Cannabis-Based Medicines and Pain: A Review of Potential Synergistic and Entourage Effects

References

• Devane WA , HanusL , BreuerAet al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science258(5090), 1946–1949 (1992).
   PubMed Web of Science ®Google Scholar
• Mechoulam R , Ben-ShabatS , HanusLet al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol.50(1), 83–90 (1995).
   PubMed Web of Science ®Google Scholar
• Sugiura T , KondoS , SukagawaAet al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun.215(1), 89–97 (1995).
   PubMed Web of Science ®Google Scholar
• Stella N , SchweitzerP , PiomelliD. A second endogenous cannabinoid that modulates long-term potentiation. Nature388(6644), 773–777 (1997).
   PubMed Web of Science ®Google Scholar
• Bisogno T , SepeN , MelckDet al. Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem. J.322(2), 671–677 (1997).
   PubMedGoogle Scholar
• Munro S , ThomasKL , AbushaarM. Molecular characterization of a peripheral receptor for cannabinoids. Nature365, 61–65 (1993).
   PubMed Web of Science ®Google Scholar
• Ryberg E , LarssonN , SjögrenSet al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol.152(7), 1092–1101 (2007).
   PubMed Web of Science ®Google Scholar
• Hohmann AG , HerkenhamM. Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neurosci.90(3), 923–931 (1999).
   PubMed Web of Science ®Google Scholar
• Price TJ , HelesicG , ParghiDet al. The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat. Neurosci.120(1), 155–162 (2003).
   Web of Science ®Google Scholar
• Bridges D , RiceASC , EgertovaMet al. Localization of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridization and immunohistochemistry. Neurosci.119, 803–812 (2003).
   PubMed Web of Science ®Google Scholar
• Yiangou Y , FacerP , DurrenbergerPet al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol.6, 12–26 (2006).
   PubMed Web of Science ®Google Scholar
• Stander S , SchmelzM , MetzeDet al. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibres and adnexal structures in human skin. J. Dermatol. Sci.38(3), 177–188 (2005).
   PubMed Web of Science ®Google Scholar
• Wotherspoon G , FoxA , McIntyrePet al. Peripheral nerve injury induces cannabinoid receptor 2 protein in rat sensory neurons. Neurosci.135(1), 235–245 (2005).
   Web of Science ®Google Scholar
• Anand U , OttoWR , Sanchez-HerreraDet al. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain138(3), 667–680 (2008).
   PubMed Web of Science ®Google Scholar
• Svizenska IH , BrazdaV , KlusakovaIet al. Bilateral changes of cannabinoid receptor Type 2 protein and mRNA in the dorsal root ganglia of a rat neuropathic pain model. J. Histochem. Cytochem.61(7), 529–547 (2013).
   PubMed Web of Science ®Google Scholar
• Patel HJ , BirrellMA , CrispinoNet al. Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation. Br. J. Pharmacol.140(2), 261–268 (2003).
   PubMed Web of Science ®Google Scholar
• Ross RA , CouttsAA , McFarlaneSMet al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacol.40(2), 221–232 (2001).
   PubMed Web of Science ®Google Scholar
• Nackley AG , ZvonokAM , MakriyannisAet al. Activation of cannabinoid CB2 receptors suppresses c-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J. Neurophysiol.92(6), 3562–3574 (2004).
   PubMed Web of Science ®Google Scholar
• Elmes SJ , JhaveriMD , SmartDet al. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naive rats and in rat models of inflammatory and neuropathic pain. Eur. J. Neurosci.20(9), 2311–2320 (2004).
   PubMed Web of Science ®Google Scholar
• Sagar DR , KellyS , MillnsPJet al. Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur. J. Neurosci.22(2), 371–379 (2005).
   PubMed Web of Science ®Google Scholar
• Malek N , KostrzewaM , MakuchWet al. The multiplicity of spinal AA-5-HT antinociceptive action in a rat model of neuropathic pain. Pharmacol. Res.111, 251–263 (2016).
   PubMed Web of Science ®Google Scholar
• Zygmunt PM , PetersonJ , AnderssonDAet al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature400, 452–457 (1999).
