Medicinal Properties of Terpenes Found in Cannabis Sativa and Humulus Lupulus

ACCEPTED MANUSCRIPT Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus

Tarmo Nuutinen 1,2,* 1 Department of Environmental and Biological Sciences, Univerisity of Eastern Finland (UEF) 2 Department of Physics and Mathematics, UEF * Email: [email protected]

Abstract Cannabaceae plants Cannabis sativa L. and Humulus lupulus L. are rich in terpenes – both are typically comprised of terpenes as up to 3-5% of the dry-mass of the female inflorescence. Terpenes of cannabis and hops are typically simple mono- and sesquiterpenes derived from two and three isoprene units, respectively. Some terpenes are relatively well known for their potential in biomedicine and have been used in traditional medicine for centuries, while others are yet to be studied in detail. The current, comprehensive review presents terpenes found in cannabis and hops. Terpenes’ medicinal properties are supported by numerous in vitro , animal and clinical trials and show anti-inflammatory, antioxidant, analgesic, anticonvulsive, antidepressant, anxiolytic, anticancer, antitumor, neuroprotective, anti-mutagenic, anti-allergic, antibiotic and anti-diabetic attributes, among others. Because of the very low toxicity, these terpenes are already widely used as food additives and in cosmetic products. Thus, they have been proven safe and well-tolerated. Keywords MANUSCRIPT Monoterpene; sesquiterpene; Cannabis sativa ; Humulus lupulus ; medicine; medicinal property

Introduction Plants produce terpenes for interactions with other organisms [1]. Terpenes protect plants against pathogens like mold, fungus and bacteria, and can attract pollinating insects or repel herbivores. Thousands of terpenes have been found across the plantae , but only a small percentage of all terpenes have been identified [2]. Despite the diversity of the known terpenes, some are concentrated in certain phyla or families such as Cannabaceae . Terpenes found in Cannabis sativa (cannabis) and Humulus lupulus (hop), or more precisely, in their essential oils (EOs), are mainly mono- and sesquiterpenes: up to 99% of all terpenes found in the EO of hops [3] and up to 98% in cannabis EO [4]. Cannabis and hop produce and accumulate a terpene-rich resin in glandular trichomes, which are most abundant on the surface of female inflorescences. Some terpene synthases are specialized to produce strictly one terpene, while others are multi-substrate enzymes producing more than one terpene [5]. Recently, a transcriptome analysis of trichomes of the hemp variety “Finola” identifiedACCEPTED 33 complete terpene synthase (TPS) genes and an additional 18 putative TPSs. At the protein level, 40 enzymes involved in the synthesis of terpenes were identified in hop [6]. Cannabis and hops have been used in traditional medicine for millennia around the world. However, all of the active constituents and their mechanisms of action have not yet been explored. Naturally, the action of cannabis is mostly based on cannabinoids, but not all of its medicinal properties. Hops, which are devoid of cannabinoids, have been used as sedative means e.g. for the treatment of insomnia, depressive symptoms, irritation, nervous tension, delirium, anxiety and digestive disorders [7]. Cannabis has been used in traditional Chinese medicine for the treatment of pain, tetany and convulsions, gout, A mania,CCEPTED insomnia, MANUSCRIPT panting and cough, headache, menstrual irregularities, itching and anemia [8], and traditional Indian medical texts have proposed the use of cannabis to stimulate digestion, and act as an analgesic and nervous system stimulant, as well as for its sedative, spasmolytic, diuretic, aphrodisiac, anti-parasitic and anti-viral actions, in the treatment of glaucoma and in skin care [9]. The medicinal properties of some terpenes were reviewed by Russo in 2011 [10] and by Russo and McPartland in 2001 [11]. In turn, hop terpenes have not yet been reviewed. More generally, monoterpenes provide various medicinal properties, including antimicrobial, antioxidant, anticancer, antiarrhythmic, anti-aggregating, anesthetic, anti-nociceptive, anti-inflammatory, antihistaminic, anti-spasmodic, antitumor and anti-diabetic [12]. These can be also attributed to the mono- and sesquiterpenes found in hops and cannabis, and the current review extends the list with many other medicinal properties evidenced by numerous in vitro , in vivo and clinical trials. It also shows some new data derived from publicly available data about the terpene contents of cannabis samples [13] and biological databases.

