No Model Dose/route of administration Key findings Ref. Healthy rodents submitted to painful experience 1 Male Wistar Rats intra‐vl‐PAG microinjection of vehicle; CBD (1.5; 3; 6 CBD and CBC: ↓ ongoing acvity of ON and OFF neurons (Maione submitted to tail flick nmol) alone or CBD (3 nmol) in combination with the (dose‐dependently); ↑ annocicepve responses in the tail et al. test and selective antagonists of TRPV1 (I‐RTX, 1 nmol), CB1 flick‐test (effects antagonized by selective antagonists of CB1 2011) measurement of the (AM251, 0.5 nmol), adenosine A1 (DPCPX, 0.05 nmol), adenosine A1 and TRPA1, but not of TRPV1 receptors); ↑ electrical activity of TRPA1 (AP18, 6 nmol), 5‐HT1A (WAY100635, 0.34 nmol); endocannabinoid levels in the ventrolateral periaqueductal anaesthetizes rat’s CBC (3; 6 nmol) alone or CBC (6 nmol) in combination grey ON and OFF neurons with I‐RTX (1 nmol), AM251 (0.5 nmol), DPCPX (0.05 OMDM‐2 and mustard oil: similar effects of the rostral nmol) or AP18 (6 nmol); OMDM‐2 (selective inhibitor of ventromedial endocannabinoid cellular reuptake, 1.5; 3 nmol) or medulla mustard oil (TRPA1 channels agonist, 3; 6 nmol) 2 Male and female Experiment 1: CBD (0, 10, 30 mg/kg) 15 min before Δ9‐ Experiment 1: (Britch et Sprague‐Dawley rats THC (0, 1.8, 3.2, 5.6, 10 mg/kg); test 15–360 min post‐Δ9‐ al. 2017) CBD alone: no antinociceptive effects; ↑ locomotor acvity tested on tail THC injection withdrawal, paw CBD+Δ9‐THC: ↑ THC‐induced paw pressure but not tail Experiment 2: CBD (30 mg/kg) 13 h or 15 min before Δ9‐ pressure and withdrawal antinociception; ↑ Δ9‐THC‐induced THC (1.8 mg/kg); test 30–480 min post‐Δ9‐THC injection locomotor activity hypolocomotion at lower Δ9‐THC doses tests Experiment 3: CBD (30 mg/kg) 13 h or 15 min before Δ9‐ No sex differences in CBD‐Δ9‐THC interactions THC (1.8 mg/kg); serum samples taken 30–360 min post‐ Δ9‐THC injection Experiments 2 and 3: CBD: no enhancement of Δ9‐THC’s effects; ↓ THC metabolism (effect greater in females than males) 3 Male and female Twice‐daily treatment with vehicle, CBD (10 mg/kg), Δ9‐ Δ9‐THC day 1: more potent in females than in males (both (Greene Sprague‐Dawley rats THC (3.6 mg/kg females; 9.3 mg/kg males) or CBD+Δ9‐ nociceptive tests) et al. submitted to tail THC for 4 days 2018) Δ9‐THC days 1‐6: ↓ of potency on the tail withdrawal test withdrawal and paw (more in females than males) pressure tests CBD+Δ9‐THC days 1‐6: greater rightward/downward shifts of the Δ9‐THC dose‐effect curve than Δ9‐THC alone Day 6 blood samples: higher serum Δ9‐THC levels in CBD+Δ9‐ THC‐treated females than in vehicle + Δ9‐THC‐treated females; Δ9‐THC’s active metabolite 11‐OH‐ Δ9‐THC and its inactive metabolite Δ9‐THC‐COOH: lower in CBD + Δ9‐THC‐ treated rats than in vehicle+ Δ9‐THC‐treated rats (both sexes); CBD: ↑ serum levels of the active metabolite cannabinol (both sexes) 4 Male Wistar Rats Naloxone (3.0 mg/kg), diazepam (1.5 mg/kg) or CBD (0.75 Naloxone and CBD: ↓ nocicepve threshold; ↓ tail‐flick (Gonçalve submitted to mg/kg,1.5 mg/kg, 3.0 mg/kg, 4.5 mg/kg, 6.0 mg/kg and latencies s et