Zhang et al., 2014)</td></tr><tr><td>O-1966 (20 mg/kg, IP, 15 before cocaine)</td><td>Conditioned place preference</td><td>✓ cocaine induced CPP</td><td>-</td><td>(Ignatowska-Jankowska et al., 2013)</td></tr><tr><td>JWH-133 (3-10 mg/kg, IP, pre-pairing administration)</td><td>Conditioned place preference</td><td>✓ cocaine induced CPP. ✓ cocaine-induced conditioned motor activity</td><td>Blocked by AM630 (5mg/kg, IP). Cocaine: 20 mg/kg, IP</td><td>(Delis et al., 2016)</td></tr><tr><td rowspan="2">Cocaine (Rat)</td><td>JWH-133 (10-20 mg/kg, IP, 30min before testing)</td><td>Cocaine self-administration</td><td>= cocaine self-administration</td><td>Cocaine: 0.5 mg/kg/injection, IV.</td><td>(Zhang et al., 2015)</td></tr><tr><td>JWH-133 (25-50µg/side, intranasal)</td><td>Cocaine self-administration</td><td>25 µg : ✓ cocaine self-administration. 50 µg : ✓ cocaine self-administration</td><td>Cocaine: 0.5 mg/kg/injection, IV.</td><td>(Zhang et al., 2015)</td></tr><tr><td>Food (Mouse)</td><td>JWH-133 (10 mg/kg, IP, 1/day during CPP development, 1h before conditioning session (8 days))</td><td>Conditioned place preference</td><td>✓ food-induced CPP</td><td>-</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td>Intracranial self-stimulation (Rat)</td><td>JWH-133 (20 mg/kg, IP, 30 min before test)</td><td>Brain stimulation reward (lateral hypothalamus)</td><td>✓ reward (✓ BSR threshold)</td><td>Attenuated by AM630 (3 mg/kg, IP)</td><td>(Spiller et al., 2019)</td></tr><tr><td>Morphine (Rat)</td><td>JWH-015 (1 mg/kg, IP)</td><td>Conditioned place preference</td><td>✓ Morphine-induced CPP</td><td>Morphine: 10 mg/kg, IP</td><td>(Grenald et al., 2017)</td></tr><tr><td>Nicotine (Mouse)</td><td>O-1966 (1-20 mg/kg, IP, 15 before nicotine)</td><td>Conditioned place preference</td><td>✓ CPP (dose dep)</td><td>Nicotine: 0.1 mg/kg, SC (=subthreshold dose)</td><td>(Ignatowska-Jankowska et al., 2013)</td></tr></tbody></table>
<table><tbody><tr><td rowspan="2">Sucrose (Mouse)</td><td>JWH-133 (1-3 µg/side, Intra VTA microinjection, 30 min before testing)</td><td>Sucrose self-administration</td><td>= sucrose self-administration</td><td>-</td><td>(Zhang et al., 2014)</td></tr><tr><td>JWH-133 (10-20 mg/kg, IP 30 min before testing)</td><td>Sucrose self-administration</td><td>✓ sucrose self-administration</td><td>No effect in KO mice (Zimmer strain)</td><td>(Zhang et al., 2015)</td></tr><tr><td>Sucrose (Rat)</td><td>JWH-133 (10-20 mg/kg, IP 30 min before testing)</td><td>Sucrose self-administration</td><td>= sucrose self-administration</td><td>-</td><td>(Zhang et al., 2015)</td></tr><tr><td colspan="6"><strong>Genetic overexpression</strong></td></tr><tr><td>Cocaine (CB2xP mouse)</td><td>-</td><td>Conditioned place preference</td><td>Conditioned place aversion. ✓ cocaine self-administration.</td><td>Cocaine: 20-40 mg/kg, IP</td><td>(Aracil-Fernández et al., 2012)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td rowspan="4">Alcohol (Mouse)</td><td>AM630 (3 mg/kg, IP, daily)</td><td>EtOH consumption monitoring</td><td>✓ Alcohol intake (not significant)</td><td>EtOH: 4%, PO</td><td>(Ishiguro et al., 2007)</td></tr><tr><td>AM630 (10 mg/kg, IP, 1h before test session, post-conditioning)</td><td>Conditioned place preference (expression)</td><td>✓ Alcohol induced CPP (no effect at 5 mg/kg)</td><td>EtOH: 2 