Myrcene Myrcene (MYR, the molecular structure of which is shown in Fig. 1A) is frequently the most abundant terpene encountered in cannabis and hops. For instance, the total terpenes of the cannabis drug chemotype 'blueberry' consist of up to 78% MYR [13]. Furthermore, some drug chemotypes, possibly due to the founder effect and selective breeding, show a high but stable composition with respect to this terpene; for instance, the medical cannabis chemotype, with low THC and high CBD, also known as “cannatonic”, mainly expresses myrcene: 63±11.5% of total terpenes (n=15 from 10 different sources [13]). In hops, myrcene may be present in a proportion of up to 52% [3]. It is well established as a flavor ingredient in the food industry and as a fragrance in soap and detergent products. It is also found in lemon grass, bay leaves, ylang-ylang, wild thyme, parsley, cardamom, and basil. It is claimed to have sedative properties, but there is only very weak support for this to date: in one study [14], it increased barbiturate-inducedMANUSCRIPT sleeping time and motor relaxation in mice, but only with doses as high as 200 mg/kg. MYR decreased IL-1β-induced nitric oxide (NO) production, nuclear factor kappa-light-chain- enhancer of activated B cells protein (NF-κB), c-Jun N-terminal kinase (JNK) and p38 mitogenactivated protein kinase (p38 MAPK) activation and the expression of inflammatory, inducible nitric oxide synthase (iNOS) and catabolic, matrix metalloproteinases 1 and 13 (MMP-1, MMP-13 genes (IC 50 =37.3 g/ml)) [15]. These anti-inflammatory and anti-catabolic effects in the cell model of osteoarthritis together imply a potential to slow down the progression of osteoarthritis. In mice, MYR ameliorated heart tissue damage after global cerebral ischemia/reperfusion (I/R) by increasing the levels of glutathione (GSH) and anti-oxidative enzymes; glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) [16]. In a mouse model of cerebral ischemia, MYR (200 mg/kg) was able to suppress oxidative stress by restoring levels of GSH, GPx, and SOD after the cerebral ischemia [17]. It also suppressed the formation of thiobarbituric acid reactive substances (TBARS). These mechanisms resulted in a significant neuroprotection. In another study, MYR orally administered to rats at a dose of 200 mg/kg/day protected against environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducedACCEPTED liver damage [18]. In the liver samples, taken at 60 days, GSH, CAT, GSH-Px and CuZn-SOD were substantially increased and the formation of TBARS was again decreased in comparison to the control. MYR also show anti-ulcer activity [19]; an oral administration of MYR at a dose of 7.50 mg/kg increased the levels of GPx, glutathione reductase (GSR), and total GSH in gastric tissue. The protective effects of MYR may in part be mediated by the decreased production of an inflammatory prostaglandin E-2 (PGE-2) [20]. At the doses of 5 and 10 mg/kg, MYR was able to prevent hypernociception in both mechanical and thermal tests on mice [21]. Another study, with neuropathic mouse models, showed that the anti- hypernociceptive activity of MYR may be mediated by α2-adrenoceptor-stimulated release of endogenous opioids [22]. It is known that some agonists of the α2-adrenergic receptor are frequently used in veterinary anesthesia.ACCEPTED MANUSCRIPT Several studies have shown that MYR is not mutagenic e.g. by the Ames test [23]. More importantly, studies have found the opposite: MYR exerts its anti-mutagenic activity by inhibiting certain forms of the cytochrome P-450 isoenzymes, which would otherwise cause the activation of pre-mutagens and pre-carcinogens [24]. Furthermore, MYR was efficient against oxidant-induced genotoxicity, which is predominately mediated by its direct radical scavenging activity [25]. Lastly, MYR had a protective role on UVB-induced human skin photoaging [26]. Thus, less toxic MYR could replace the UV-filter chemicals that are currently being used in sunscreen products. In summary, MYR protects the brain, heart and skin tissues from inflammation and oxidative damage; it also shows anti-nociceptive properties. However, there is only weak support for the alleged sedative effect of MYR.

β-caryophyllene β-caryophyllene (BCP, Fig. 1B) is frequently the predominant terpenoid in cannabis and present in hops. For instance, it comprises 64% of terpenes in the cannabis drug chemotype 'gorilla glue' [13], but is almost absent (1.2±0.2%) in some other samples [27]. It is typically less abundant in hops, making up to 15% of the EO of a wild-growing hop [3]. It is also widely present in a large number of plants e.g. clove, rosemary, black pepper and lavender. Unlike any other terpenes, BCP has a notable affinity (150 nM) toward cannabinoid receptor 2 (CB2), being a selective, full agonist of the receptor [28]. This also makes it the only phytocannabinoid found outside the Cannabis genus to date. The CB2 agonism may be the most important feature of BCP against inflammation. For instance, it produces strong anti-inflammatory activity at a dose of 5 mg/kg in wild type but not CB2 knockout mice [28]. Thus, the specific CB2 agonist holds a great deal of potential for the treatment of various diseases without any intoxicating effects [29]. The Ki value of BCP is 150 nm while EC 50 is 1.9 M [30].