   PubMed Web of Science ®Google Scholar
• Bisogno T , HanusL , DePetrocellis Let al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anadamide. Br. J. Pharmacol.134(4), 845–852 (2001).
   PubMed Web of Science ®Google Scholar
• Iannotti FA , HillCL , LeoAet al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem. Neurosci.5(11), 1131–1141 (2014).
   PubMed Web of Science ®Google Scholar
• Anand U , JonesB , KorchevYet al. CBD effects on TRPV1 signaling pathways in cultured DRG neurons. J. Pain Res.13, 2269–2278 (2020).
   PubMed Web of Science ®Google Scholar
• Caterina MJ , SchumacherMA , TominagaMet al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature389, 816–824 (1997).
   PubMed Web of Science ®Google Scholar
• Davis JB , GrayJ , GunthorpeMJet al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature405, 183–187 (2000).
   PubMed Web of Science ®Google Scholar
• Richardson JD , AanonsenL , HargreavesKM. Antihyperalgesic effects of spinal cannabinoids. Eur. J. Pharmacol.345, 145–153 (1998a).
   PubMed Web of Science ®Google Scholar
• Richardson JD , KiloS , HargreavesKM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain75, 111–119 (1998b).
   PubMed Web of Science ®Google Scholar
• Ben-Shabat S , FrideE , SheskinTet al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol.353(1), 23–31 (1998).
   PubMed Web of Science ®Google Scholar
• Fride E , FooxA , RosenbergEet al. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a “CB3” receptor. Eur. J. Pharmacol.461, 27–34 (2003).
   PubMed Web of Science ®Google Scholar
• Smart D , JonssonKO , VandevoordeSet al. ‘Entourage’ effects of N-acylethanolamines at human vanilloid receptors. Comparison of effects upon anandamide-induced vanilloid receptor activation and upon anandamide metabolism. Br. J. Pharmacol.136(3), 452–458 (2002).
   PubMed Web of Science ®Google Scholar
• Garcia MDC , Adler-GraschinskyE , CeluchSM. Enhancement of the hypotensive effects of intrathecally injected endocannabinoids by the entourage compound palmitoylethanolamide. Eur. J. Pharmacol.610, 75–80 (2009).
   PubMed Web of Science ®Google Scholar
• Zygmunt PM , ErmundA , MovahedPet al. Monoacylglycerols activate TRPV1 – a link between phospholipase C and TRPV1. PLoS ONE8(12), e81618 (2013).
   PubMed Web of Science ®Google Scholar
• Mechoulam R , FrideE , HanuLet al. Anandamide may mediate sleep induction. Nature389, 25–26 (1997).
   PubMed Web of Science ®Google Scholar
• Notcutt WG , PriceM , ChapmanG. Clinical experience with nabilone for chronic pain. Pharmaceutical Sci.3(11), 551–555 (1997).
   Google Scholar
• De Petrocellis L , LigrestiA , MorieloASet al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol.163(7), 1479–1494 (2011).
   PubMed Web of Science ®Google Scholar
• Comelli F , GiagnoniG , BettoniI , ColleoniM , CostaB. Antihyperalgesic effect of a Cannabis Sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother. Res.22(8), 1017–1024 (2008).
   PubMed Web of Science ®Google Scholar
• Santiago M , SachdevS , ArnoldJCet al. Absence of Entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1 and CB2 receptors. Cannabis Cannabinoid Res.4(3), 165–176 (2019).
   PubMedGoogle Scholar
• Hohmann U , PelzerM , KleineJet al. Opposite effects of neuroprotective cannabinoids, palmitoylethanolamide, and 2-arachidonoylglycerol on function and morphology of microglia. Front. Neurosci.13, 1180–1189 (2019).
   PubMed Web of Science ®Google Scholar
• Harris HM , RousseauMA , WanasASet al. Role of cannabinoids and terpenes in Cannabis-mediated analgesia in rats. Cannabis Cannabinoid Res.4(3), 177–182 (2019).
   PubMedGoogle Scholar
• Okine BN , GasparJC , FinnDP. PPARs and pain. Br. J. Pharmacol.176(10), 1421–1442 (2018).
   PubMed Web of Science ®Google Scholar
• Russo EB . Cannabinoids in the management of difficult to treat pain. Ther. Clin. Risk Manag.4(1), 245–259 (2008).