g/kg, IP</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td>AM630 (10 mg/kg, IP, 1/day during conditioning for 8 days)</td><td>Conditioned place preference (development)</td><td>= Alcohol induced CPP</td><td>EtOH: 2 g/kg, IP</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td>AM630 (10-20 mg/kg, IP)</td><td>Conditioned place preference</td><td>= Alcohol intake, = alcohol-induced CPP expression</td><td>EtOH: 2 g/kg, IP</td><td>(Powers et al., 2015)</td></tr><tr><td rowspan="2">Alcohol, Chronic Mild Stress (Mouse)</td><td>AM630 (3 mg/kg, IP, daily)</td><td>EtOH consumption monitoring</td><td>= Alcohol intake</td><td>EtOH: 4%, PO</td><td>(Ishiguro et al., 2007)</td></tr><tr><td>AM630 (1 mg/kg, IP, daily)</td><td>EtOH consumption monitoring</td><td>✓ Alcohol intake</td><td>-</td><td>(Onaivi et al., 2008)</td></tr><tr><td>Cocaine (Mouse)</td><td>AM630 (3 µg/side, intra VTA microinjection)</td><td>Intravenous self-administration</td><td>= cocaine self-administration</td><td>-</td><td>(Zhang et al., 2014)</td></tr><tr><td rowspan="2">Cocaine (Rat)</td><td>SR14452B (0.1-1 mg/kg, IP, 45 min before test session)</td><td>Cocaine self-administration</td><td>✓ cocaine-induced reinstatement to drug seeking, = cocaine self-administration maintenance</td><td>-</td><td>(Adamczyk et al., 2012)</td></tr><tr><td>AM630 (5 mg/kg, IP, pre-pairing)</td><td>Conditioned place preference</td><td>= Cocaine induced CPP. = Cocaine-induced conditioned motor activity</td><td>Cocaine: 20 mg/kg, IP</td><td>(Delis et al., 2016)</td></tr><tr><td>Food (Mouse)</td><td>AM630 (10 mg/kg, IP, 1h before test session, post-conditioning)</td><td>Conditioned place preference (expression)</td><td>= Food induced CPP</td><td>-</td><td>(Martín-Sánchez et al., 2019)</td></tr><tr><td rowspan="2">Nicotine (Mouse)</td><td>AM630 (3mg/kg, IP)</td><td>Conditioned place preference</td><td>✓ Nicotine-induced CPP (abolished). ✓ Nicotine self-administration</td><td>Nicotine: 0.5-25mg/kg/day, IV</td><td>(Navarrete et al., 2013)</td></tr><tr><td>SR14452B (1-3 mg/kg, IP, 15 min before nicotine)</td><td>Conditioned place preference</td><td>✓ Nicotine-induced CPP (abolished at 3 mg/kg)</td><td>Nicotine: 0.5 mg/kg, SC</td><td>(Ignatowska-Jankowska et al., 2013)</td></tr><tr><td>Nicotine (Rat)</td><td>AM630 (5 mg/kg, IP, 30 min before the session)</td><td>Nicotine self-administration</td><td>= Nicotine self-administration</td><td>Nicotine: 30 µg/kg/infusion</td><td>(Gamaleddin et al., 2012)</td></tr><tr><td colspan="6"><strong>Genetic invalidation</strong></td></tr><tr><td rowspan="2">Alcohol, CB2R KO (Zimmer strain)</td><td>-</td><td>Conditioned place preference, two-bottle free choice assay</td><td>✓ Alcohol-induced CPP. ✓ Alcohol consumption</td><td>EtOH: 2 g/kg, PO</td><td>(Ortega-Alvaro et al., 2015)</td></tr><tr><td>-</td><td>Conditioned place preference</td><td>✓ Alcohol-induced CPP</td><td>EtOH: 2 g/kg, IP</td><td>(Powers et al., 2015)</td></tr><tr><td>Alcohol, Cx3cr1-CB2R cKO</td><td>-</td><td>Conditioned place preference</td><td>= alcohol induced CPP</td><td>EtOH: 8%, PO</td><td>(Liu et al., 2020)</td></tr><tr><td>Alcohol, DATCnr2 cKO</td><td>-</td><td>Conditioned place preference</td><td>✓ alcohol induced CPP</td><td>EtOH: 8%, PO</td><td>(Liu et al., 2020)</td></tr><tr><td>Alcohol, Subacute stress, DAT-CB2R cKO</td><td>-</td><td>EtOH