BCP possesses significant anticancer activities, affectingMANUSCRIPT the growth and proliferation of numerous cancer cells. The anticancer qualities are reviewed in detail elsewhere [31]. Briefly, the most important function of BCP may be the induction of the expression of proapoptotic and cancer- suppressing genes, encoding proteins like p53, bcl-2-like protein 4 (bax), Bcl-2 homologous antagonist/killer (bak), caspase 8, caspase 9 and ATM serine/threonine kinase (ATM) and suppression the genes encoding anti-apoptotic genes, such as B-cell lymphoma 2 (bcl ‐2), E3 ubiquitin-protein ligase Mdm2 (mdm2), cyclooxygenase 2 (COX ‐2), and myeloblastosis c ‐myb (c-myb). In addition, despite the low cytotoxicity, it can potentiate the efficacy of classical cancer drugs by augmenting their concentrations inside the cells [32]. Furthermore, it exhibits a synergistic anticancer activity with humulene and isocaryophyllene, as shown by studies on MCF-7, DLD-1 and L-929 cell lines [33]. Lastly, 10 g/mL BCP was able to potentiate the activity of paclitaxel (PAC) by a 10-fold increase. Possible mechanisms include the capability to alter levels of mitogenactivated protein kinase (MAPK) and PI3K/AKT/mTOR/S6K1 (phosphatidylinositol-3- kinase/protein kinase B/mammalian target of rapamycin/ribosomal protein S6 kinase β-1) and signal transducer and activator of transcription 3 (STAT3) pathways [31]. ACCEPTED Various other pharmacological activities of BCP include cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, anti-inflammatory and immunomodulatory actions (reviewed in [34]). BCP possesses potent therapeutic promises for neuropathic pain, and neurodegenerative and metabolic diseases; the mechanisms of action are mediated not only through CB2 agonism but also via the activation of peroxisome proliferated activator receptors (PPARs), the toll like receptor complex CD14/TLR4/MD2, synergy with µ-opioid receptor-dependent pathways and antagonism on nicotinic acetylcholine receptor α7 ( α7-nAChRs), among others. The beneficial effects of BCP (25 mg/kg twice/day) in a multiple sclerosis (MS) model included the suppression of neuroinflammation by the upregulation of interleukin 10 (IL-10) and a reduction in the production of interferon γ (IFN-γ) [35]. The AefficacyCCEPTED was comparable MANUSCRIPT to that of a research chemical JWH-015, which is a CB2 agonist. Furthermore, the immunomodulatory effect of BCP seems to be related to its ability to inhibit microglial cells, and CD4+ and CD8+ T lymphocytes. Through the activation of CB2, axonal demyelination was ameliorated and the immune balance of the cells was restored. BCP displayed marked inhibitory effects in various inflammatory experimental models in mice and rats [36]. BCP diminished tumor necrosis factor α (TNF α) release and reduced the production of PGE-2, iNOS and COX-2 expressions. The effects were comparable to those of the corticosteroid dexamethasone in animal models.

BCP inhibits hypoxia-induced cytotoxicity and neuroinflammation, inhibiting NF-κB activation in microglia [37]. Also, it inhibits the release of pro-inflammatory cytokines, IL-1β, TNF-α, and IL-6 and reactive oxygen species (ROS). In a PC12 cell model, by activating tropomyosin receptor kinase A (TrkA) receptors, BCP (10 M and less) evoked neurogenesis independently from neurotrophic factor (NGF) or cannabinoid receptors [38]. This was due to its ability to increase the expression of axonal-plasticity-associated proteins: growth-associated protein-43 (GAP-43), synapsin and synaptophysin. BCP also protected astrocytes against Glu-induced cytotoxicity. It ameliorated the Glu-induced increase in intracellular ROS and mitochondrial dysfunction by the activation and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [39]. Nrf2 activation was only partly dependent on the activation of CB2. Another study [40], using a rat model of I/R injury, showed that BCP was able to activate the PI3K/Akt signaling pathway and thus exhibited neuroprotection in the hippocampus, as evidenced by reduced apoptosis. This was seen as the down-regulation of expression of the pro-apoptotic Bax and p53 proteins and up-regulation of the expression of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein. Moreover, BCP, at M concentrations, significantly reduced the number of necroptotic neurons, infarct volumes and neuronal necrosis in a cerebral I/R injury model [41]. BCP in combination with hydroxypropyl-β- cyclodextrin diminished cognitive deficits in vascular dementia (VD) rats and attenuated learning and memory deficits in rats [42]. Moreover, BCP promoted cerebral blood flow, and increased the expression levels of CB2 in the hippocampus and whiMANUSCRIPTte matter tissues and the expression of PI3K, which has been linked to the induction of long-term potentiation (LTP). Protective features were also seen in experimental autoimmune encephalomyelitis (EAE) models of MS in the M range [43]: in vitro (20 M) and in vivo (25 mg/kg/day), BCP inhibited the production of H 2O2, NO, IFN- γ, and TNF-α, while, in vivo, also IL-17. BCP treatment significantly reduced the number of inflammatory infiltrates and attenuated the neurological damage in the central nervous system (CNS).

