TABLE 1.

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

Monoterpene	Proposed Molecular Targets and Mechanisms	Preclinical Models and In Vivo Effects	References
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
Sesquiterpene	Proposed molecular targets and mechanisms	Preclinical 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.