   PubMedGoogle Scholar
• Anand P , WhitesideG , FowlerCJet al. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res. Rev.60(1), 255–266 (2009).
   PubMedGoogle Scholar
• Holdcroft A , MazeM , DoréCet al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology104(5), 1040–1046 (2006).
   PubMed Web of Science ®Google Scholar
• Berman JS , SymondsC , BirchR. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain112(3), 299–306 (2004).
   PubMed Web of Science ®Google Scholar
• Langford RM , MaresJ , NovotnaAet al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J. Neurol.260(4), 984–997 (2013).
   PubMed Web of Science ®Google Scholar
• Pertwee RG . The pharmacology and therapeutic potential of cannabidiol. In: DiMarzo V ( Ed.). CannabinoidsKluwer Academic/Plenum Publishers, NY, USA, 32–83 (2004).
   Google Scholar
• Devinsky O , CilioMR , CrossHet al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia55(6), 791–802 (2004).
   Google Scholar
• Devinsky O , MarshE , FriedmanDet al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol.15(3), 270–278 (2016).
   PubMed Web of Science ®Google Scholar
• Devinsky O , PatelAD , ThieleEAet al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology90(14), e1204–e1211 (2018a).
   PubMed Web of Science ®Google Scholar
• Szaflarski JP , BebinEM , ComiAMet al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia59(8), 1540–1548 (2018).
   PubMed Web of Science ®Google Scholar
• Wade DT , MakelaP , RobsonPet al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo controlled study on 160 patients. Mult. Scler.10, 434–441 (2004).
   PubMed Web of Science ®Google Scholar
• Pertwee RG . Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther.74, 129–180 (1997).
   PubMed Web of Science ®Google Scholar
• Costa B , GiagnoniG , FrankeCet al. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br. J. Pharmacol.143, 247–250 (2004).
   PubMed Web of Science ®Google Scholar
• Patwardhan AM , JeskeNA , PriceTJet al. The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc. Natl Acad. Sci. USA103(30), 11393–11398 (2006).
   PubMed Web of Science ®Google Scholar
• Lowin T , SchneiderM , PongratzG. Joints for joints: cannabinoids in the treatment of rheumatoid arthritis. Curr. Opin. Rheumatol.31, 271–278 (2019).
   PubMed Web of Science ®Google Scholar
• Karniol I , CarliniE. Pharmacological interaction between cannabidiol and Δ9-tetrahydrocannabinol. Psychopharmacologia33(1), 53–70 (1973).
   PubMedGoogle Scholar
• Schubart CD , SommerIE , van GastelWAet al. Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr. Res.130(1–3), 216–221 (2011).
   PubMed Web of Science ®Google Scholar
• Gallily R , YekhtinZ , HanusLO. Overcoming the bell-shaped dose-response of cannabidiol by using cannabis extract enriched in cannabidiol. Pharmacol. Pharm.6(2), 75–85 (2015).
   Google Scholar
• Pryce G , BakerD. Potential control of multiple sclerosis by cannabis and the endocannabinoid system. CNS Neurol. Disord. Drug Targets11(5), 624–641 (2012).
   PubMed Web of Science ®Google Scholar
• Nurmikko TJ , SerpellMG , HoggartBet al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain133(1), 210–220 (2007).
   PubMed Web of Science ®Google Scholar
• Casey SL , AtwalN , VaughanCW. Cannabis constituent synergy in a mouse neuropathic pain model. Pain158(12), 2452–2460 (2017).
   PubMed Web of Science ®Google Scholar
• Ward SJ , RamirezMD , NeelakantanHet al. Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth. Analg.113(4), 947–950 (2011).
   PubMed Web of Science ®Google Scholar
• Ware MA , WangT , ShapiroSet al. Cannabis for the management of pain: assessment of safety study (COMPASS). J. Pain16(12), 1233–1242 (2015).
   PubMed Web of Science ®Google Scholar
• Poli P , CrestaniF , SalvadoriCet al. Medical cannabis in patients with chronic pain: effect on pain relief, pain disability, and psychological aspects. A prospective non randomized single arm clinical trial. Clin. Ther.169(3), e102–e107 (2018).