Recent studies have suggested a protective role of the cannabinoid signaling system in Parkinson's disease (PD) [29]. The neuroprotective effects of BCP were found in a 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced murine model of PD [44]. BCP (10 mg/kg, intraperitoneal, [i.p.]) improved motor function, protected dopaminergic neurons in the substantia nigra and striatum and diminished glial activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. These effects were reversed upon treatment with a CB2 selective antagonist, AM630, implicating the involvement of CB2 agonism. In a rat model of PD, the neuroprotectiveACCEPTED property of BCP (with daily intake for 4 weeks at a dose of 50 mg/kg) against rotenone-induced oxidative stress and neuroinflammation was demonstrated [45]. Again, BCP was able to rescue the loss of dopaminergic neurons. Furthermore, it decreased the activation of microglia and astrocytes by the reduced expression of ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP). In addition, it restored levels of the antioxidant enzymes and GSH and down-regulated the pro-inflammatory molecules COX-2 and iNOS. In another in vivo study, BCP (50 mg/kg) suppressed neutrophil migration and chemokine (C-X-C motif) ligand 1 (CXCL1), leukotriene B 4 (LTB 4), IL-12, and the NO production induced by Mycobacterium bovis [46].

CB2 agonists are also known to ApossessCCEPTED analgesic MANUSCRIPT properties [29]. This is also true in the case of BCP; in mouse models of inflammatory and neuropathic pains, BCP at a dose of 1 mg/kg exerted analgesic effects, evidenced as reduced thermal hyperalgesia, mechanical allodynia and spinal neuroinflammation [47]. However, BCP failed to show these effects in CB2-knockout mice, implicating the involvement of CB2-dependent mechanisms. BCP alleviated PAC-induced peripheral neuropathy in a mouse model and reduced the activation of p38 MAPK and NF-κB and the increased Iba-1 and IL-1β levels, while treatment with AM630 (a CB2 antagonist) abrogated these effects [48]. In addition, BCB seems to be an anxiolytic and anti-depressant, but these effects can be fully reversed by treatment with AM630 [49]. This indicates that CB2 signaling is also involved in depression. Another study [50] noted that the anxiolytic effect of BCP was mediated by 5-HT(1A) without the involvement of GABA(A) receptors. Finally, BCP (100 mg/kg) displayed anticonvulsant activity against seizures induced by pentylenetetrazole (PTZ) [51]. No adverse effects were observed.

In hypercholesterolemic rats, BCP treatment was able to protect the cardiac tissue against atherosclerosis by antioxidant mechanisms [52]. It prevented lipid oxidation by decreasing cardiac levels of ROS and TBARS and increasing GSH levels and GPx activity. BCP also significantly decreased the atherogenic index (AI) and coronary risk index (CRI). Another study also reported that BCP reduced the total serum levels of cholesterol and triglycerides while macrophage infiltration to the aortic surface was also inhibited [53]. Importantly, it was able to prevent the attachment of leukocyte cells to endothelial cells. Moreover, it inhibited the induction of vascular cell adhesion molecule-1 (VCAM-1) both in vitro and in vivo through CB2 activation.