al. transcutaneous 12.0 mg/kg) i.p. 10 min after the acute administration,10 2014) Diazepam: no alterations in the nociceptive threshold electrical nerve Hz or 150 Hz TENS was performed for 30 min stimulation (TENS) and the tail‐flick test Neuropathic pain 5 Sciatic nerve injury Gelatin oral self‐administration paradigm ‐ mice Δ9‐THC gelatin: ↓ allodynia; ↓ hyperalgesia; ↓ ultrasonic (Abraham mouse model consumed Δ9‐THC‐, CBD‐, or morphine‐containing vocalizations et al. gelatins ad libitum for 3 weeks 2020) CBD gelatin: ↓ allodynia; ↓ ultrasonic vocalizaons Morphine gelatin: ↓ allodynia (tolerance aer 1 week); ↓ ultrasonic vocalizations 6 Ligation of L5 spinal CBD (3, 10, 50 ug i.t.) CBD and its modified derivatives: ↓ chronic neuropathic pain (Xiong et nerve neuropathic (positively correlated with cannabinoid potentiation of the α3 al. 2012) Dihydroxyl‐CBD, DH‐CBD (10, 30, 50 mg/kg i.p.) pain model in rats GlyRs, but not with their binding affinity for CB1 and CB2 Didesoxy‐CBD, DD‐CBD (0.1, 1, 10, 15 mg/kg i.p.) receptors); ↑ glycine currents in dorsal horn neurons in rat spinal cord slices Antagonist tested: strychnine 1 µM (GlyR antagonist) 7 Foramen Rotundum orally ‐ 5 uL of whole plant extracted hemp oil combined CBD: ↓ mechanical allodynia within 1 h with a peak reversal (Vigil et Inflammatory with a peanut butter vehicle (0.138 mg/kg) effect at 4 h; remained significant throughout the 6 h al. 2020) Constriction Trigeminal Infraorbital Nerve injury mouse model 8 Sciatic nerve chronic Oral administration of CBD (2.5–20 mg/kg) daily from day CBD in neuropathic pain model: ↓ hyperalgesia to thermal (Costa et constriction 7 to 14 after the injury and mechanical stimuli; the 20 mg/kg dose normalized PGE2 al. 2007) plasma concentration and paw tissue malondialdehyde, NO Antagonists tested: capsazepine, rimonabant, SR144528 and glutathione‐related enzymes levels Vanilloid antagonist capsazepine: prevention of anti‐ hyperalgesic effect Cannabinoid receptor antagonists (rimonabant and SR144528): no effect on the withdrawal threshold 9 Mouse chronic Subcutaneous Δ9THC, CBD and Δ9‐THC:CBD co‐ Δ9‐THC: ↓ mechanical and cold allodynia; ↑ motor (Casey, constriction injury administration in doses: 0.01‐56 mg/kg incoordination, catalepsy, sedation (dose‐dependently) Atwal, (CCI) model of and Antagonists tested: AM281, AM630 (3 mg/kg) CBD: ↓ allodynia (dose‐dependently, smaller effect than Δ9‐ neuropathic pain Vaughan THC); no side effects 2017) Δ9‐THC:CBD co‐administration: ↓ allodynia (dose‐ dependently); 200‐fold increase in anti‐allodynic potency (at low doses); only high doses gave side effects (similar to Δ9‐ THC alone) AM281 (CB1 receptor antagonist): abolition of the THC effect on mechanical allodynia and cold allodynia (only parital) 10 Spinal cord injury CBD 1,5 mg/kg i.p. for 10 weeks CBD: ↓ pro‐inflammatory cytokines and chemokines; ↓ (Li et al. mouse model moderate to severe thermal sensitivity development 2018) (compared to vehicle group) 11 Peripheral sciatic Orally, in medium chain triglyceride oil, for 14 days All groups: ↓ hypersensivity in male rats (parcularly CBD: (Linher‐ nerve cuff (surgically Δ9‐THC combination); ↑ beneficial changes in myelinated Aβ Melville CBD ‐ 25 mg/60 kg per day induced neuropathic mechanoreceptive fibers et al. pain rat model) Δ9‐THC ‐ 5 mg/60 kg per day 2020) CBD: Δ9‐THC ‐ 12,5:12,5 mg/60 kg per day 12 Naive rats and 1. Intravenous (i.v.) increasing doses of CBD (0.1‐1.0 Naïve rats: acute CBD ↓ the firing rate of 5‐HT neurons in (De Spared nerve injury mg/kg) ‐ naive rats only dorsal raphe nucleus (blocked by WAY100635, 5HT1A Gregorio neuropathic pain rat antagonist and capsazepine, the TRPV1 antagonist); repeated et al. Antagonists tested: WAY 100635 (300 mg/kg), AM 251 (1 model CBD ↑ 5‐HT firing through desensitization of 5‐HT1A 2019) mg/kg), capsazepine (1 mg/kg) i.v. receptors 2. Repeated treatment with CBD (5 mg/kg/day, SNI rats: repeated CBD ↓ mechanical allodynia (blocked by subcutaneously, for 7 days ‐ naive and SNI rats capsazepine and partially by WAY100635), anxiety‐like behavior (blocked by WAY100635); normalized 5‐HT activity Antagonists tested: WAY (2 mg/kg, capsazepine (10 mg/kg) subcutaneously 13 Paclitaxel (PAC)‐ CBD 5 or 10 mg/kg i.p. CBD: prevention of cold and mechanical allodynia (Ward et induced allodynia development al. 2011) mouse model 14 PAC‐induced CBD pretreatment (2.5, 5.0 mg/kg, i.p.) CBD: PAC‐induced mechanical sensitivity prevention (effect (Ward et neuropathic pain reversed by the 5‐HT1A antagonist, but not the CB1 or CB2 al. 2014) Antagonists tested: SR141716A (CB1), SR144528 (CB2), mouse model antagonists) WAY100635 (5HT‐1A) 5 mg/kg i.p. CBD + PAC: additive to synergistic inhibition of breast cancer cell viability 15 PAC, oxaliplatin or Paclitaxel‐treated mice pretreated with CBD (0.625–20.0 CBD alone: ↓ mechanical allodynia in PAC‐ and oxaliplatin‐ (King et vincristine‐induced mg/kg i.p.), Δ9‐THC (0.625–20.0 mg/kg i.p.) or CBD + Δ9‐ treated mice al. 2017) neuropathic pain THC (0.04 + 0.04–20.0 + 20.0 mg/kg i.p.) Δ9‐THC alone: ↓ mechanical allodynia in PAC‐ and vincristine‐ mouse model Oxaliplatin/vincristine‐treated mice pretreated with CBD treated mice (1.25–10.0 mg/kg i.p.), Δ9‐THC (10.0 mg/kg i.p.) or Δ9‐ CBD + Δ9‐THC: synergistic effect of low, ineffective doses THC + CBD (0.16 mg/kg THC + 0.16 mg/kg CBD i.p.) 16 Cisplatin‐induced Experiment 1: after 8 daily administrations of cisplatin Experiment 1: ↓ neuropathy in all groups (Harris et neuropathy mouse (2,3 mg/kg): vehicle, 100 mg/kg gabapentin, 2 mg/kg Δ9‐ al. 2016) Experiment 2: no prevention of neuropathy development model THC, or 2 mg/kg CBD i.p. Experiment 2: CBD (0.0, 0.5, 1.0, and 2.0 mg/kg) or Δ9‐ THC (0.0, 0.5, 1.0, and 2.0 mg/kg) i.p. 30 min prior to cisplatin administration 17 Cisplatin‐induced CBD 2.5 to 10 mg/kg i.p. every day, starting 1.5 h before CBD: ↓ induced oxidave/nitrosave stress, inflammaon, (Pan et al. nephropathy mouse the cisplatin exposure cell death in the kidney; ↑ renal funcon 2009) model 18 Murine type I CBD: 0.1; 1; 2 mg/kg intranasal (i.n.) or 1; 10; 20 mg/kg Moderate‐high doses of intranasal and i.p.