   Google Scholar
• Sohler NL , StarrelsJL , KhalidLet al. Cannabis use is associated with lower odds of prescription opioid analgesic use among HIV-infected individuals with chronic pain. Subst. Use Misuse53(10), 1602–1607 (2018).
   PubMed Web of Science ®Google Scholar
• Capano A , WeaverR , BurkmanE. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad. Med.132(1), 56–61 (2020).
   PubMed Web of Science ®Google Scholar
• Russo EB . Taming THC: potential cannabis synergy and phytocannabinoid – terpenoid entourage effects. Br. J. Pharmacol.163(7), 1344–1364 (2011).
   PubMed Web of Science ®Google Scholar
• Baron EP . Medicinal properties of cannabinoids, terpenes, and flavonoids in Cannabis, and benefits in migraine, headache, and pain: an update on current evidence and Cannabis science. Headache58(7), 1139–1186 (2018).
   PubMed Web of Science ®Google Scholar
• Jansen C , ShimodaLMN , KawakamiJKet al. Myrcene and terpene regulation of TRPV1. Channels13(1), 344–366 (2019).
   PubMed Web of Science ®Google Scholar
• Fischedick JT , HazekampA , ErkelensTet al. Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry71(17–18), 2058–2073 (2010).
   PubMed Web of Science ®Google Scholar
• Hillig KW . A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabacea). Am. J. Bot.91(6), 966–975 (2004).
   PubMed Web of Science ®Google Scholar
• Ibrahim MM , PorrecaF , LaiJet al. CB2 Cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl Acad. Sci. USA102(8), 3093–3098 (2005).
   PubMed Web of Science ®Google Scholar
• da Fonseca Pacheco D , KleinA , deCastro Perez Aet al. The mu-opioid receptor agonist morphine, but not agonists at delta- or kappa-opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors. Br. J. Pharmacol.154(5), 1143–1149 (2008).
   PubMed Web of Science ®Google Scholar
• Reche I , FuentesJA , Ruiz-GayoM. Potentiation of delta 9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of mu- and kappa-opioid receptors. Eur. J. Pharmacol.318(1), 11–16 (1996).
   PubMed Web of Science ®Google Scholar
• Yesilyurt O , DogrulA , GulHet al. Topical cannabinoid enhances topical morphine antinociception. Pain105(1–2), 303–308 (2003).
   PubMed Web of Science ®Google Scholar
• Finn DP , BeckettSR , RoeCHet al. Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain. Eur. J. Neurosci.19(3), 678–686 (2004).
   PubMed Web of Science ®Google Scholar
• Tham SM , AngusJA , TudorEMet al. Synergistic and additive interactions of the cannabinoid agonist CP55,940 with mu opioid receptor and alpha2-adrenoceptor agonists in acute pain models in mice. Br. J. Pharmacol.144(6), 875–884 (2005).
   PubMed Web of Science ®Google Scholar
• Cox ML , HallerVL , WelchSP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur. J. Pharmacol.567(1–2), 125–130 (2007).
   PubMed Web of Science ®Google Scholar
• Guindon J , LoVermeJ , DeLéan Aet al. Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: a role for endogenous fatty-acid ethanolamides? Eur. J. Pharmacol. 550(1–3), 68–77 (2006).
   PubMed Web of Science ®Google Scholar
• Ulugöl A , OzyigitF , YesilyurtOet al. The additive antinociceptive interaction between WIN 55,212-2, a cannabinoid agonist, and ketorolac. Anesth. Analg.102(2), 443–447 (2006).
   PubMed Web of Science ®Google Scholar
• Grim TW , GhoshS , HsuKLet al. Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. Pharmacol. Biochem. Behav.124, 405–411 (2014).
   PubMed Web of Science ®Google Scholar
• Naidu PS , BookerL , CravattBFet al. Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J. Pharmacol. Exp. Ther.329(1), 48–56 (2009).
   PubMed Web of Science ®Google Scholar
• Pini LA , GuerzoniS , CainazzoMMet al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active controlled, randomized trial. J. Headache Pain13(8), 677–684 (2012).
   PubMed Web of Science ®Google Scholar
• Huestis MA . Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol. Handb. Exp. Pharmacol.168, 657–690 (2005).
   PubMedGoogle Scholar