Several recent studies have suggested that the CB2 cannabinoid receptors in the brain play a major role in feeding behavior, addiction and alcohol reward [29]. Indeed, the CB2 agonist BCP decreased alcohol consumption in mice in a dose-dependent manner [54]. This was reversed when the mice were pre-injected with AM630. On the other hand, BCP is protective against chronic and binge alcohol intake-induced liver injury and inflammatioMANUSCRIPTn [55]. It suppressed the pro-inflammatory phenotypic `M1` switch of Kupffer cells and neutrop hil infiltration by decreasing the expression of VCAM-1, E-Selectin and P-Selectin. It also beneficially influenced hepatic metabolic dysregulations (steatosis, protein hyperacetylation and PPAR-α signaling). These protective effects of BCP against alcohol-induced liver injury were again dependent on CB2 agonism. Nonetheless, in Caenorhabditis elegans, the administration of 50 M of BCP increased the lifespan by over 22% (P ≤0.0001) and decreased free radical levels in cells [56]. Furthermore, BCP diminished intestinal pro-aging lipofuscin levels. Moreover, this terpene potentially inhibits spontaneous contraction in the guinea pig ileum at a concentration of 1.5 µM https://pubchem.ncbi.nlm.nih.gov/compound/5281515#. Finally, BCP shows antibacterial properties [34] and is safe and anti-mutagenic [57].

In conclusion, BCP is a selective, full agonist of CB2 and may mediate it as part of its actions through mu-opioid, alpha7-nAChR and 5-HT(1A) receptors. BCP, along with CB2 agonists, participates in dopaminergic cell protection, the inhibition of microglia and astrocyte activation and neuroprotection andACCEPTED modulates nociception, feeding behavior, addiction and alcohol consumption, also preventing alcohol-induced damage. It also shows anti-inflammatory and anti-convulsive properties. Taken together, it shows multi-target potential for the treatment of MS and PD and other neuroinflammatory conditions.

Caryophyllene oxide The oxidized derivative of BCP, caryophyllene oxide (BCPO, Fig. 1C)), is also found in plants outside of Cannabaceae, such as guava ( Psidium guajava ), oregano ( Origanum vulgare ), cinnamon (Cinnamomum spp.) clove ( Eugenia caryophyllata ), black pepper ( Piper nigrum ), lemon balm (Melissa officinalis ) and eucalyptus (Melaleuca stypheloides ), whose EO contains 44% BCPO [58]. BCPO is a non-toxic and non-sensitizingACCEPTED agent ([10] MANUSCRIPT and refs), which is often used as a preservative in foods, drugs and cosmetics, as well as an insecticidal. Unlike BCP, BCPO does not possess any remarkable binding affinity towards CB2; however, it seems to be a multi-target molecule, known for its anticancer and analgesic properties. These properties were reviewed in [31]. The potential for its use as a cancer drug is enhanced by negative genotoxic findings and its efficient absorption through cell membranes [57, 59].

In many cancers, the PI3K/AKT/mTOR/S6K1 pathway is overactive, thus reducing apoptosis and allowing cells to proliferate. Despite the various anticancer activities of BCPO, the suppression of this pathway may be its most important mechanism of action [58], via suppression of the STAT3 (signal transducer and activator of transcription 3) pathway by activation of the Src homology region 2 domain-containing phosphatase-1 (SHP-1) protein tyrosine phosphatase [60]. In vitro , it also induces gene expression of the pro-apoptotic bax, bak1, caspase 8, caspase 9, and ATM proteins, while mRNA levels of anti-apoptotic genes, such as bcl-2, mdm2, and c-myb were decreased [58]. Furthermore, it activated the pro-apoptotic ERK, JNKs and p38 MAPK pathways but down-regulated the expression of gene products that mediate cell proliferation: cyclin D1, COX-2, vascular endothelial growth factor (VEGF) and apoptosis inhibitors: bcl-2, bcl-xL (bcl extra-large), IAP-1, IAP-2 (inhibitor of apoptosis 1 and 2) and survivin. BCPO also increases the expression of the tumor suppressor proteins p53 and p21. Furthermore, a previous study [61] reported inhibition of the activation of tumor marker protein Transcription factor p65 (p65). Despite the low cytotoxicity, it potentiates the efficacy of classical drugs [31]. For instance, it enhanced the cytotoxicity of doxorubicin (DOX) in various cell lines in a synergistic manner [32, 62]. Additional effects are contributed by its capability to inhibit cytochrome P4503A (CYP3A) activity in the liver [63]. Thus, this terpene increases the levels of CYP3A-metabolized drugs and prolongs their action. This action is supported by quantitative high-throughput screening (qHTS) assays, in which it inhibited CYP2C19 and CYP2C9 at concentrations of 13 µM and 25 µM, respectively (https://pubchem.ncbi.nlm.nih.gov/compound/6604672#). MANUSCRIPT It is known that the 15-lipoxygenase (15-LOX) enzym e reacts with fatty acids producing active lipid metabolites that are involved in a number of significant diseases: type 1 and type 2 diabetes, cardiovascular disease, hypertension, renal diseases, and neurological conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). It was reported that BCPO acts as a potent anti-inflammatory agent by inhibiting 15-LOX enzyme activity [64]. At a dose of 12.5 mg/kg, BCPO showed significant central and peripheral analgesic and anti-inflammatory activity [65]. As a calcium and potassium current suppressor, it could be used in certain types of arrhythmias [66]. Finally, BCPO is a strong anti-oxidant, bactericide [67] and fungicide [68]. Unlike BCP, BCPO does not possess any remarkable binding affinity towards CB2; however, it seems to be a multi-target molecule, known for its anticancer and analgesic properties, and it is an anti-oxidant and bactericide. Moreover, it may have role in the control of type 1 and type 2 diabetes, cardiovascular disease, hypertension, renal diseases, and neurological conditions such as AD and PD via the inhibition of 15-LOX.

