Summary of the pharmacological properties and preclinical studies of selected Cannabis terpenes

MonoterpeneProposed Molecular Targets and MechanismsPreclinical Models and In Vivo EffectsReferences
Limonene- Elevated superoxide dimutase (SOD) expression
- Inhibition of TNF-α, IL-1β, and IL-10 cytokine production
- Modulation of TRPA1 channel activity
- Activation of the NO/cGMP pathway
- Reduced leukocyte and neutrophil migration, vascular permeability, and myeloperoxidase activity
- Dose-dependent, naloxone-insensitive (occasionally sensitive)
- Acute and chronic antinociception in various pain (acetic acid, hot-plate, formalin, histamine, PGE2 and serotonin) and anti-inflammatory (SNI, carrageenan) models
- Anti-hyperalgesic, anti-inflammatory properties
de Almeida et al., 2017
do Amaral et al., 2007
Kaimoto et al., 2016
Khodabakhsh et al., 2015
Piccinelli et al., 2015
Piccinelli et al., 2017
Terpinene Terpineol- Inhibition of NO, PGE2, TNF-α, IL-1β, and IL-6 production
- Blockage of JNK, Erk, and NF-kB signaling in LPS-challenged RAW 264.7 cells
- Reduced neutrophil and microglial migration
- Activation of the arginine/SNAP/NO/cGMP/KATP channel pathway
- Multitargeting, dose-dependent
- Opioid-, ATP-sensitive potassium channel–, muscarinic acetylcholine receptor–, nicotinic acetylcholine receptor–dependent antinociception
- Acute pain (formalin, glutamate, writhing, and capsaicin) and inflammatory (carrageenan and CCI) models
- Reduced hyperalgesia without motor impairment
Passos et al., 2015
de Oliveira et al., 2012
Kim et al., 2013
Nogueira et al., 2014
Quintans-Junior et al., 2011
Ramalho et al., 2015
Safaripour et al., 2018
Soleimani et al., 2019
Pinenes- Inhibition of IL-6, TNF-α, and NO production
- Suppression of MAPK and NF-κB activities in peritoneal macrophages
- No direct CB1 or CB2 receptor activation based on potassium channel activity measurement
- Dose-dependent
- Naloxone and atropine-sensitive analgesia
- Various pain models (formalin, acetic acid, hot-plate, and tail-flick)
- Anti-inflammatory in LPS and carrageenan models
- Involvement of the opioid, cholinergic and possibly the serotonergic system
Huang et al., 2019
Khalilzadeh et al., 2015
Kim et al., 2015
Liapi et al., 2007
Martinez et al., 2009
Popovic et al., 2014
Santiago et al., 2019
Sousa et al., 2008
Linalool- Regulation of K+, voltage-gated Na+, and Ca2+ channels
- Activation of the Akt signaling pathway
- Antiallodynic and anti-hyperalgesic effect in various acute and chronic pain and inflammatory models (SNL, fibromyalgia, glutamate)
- Reduces morphine tolerance and dependence
- Multiple possible targets and mechanisms including possible interactions with the opioid, dopaminergic, cholinergic, glutamatergic, cannabinoid, GABAergic, and adenosine-receptor systems
Batista et al., 2008
Berliocchi et al., 2009
Brum et al., 2001
Donatello et al., 2020
Elisabetsky et al., 1999
Katsuyama et al., 2012, 2015
Leal-Cardoso et al., 2010
Li et al., 2020
Nascimento et al., 2014
Peana et al., 2003, 2004a,b, 2006
Brum et al., 2001
β-Myrcene- Possible TRPV1 channel activation- Naloxone- and yohimbine-sensitive antinociception
- Acute, neurogenic, and anti-inflammatory pain models (hot-plate, carrageenan, PGE2, DbcAMP)
- Suggesting the involvement of the opioid and noradrenergic systems
Duarte et al., 1992
Heblinski et al., 2020
Jansen et al., 2019
Lorenzetti et al., 1991
Paula-Freire et al., 2013
Rao et al., 1990
Geraniol- In SCI model, it increases NeuN-positive cell count; suppresses the expression of GFAP and inducible nitric oxide synthase; and reduces CD68-positive cells, TNF-α level, and caspase-3 activity and levels of malondialdehyde and 3-nitrotyrosine