consumption monitoring</td><td>✓ alcohol consumption</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>Alcohol, Chronic Mild Stress, DAT-CB2R cKO</td><td>-</td><td>EtOH consumption monitoring</td><td>= alcohol consumption</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>Alcohol, cocaine, DAT-CB2R cKO</td><td>-</td><td>Conditioned place preference</td><td>✓ alcohol consumption. ✓ alcohol induced CPP. ✓ cocaine induced CPP</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>Cocaine, Amphetamine, Metamphetamine DAT-CB2R cKO</td><td>-</td><td>Conditioned place preference</td><td>✓ cocaine, amphetamine and methamphetamine-induced CPP</td><td>Cocaine: 7.5 mg/kg, IP, amphetamine: 5 mg/kg, IP, methamphetamine: 1 mg/kg, IP</td><td>(Canseco-Alba et al., 2019)</td></tr><tr><td>Nicotine, CB2R KO (Zimmer strain)</td><td>-</td><td>Conditioned place preference</td><td>✓ Nicotine-induced CPP (abolished). ✓ Nicotine self-administration.</td><td>Nicotine: 0.7 and 1 mg/kg, IP</td><td>(Navarrete et al., 2013)</td></tr><tr><td>Nicotine, CB2R KO (Deltagen strain)</td><td>-</td><td>Conditioned place preference</td><td>✓ Nicotine-induced CPP (abolished)</td><td>Nicotine: 0.5 mg/kg, SC</td><td>(Ignatowska-Jankowska et al., 2013)</td></tr></tbody></table>

**Abbreviations:** CB2xP, mice overexpressing CB2R; cKO, conditional knock-out; CPP, Conditioned place preference; CX3CR1, CX3C motif chemokine receptor 1; DAT, dopamine active transporter; dose-dep, dose-dependent; EtOH, ethanol; IP, intra-peritoneal; IV, intra-veinous; KO, knock-out; PO, per os; Ref, reference; SC, sub-cutaneous; VTA, Ventral tegmental area.
<table><caption>Supplementary Table 11. Analgesia. Behavioral outcome following CB2R activation or blockade is either enhanced (▲), decreased (▼) or unchanged. (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2tm1Dgen/), #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).</caption><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td rowspan="7">Healthy (Mouse)</td><td>GP1a (1-10 mg/kg, SC, local (dorsal flank))</td><td>Formalin pain assay (+/-morphine)</td><td>Analgesic effect (alone, non dose-dep). = morphine-induced analgesia</td><td>-</td><td>(Chen et al., 2019)</td></tr><tr><td>GP1a (1-10 mg/kg, IP)</td><td>Carrageenan pain assay (+/-morphine)</td><td>No analgesic effect (alone). ▲morphine-induced analgesia</td><td>-</td><td>(Chen et al., 2019)</td></tr><tr><td>JWH-015 (0.1-100 mg/kg, IP)</td><td>Formalin flinch test (inflammatory pain)</td><td>Alone: analgesic effect (dose-dep). + ▲morphine-induced analgesia</td><td>-</td><td>(Grenald et al., 2017)</td></tr><tr><td>JWH-133 (20 mg/kg, IP)</td><td>Tail-flick test and hot plate test</td><td>= pain threshold</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>HU-910 (30 mg/kg, IP)</td><td>Hot plate test</td><td>Analgesic effect</td><td>-</td><td>(Cortez et al., 2022)</td></tr><tr><td>β-caryophyllene (5 mg/kg, PO), JWH-133 (10 mg/kg, SC)</td><td>Formalin pain assay</td><td>Analgesic effect</td><td>No effect at lower doses. Blocked with SR144528 (3 mg/kg, IP). No effect in KO mice (Zimmer)</td><td>(Klauke et al., 2014)</td></tr><tr><td rowspan="3">Healthy (Rat)</td><td>AM1241 (2.5 mg/kg, IP, twice daily for 6 days. Co-administered with morphine)</td><td>Hyperalgesia: method of Hargreaves. Allodynia: Von Frey