Humulene ACCEPTED Humulene (HUM, Fig. 1D) is one of the predominant terpenes in C. sativa and H. lupulus : it makes up 52% [3] and 19±7.6% [5] of their total volatile fraction, respectively. It is widely found across the planta e.g. sage, ginseng and Syzygium zeylanicum (Myrtaceae) . HUM is also called α- caryophyllene, but it does not contain the cyclobutane ring as β-caryophyllene does, and has not yet been characterized as a CB2 ligand.

However, HUM possesses anti-inflammatory and anticancer properties. A study revealed that oral treatment with HUM inhibited a variety of inflammatory factors in mice and rats [36]. The systemic treatment with HUM (50 mg/kg)A reducedCCEPTED TNF αMANUSCRIPT and IL-1β and reduced the production of PGE2, iNOS and COX-2. Because of these features, it was effective against edema (5 mg/kg). The study found that the anti-inflammatory effects of HUM were similar to those of dexamethasone (a corticoid drug). Furthermore, in another study [69], HUM (oral, 50 mg/kg for 22 days) significantly reduced the recruitment of eosinophils to the bronchoalveolar lavage fluid by the recovery of IFN-γ and the reduction of IL-5. These are best known for the stimulation of B cell growth, increased immunoglobulin secretion and the activation of eosinophils. It also reduced the levels of eosinophil chemotactic protein (CCL11) and LTB4. Furthermore, HUM decreased the activation of NF-kB and activator protein 1 (AP-1), the expression of P-selectin and the increased mucus secretion in the lungs. In six different cancer cell lines, HUM, however, decreased the cellular GSH levels and promoted ROS production [70]. This resulted in the inhibition of cancer cell growth. Moreover, HUM induced apoptosis in colorectal cancer HT29 cells via death receptor 5 (DR5) and the caspase-8 and -3-dependent signaling pathways with an IC50 value of 54±3.0 M [71]. On the other hand, HUM (100 µg/ml) can substantially – and specifically – increase the secretion of the pro- inflammatory cytokine IL-8 in human intestinal epithelial Caco-2 cells [72]. Of particular note, IL-8 is known to exert proangiogenic, proliferative and pro-motility functions, which is common to several cancer types.