- Upregulates protein expression of nuclear factor erythroid 2–related factor 2 and heme oxygenase 1
- Downregulates protein expression of the NMDA-1 receptor in the injured lesion
- In HMC-1 cellular and allergic rhinitis mouse model, it reduced the production of proinflammatory cytokines such as TNF-α, IL-1β, MCP-1, and IL-6
- p38 MAPK and NF-κB p65 were found to be hypophosphorylated upon treatment with geraniol
- Dose-dependent, antiallodynic, and anti-hyperalgesic
- Various pain models (writhing, formalin, and glutamate tests)
- Opioid-dependent mechanism is unclear; however, it seems to interact with the GABAergic as well as the serotonergic systems
Chirumbolo and Bjørklund, 2017
Hernandez-Leon et al., 2020
Huang et al., 2018
La Rocca et al., 2017
Lei et al., 2019
Lv et al., 2017
SesquiterpeneProposed molecular targets and mechanismsPreclinical models and in vivo effects
β-Caryophyllene- A putative CB2 receptor full agonist (some authors question this though)
- It activates JNK, Erk, and PPARs and inhibits the toll-like receptor CD-14/TLR4/MD2 axis
- It reduces the expression and production of proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α
- It may also interact with the TLR4
- Antiallodynic, antinociceptive, anti-inflammatory, and neuroprotective in various pain models
- In cerebral ischemia-reperfusion injury model, it rescues neurons, inhibits microglial activation, and decreases the release of proinflammatory cytokines
Aguilar-Ávila et al., 2019
Alberti et al., 2017
Aly et al., 2019
Araldi et al., 2019
Eidson et al., 2017
Fidyt et al., 2016
Gertsch 2008
Katsuyama et al., 2013
Klauke et al., 2014
Paula-Freire et al., 2014
Santiago et al., 2019
Tian et al., 2019
Varga et al., 2018
Wu et al., 2014
Yang et al., 2017
Bisabolol- It activates TRPA1
- It decreases leukocyte migration, neutrophil degranulation, and protein extravasation
- It reduces TNF-α, IL-10, and IBA-1 levels
- It downregulates expression of iNOS and COX-2 genes through inhibition of NF-κB and AP-1 (ERK and p38) pathways
- Anti-hyperalgesic, antinociceptive, and anti-inflammatory in acute dermatitis, acute corneal, acetic acid–induced visceral and orofacial nociception, carrageenan-induced paw edema, and intraplantar formalin tests
- Synergistic antinociceptive and anti-inflammatory effect with diclofenac
Barreto et al., 2016
Leite Gde et al., 2011
Fontinele et al., 2019
Kim et al., 2011
Rocha et al., 2011
Ortiz et al., 2018
Teixeira et al., 2017
Humulene- It decreases leukocyte and neutrophil migration
- Possible involvement of the PGE2 signaling pathway
- Opioid-independent antinociception and anti-inflammatory property in various preclinical models (acetic acid–, formalin-, hot-plate–, carrageenan-, and dextran-induced)Pinheiro et al., 2011
Basting et al., 2019
Nerolidol- It decreases TNF-α and IL-1β in LPS-stimulated peritoneal macrophages
- Possible involvement of TLR4, Nrf2, and/or NF-κB as signaling mechanisms
- Dose-dependent antinociception and anti-inflammatory properties in various animal models (acetic acid writhing, formalin, edema, peritonitis, and hot-plate) without impaired motor function
- Opioid-insensitive, GABAergic mechanisms without the involvement of ATP-sensitive (K+) channels
Fonseca et al., 2016
Iqubal et al., 2019
Khodabakhsh et al., 2015
Ni et al., 2019
Ogunwande et al., 2019
Pinheiro et al., 2011
Zhang et al., 2017
  • HMC-1, human mast cell line 1; IBA-1, ionized calcium-binding adapter molecule 1; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein 1; PPAR, peroxisome proliferator–activated receptor.