filaments</td><td>▲ Morphine-mediated thermal hyperalgesia and tactile allodynia</td><td>Attenuated by AM630 (0.6 mg/kg, IP)</td><td>(Tumati et al., 2012)</td></tr><tr><td>GW405833 (100 mg/kg, IP, 1 to 5h pre-test)</td><td>Tail flick and hot plate assay</td><td>Antinociceptive effect</td><td>No effect at 30 mg/kg</td><td>(Valenzano et al., 2005)</td></tr><tr><td>JWH-015 (5 mg/kg, IP, 30, 60, 90 and 120 min before test)</td><td>Tail-flick test and hot plate test</td><td>Analgesic effect (alone). ▲morphine-induced analgesia</td><td>-</td><td>(Altun et al., 2015)</td></tr><tr><td>Chronic inflammatory pain (Mouse)</td><td>JWH-015 (16-300 µg, subplantar administration)</td><td>Von Frey filaments, plantar test</td><td>▲ mechanical CFA-induced allodynia, ▲thermal CFA-induced hyperalgesia (dose dep)</td><td>Blocked by AM630 (60 µg, subplantar)</td><td>(Negrete et al., 2011)</td></tr><tr><td>EAE (Mouse)</td><td>β-caryophyllene (50 mg/kg, PO, twice a day for 10 days)</td><td>Von Frey filaments</td><td>▲ mechanical hyperalgesia</td><td>-</td><td>(Alberti et al., 2017)</td></tr><tr><td>High Fat Diet (Mouse)</td><td>HU308 (4 mg/kg/day, PO, for 3 months)</td><td>Dynamic Plantar Aesthesiometer (Von frey-like filaments), Hargreaves Test</td><td>▲ mechanical and thermal hypersensitivity</td><td>-</td><td>(Schmitz et al., 2016)</td></tr><tr><td>Incisional pain (Rat)</td><td>GW405833 (0.3-30 mg/kg, IP, 24h post injury)</td><td>Hind paw withdrawal thresholds (PWT)</td><td>▲ mechanical hyperalgesia</td><td>-</td><td>(Valenzano et al., 2005)</td></tr><tr><td>Inflammation (CFA, Rat)</td><td>GW405833 (0.01-30 mg/kg, IP, 24h post injury)</td><td>Hind paw withdrawal thresholds (PWT)</td><td>▲ mechanical hyperalgesia</td><td>No effect in KO mouse (Deltagen strain)</td><td>(Valenzano et al., 2005)</td></tr><tr><td rowspan="2">Neuropathic pain (PSN, Mouse)</td><td>β-caryophyllene (0,1-10 mg/kg daily, PO, starting 1 day post injury)</td><td>Von Frey filaments, Hargreaves test</td><td>▲ mechanical and thermal hyperalgesia</td><td>No effect in KO mice (Zimmer strain)</td><td>(Klauke et al., 2014)</td></tr><tr><td>JWH-133 (0.3 mg/kg/inf, IV self-administration)</td><td>Plantar and von Frey tests</td><td>▲ mechanical hypersensitivity</td><td>No effect in KO mice (Zimmer strain)</td><td>(Cabañero et al., 2020)</td></tr><tr><td>Neuropathic pain (PSN, Rat)</td><td>GW405833 (0.3-30 mg/kg, IP, 24h post injury)</td><td>Hind paw withdrawal thresholds (PWT)</td><td>▲ mechanical hyperalgesia</td><td>-</td><td>(Valenzano et al., 2005)</td></tr><tr><td rowspan="3">Neuropathic pain (SNL, Rat)</td><td>AM1241 (0.1-3 mg/kg, IP, 15 min before testing)</td><td>Thermal and tactile Withdrawal Threshold</td><td>▲ tactile and thermal hypersensitivity (dose-dep)</td><td>Blocked by AM630 (0.3 mg/kg, IP)</td><td>(Ibrahim et al., 2003)</td></tr><tr><td>AM1241 (1 µmol/h, Continuous intrathecal infusion for 7 days)</td><td>Von Frey filaments, radiant heat tests</td><td>Analgesic effect (▲ nerve ligation-induced mechanical allodynia and thermal hyperalgesia)</td><td>-</td><td>(Shiue et al., 2017)</td></tr><tr><td>JWH-015 (1-10 mg/kg, IP, 1-week post-injury)</td><td>Elevated Plexiglas chambers from a thermal radiant heat source, calibrated von Frey filaments</td><td>Alone: analgesic effect (dose-dep). + ▲morphine-induced analgesia</td><td>-</td><td>(Grenald et al., 2017)</td></tr><tr><td>Neuropathic pain (Retrovirus induced, Mouse)</td><td>JWH-015, JWH-133, GP1a or HU308 (5 mg/kg, IP, weekly starting at week 5 post injury.)