Nonetheless, HUM provides a basis for the development of new drugs exhibiting improved properties. A new HUM derivative, 5-hydroxyzerumbone (5-hydroxy-2E,6E,9E-humulatrien-8- one), and a known HUM derivative, zerumboneoxide, were found to inhibit lipopolysaccharide (LPS)-induced NO production in murine macrophage RAW 264.7 cells, with IC50 values of 14.1 and 23.5 M, respectively [73]. Accordingly, the 5-hydroxy-derivative inhibited the expression of both iNOS mRNA and protein in a concentration-dependent manner. This was likely via the regulation of NF-κB activity [74]. One of the HUM derivatives from Asteriscuc vogelii was found to be active against P-338 lymphoma, A-549 lung carcinoma, HT-29 colon carcinoma and MEL-28 melanoma cells with IC 50 values of 1-2 M [75]. MANUSCRIPT Traditionally, HUM-containing plants have been used for the treatment of insomnia, depression, nervousness, delirium, anxiety and digestive disorders. This is not yet recognized by modern science, but HUM and its derivatives have shown anti-allergic, anti-inflammatory and anticancer potential. α-Pinene α-Pinene ( α-PN, Fig. 2A) is the most widely encountered terpenoid in nature, since it is found in conifers in large amounts. It is sometimes the dominant terpene in cannabis; for instance, an inflorescence sample of the drug chemotype 'bubba hash' contained 48% α-PN in the total terpenes [13] and the hemp cultivar finola contained 23±17% [5]. It can be also found in the essential oils of salvia, Spanish sage, black plum and lesser galangal, etc. Interestingly, α-PN is source material for the synthesis of the CB2 ligands SR-144,528 and HU-308 [76]. α-PN itself has no known affinity towards CB receptors. Pine needle oil from crude extract of pine needles has been used as an anticancer agent in traditional Chinese medicine. Its anti-cancer action is not devoid of scientific support today. ACCEPTED Initially, α-PN was found to be very effective in the treatment of metastatic melanoma by its pro- apoptotic and anti-metastatic activity in a mouse model [77]. It was able to reduce the number of lung tumor nodules, likely via caspase-3-induced apoptosis. In vitro , α-PN down-regulated M-phase inducer phosphatase 3 (Cdc25C) mRNA and protein expression and reduced cycle dependence on kinase 1 (CDK1) in BEL-7402 cells [78]. This was evidenced by cell cycle arrest of the cells at the G2/M phase of the cell cycle. However, effective concentrations were in the mM range. The mechanisms have been revealed by in vitro and in vivo studies and included up-regulation of the checkpoint proteins Chk1 and Chk2 and down-regulation cyclin B, cell division cycle 25 (Cdc25) and CDK1 levels [79]. In addition,A CCEPTEDin a mouse xenog MANUSCRIPTraft model, the proliferation marker Ki67 and proliferation cell nuclear antigen (PCNA) were down-regulated by the administration of α-PN [80]. Last, a synergistic effect with a broad-spectrum anticancer drug, Baclitaxel, was observed against non-small-cell lung cancer cells (NSCLC) [81]. α-PN is an antioxidant and anti-inflammatory terpene. A previous study [82] demonstrated the antioxidant and protective potential of α-PN against H 2O2-induced oxidative stress in PC12 cells. α- PN restored the expression of antioxidant enzymes including CAT, SOD, GPx, GSR and heme- oxygenase 1 (HO-1). In addition, the terpenes were able to decrease apoptosis via reduced caspase- 3 activity. Another report [83] showed that pretreatment with α-PN protected U373-MG cells (astrocytes) against H 2O2-induced oxidative injury in terms of cell viability (with IC 50 of 80 µM) and cell morphology. It also promoted ROS scavenging and decreased the level of lipid peroxidation by increasing the levels of CAT, SOD, GSR, GPx, and HO-1, thereby increasing intracellular GSH. In mouse models, the topical application of α-PN exhibited significant anti- inflammatory and analgesic effects against nociceptive stimulus-induced inflammatory infiltrates and COX-2 over-expression [84]. The anti-inflammatory action of α-PN was evidenced as reversal of the LPS-induced production of IL-6, TNF-α, and iNOS in peritoneal macrophages [85]. Furthermore, α-PN inhibited LPS-induced COX-2 expression and the activation of MAPKs and NF- κB. In a mouse model of allergic rhinitis, the level of IL-4 was decreased in the spleen tissues of α- PN treated mice [86]. In addition to the decreased activity of TNF-α and NF-κB, the activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2), iInhibitor of nuclear factor kappa-B kinase subunit β (IKK-β), caspase-1, intercellular adhesion molecule-1 (ICAM-1) and macrophage inflammatory protein-2 (MIP-2) was inhibited, which may explain the observed suppression of the migration of eosinophils and mast cells into an injury lesion. Lastly, it decreased the levels of nasal immunoglobulin E. α-PN exhibited anti-inflammatory features in an in vivo model of acute pancreatitis: α-PN reduced the pancreatic weight in relation to body weight and the serum levels of amylase and lipase, indicating reversal of the cerulein-induced tissue damage [87]. This was likely due to the reduced production of pancreatic TNF-MANUSCRIPTα, IL-1β, and IL-6 and the deactivation of myeloperoxidase (MPO) in the pancreas and lungs in response to the α-PN pretreatment. α-PN was a potent inhibitor of the IL-1β-induced inflammatory and catabolic pathways in cartilage-derived cells substantiated as the inhibition of the NF-κB and JNK activation and the expression of iNOS and the catabolic MMP-1 and -13 genes [88]. While the (+)-α-PN was the more active than its (-)- enantiomer, the β-pinene was inactive. Again, in yet another report [89], the activation of p38 and JNK was attenuated by α-PN, but this time in IEC-6 cells (normal epithelial cells from rat intestine) and after aspirin-induced oxidative stress. Cell viability was further increased by the higher antioxidant enzyme activity and GSH production.