</td><td>Mouse Metelectronic von Frey system</td><td>▲ allodynia (▲ mechanical hypersensitivity)</td><td>No effect 24h post agonist injection</td><td>(Sheng et al., 2019)</td></tr><tr><td>Post-operative pain (Rat)</td><td>JWH-015 (1-10 mg/kg, IP, 24h post-injury)</td><td>Elevated Plexiglas chambers from a thermal radiant heat source, calibrated von Frey filaments</td><td>Alone: analgesic effect (dose-dep). + ▲morphine-induced analgesia</td><td>-</td><td>(Grenald et al., 2017)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td>Healthy (Rat)</td><td>JTE907 (5 mg/kg, IP)</td><td>Tail flick and hot plate test</td><td>= analgesia (alone). ▲morphine-induced analgesia</td><td>-</td><td>(Altun et al., 2015)</td></tr><tr><td>Chronic Inflammatory Pain (Mouse)</td><td>AM630 (60 µg, Subplantar administration)</td><td>Von Frey filaments, plantar test</td><td>= mechanical CFA-induced allodynia and thermal hyperalgesia</td><td>-</td><td>(Negrete et al., 2011)</td></tr><tr><td colspan="6"><strong>Genetic invalidation</strong></td></tr><tr><td>CB2R KO (Zimmer strain)</td><td>-</td><td>Plantar test, cold plate test, von Frey stimulation model</td><td>▲ basal nociceptive response</td><td>-</td><td>(Racz et al., 2008)</td></tr><tr><td>Cx3cr1-CB2R cKO</td><td>-</td><td>Tail flick test</td><td>= pain threshold</td><td>-</td><td>(Liu et al., 2020)</td></tr><tr><td>DAT-CB2R cKO</td><td>-</td><td>Hotplate and tail flick test</td><td>▲ pain threshold (tail flick but not hot plate test)</td><td>-</td><td>(Liu et al., 2017)</td></tr><tr><td>DAT-CB2R cKO</td><td>-</td><td>Tail flick test</td><td>▲ pain threshold</td><td>-</td><td>(Liu et al., 2020)</td></tr></tbody></table>
<table><tr><td>Neuropathic pain, CB2R KO (Zimmer strain)</td><td>-</td><td>Plantar test, cold plate test, von Frey stimulation model</td><td>✓ thermal hyperalgesia, mechanical and thermal allodynia</td><td>-</td><td>(Racz et al., 2008)</td></tr><tr><td>Neuropathic pain, Cell-specific deletion (CB2R KO BM chimeric mice)</td><td>-</td><td>Plantar test, cold plate test, von Frey stimulation model</td><td>✓ thermal hyperalgesia, mechanical and thermal allodynia</td><td>-</td><td>(Racz et al., 2008)</td></tr></table>

**Abbreviations**: BM, bone marrow; CFA, complete Freund's adjuvant; cKO, conditional knock-out; CX3CR1, CX3C motif chemokine receptor 1; DAT, dopamine active transporter; Dose-dep, dose-dependent; EAE, experimental autoimmune encephalomyelitis; IP, intra-peritoneal; IV, intra-veinous; KO, knock-out; PO, per os; PSN, partial sciatic nerve ligation model; ref, reference; SNL, sciatic nerve ligation; SC, sub-cutaneous.

**Supplementary Table 12. Seizure activity.** Behavioral outcome following CB2R activation or blockade is either enhanced (✓) or decreased (✓) or unchanged (=). In some studies, the specificity of the ligand used has been challenged by the use of CBR2 KO mice (the "Deltagen strain", with a deletion of the sequence encoding the N-terminal part of the protein (The Jackson Laboratory, Cnr2tm1Dgen/), #005786), or the "Zimmer strain" with a deletion of the sequence encoding the C-terminal part of the protein (Buckley et al., 2000)).

<table><thead><tr><th>MODEL</th><th>TREATMENT</th><th>TESTS</th><th>BEHAVIORAL OUTCOME</th><th>OTHER</th><th>REF</th></tr></thead><tbody><tr><td colspan="6"><strong>CB2R ACTIVATION</strong></td></tr><tr><td colspan="6"><strong>Pharmacological activation</strong></td></tr><tr><td>MES (Mouse)</td><td>β-caryophyllene (30-300 mg/kg, IP, 30 min before MES)</td><td>MES: Corneal electrode, electric stimulus and hind limb extension measurement</td><td>✓ tonic-clonic seizure (66%)</td><td>-</td><td>(Tchekalarova et al., 2018)</td></tr><tr><td rowspan="2">PTZ (Mouse)</td><td>β-caryophyllene (100 mg/kg, IP, 60 min before PTZ)</td><td>IP injection of PTZ (60 mg/kg)</td><td>✓ latency to the first myoclonic jerk (MJ)</td><td>-</td><td>(Oliveira et al., 2016)</td></tr><tr><td>β-caryophyllene (30-300 mg/kg, 4h before PTZ)</td><td>Subcutaneous (SC) PTZ seizure test</td><td>No effect</td><td>-</td><td>(Tchekalarova et al., 2018)</td></tr><tr><td>PTZ, PTZ+toxoplasmosis (Mouse)</td><td>HU308 (1-10 µg, icv, 10 min before PTZ)</td><td>Intravenous PTZ injection (10 mg/mL)</td><td>✓ seizure threshold</td><td>-</td><td>(Ghanbari et al., 2020)</td></tr><tr><td>PTZ (Rat)</td><td>AM1241 (0.01, 1 or 10 g/2 l, ICV microinfusion, 5 min before PTZ)</td><td>IP injection of PTZ (70 mg/kg)</td><td>✓ tonic-clonic seizure incidence and severity</td><td>Blocked by AM630 (1 mg/kg, IP)</td><td>(de Carvalho et al., 2016)</td></tr><tr><td>PTZ, DMCM (Rat)</td><td>HU-308 (2-10 mg/kg, IP, 20 min before PTZ)</td><td>SC injection of PTZ (100 mg/kg), or IP injection of DMCM (600 µg/kg)</td><td>No effect</td><td>-</td><td>(Huizenga et al., 2017)</td></tr><tr><td>Pilocarpine (Rat)</td><td>JWH-133 (1.5 mg/kg, IP, every 6h following SE)</td><td>IP administration of pilocarpine (375 mg/kg)</td><td>✓ latent period of first seizure attack, ✓ mortality</td><td>Blocked by AM630 (1.5 mg/kg, IP)</td><td>(Cao et al., 2021)</td></tr><tr><td colspan="6"><strong>CB2R BLOCKADE</strong></td></tr><tr><td colspan="6"><strong>Pharmacological blockade</strong></td></tr><tr><td>PTZ (Mouse)</td><td>SR144528 (30 min before PTZ)</td><td>SC injection of PTZ (100 mg/kg)</td><td>✓ latencies to the first MJ and generalized tonic-clonic seizure (GTCS)</td><td>No effect in KO mice (Deltagen strain)</td><td>(Shapiro et al., 2019)</td></tr><tr><td>PTZ, DMCM (Rat)</td><td>AM630 (2-10 mg/kg, IP, 20 min before PTZ)</td><td>SC injection of PTZ (100 mg/kg), or IP injection of DMCM (600 µg/kg)</td><td>No effect</td><td>-</td><td>(Huizenga et al., 2017)</td></tr><tr><td>PTZ, PTZ+toxoplasmosis (Mouse)</td><td>AM630 (1-5 µg, icv, 10 min before PTZ)</td><td>Intravenous PTZ injection (10 mg/mL)</td><td>✓ seizure threshold</td><td>-</td><td>(Ghanbari et al., 2020)</td></tr><tr><td colspan="6"><strong>Genetic invalidation</strong></td></tr><tr><td rowspan="2">CB2R KO (Zimmer strain)</td><td>Alcohol (4 g/kg, IP.) induced HIS</td><td>✓ alcohol-induced HIC</td><td>No effect</td><td>-</td><td>(Ortega-Álvaro et al., 2015)</td></tr><tr><td>Handling induced seizures</td><td>No seizure</td><td>-</td><td>-</td><td>(Rowley et al., 2017)</td></tr><tr><td>CB2R KO (✓ and -✓ Zimmer strain)</td><td>SC injection of PTZ (100 mg/kg)</td><td>✓ latencies to the first MJ and GTCS. ✓ % of mice reaching GTCS</td><td>-</td><td>-</td><td>(Shapiro et al., 2019)</td></tr><tr><td>CB2R KO (Deltagen strain)</td><td>6 Hz seizure induction paradigm</td><td>✓ average Racine score</td><td>-</td><td>-</td><td>(Shapiro et al., 2019)</td></tr><tr><td>CB1R/CB2R KO</td><td>Handling induced seizures</td><td>HIS in 27.6%. >1 spontaneous electrographic seizure in 80% of mice</td><td>-</td><td>-</td><td>(Rowley et al., 2017)</td></tr></tbody></table>

**Abbreviations**: DMCM, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; GTCS, generalized tonic-clonic seizure; HIS, handling-induced seizure; ICV, intra-cerebroventricular; IP, intra-peritoneal; KO, knock-out; MES, maximal electroshock seizure; MP, myoclonic jerk; PTZ, Pentylenetetrazol; Ref, reference; SC, subcutaneous.