α-PN shows anxiolytic and hypnotic effects upon inhaled administration. α-PN evokes its hypnotic action through direct binding to GABA A as a partial modulator at the benzodiazepine binding site [90]. Additionally, it was capable of increasing the duration of non-rapid eye movement sleep (NREM) without affecting the duration of rapid eye movement sleep (REM) and delta activity. Another study [91] found an anxiolytic effect in terms of mice behavior in the elevated plus maze (EPM). The effect ACCEPTEDremained several days after the highest concentrations of α-PN were reached in the brain and liver tissues, indicating that the accumulation of α-PN in the body keeps the anxiolytic-like action constant. In another study [92], again employing EPM as the probe for the anxiolytic effect of α-PN, an increased locomotor activity was observed. It also found that the expression of tyrosine hydroxylase (TH) mRNA in the midbrain was significantly elevated after 60 min of inhalation of this terpene. Of particular note, because TH catalyzes the rate limiting step in the synthesis of catecholamines, e.g. epinephrine and noradrenaline, it could be hypothesized that α- PN contribute to the increased locomotor activity in EPM, with this mechanism being greater than the anxiolytic activity via GABA A. Nevertheless, α-PN is a bronchodilator in humans at low exposure levels and a broad-spectrum antibiotic against MRSA ([10] and references). qHTS data suggests that Aα-PNCCEPTED MANUSCRIPT inhibits IL-1β-induced iNOS (https://pubchem.ncbi.nlm.nih.gov/compound/440968#) and TIMP1, MMP1 and MMP13 mRNA expression at a concentration of 200 µg/ml (https://pubchem.ncbi.nlm.nih.gov/compound/82227#)

In summary, α-PN, according to the studies referred herein, show anti-metastatic and anti-tumor activities. Moreover, it seems to be anti-inflammatory, anti-oxidant and an anti-allergic bronchodilator and can produce anxiolytic and hypnotic effects via the GABAergic system. Finally, it provides a molecular basis for the development of CB2 ligands.

β-Pinene β-PN (Fig. 2B) is one of the most abundant compounds released by conifers, but it is regularly found in cannabis (6.1±0.4%) [27] and hop cultivars in moderate amounts [93]. It is found also in e.g. Cuminum cyminum and Clausena anisata . In contact with air, it is oxidized to pinocarveol and myrtenol and other molecules and it is easily converted to other terpenes.

β-PN (100 mg/kg) showed antidepressant and sedative activities in mice with several experimental models [94]. Elsewhere, it was indicated that β-PN (100 mg/kg) produces its antidepressant effect through the monoaminergic system [95]. β-PN exerted supraspinal anti-nociceptive actions in a hot- plate test with rats and reversed the anti-nociceptive effect of morphine in a degree equivalent to naloxone, indicating that β-PN is a partial agonist of the µ-opioid receptors [96]. β-PN, when complexed with β-cyclodextrin, provoked an antihypertensive effect in rats [97]. Furthermore, the β-PN/ β-cyclodextrin complex induced endothelium-independent vasorelaxation, possibly caused by the inhibition of Ca 2+ influx through L-type Ca 2+ channels. In addition to these properties, it showed synergistic interactions with PAC against non-small-cell lung cancer cells (NSCLC) [81]. Moreover, β-PN exhibit antiviral activity against herpes simplex virus [98]. qHTS data suggests that it could be an antagonists of peroxisome proliferator-activated receptor δ (PPAR δ) signaling pathway with activity value of 780 nM https://pubchem.ncbi.nlm.nMANUSCRIPTih.gov/compound/440967# https://pubchem.ncbi.nlm.nih.gov/compound/14896# and thus, could be a player in the development of treatments for several chronic diseases, including diabetes, obesity, atherosclerosis and cancer.

Linalool D-linalool (LNL, Fig. 2C) is rarely found as a predominant terpene in cannabis; e.g. 25% of all terpenes found in the “Sour OG” drug chemotype [13]. It is a constituent of hop EO at least in minor amounts [99]. Lavender ( Lavandula angustifolia ) EO can contain around 50% linalyl acetate and 35% LNL; of particular note is that linalyl acetate is readily converted to LNL in the gastric system. Lavender (EO) is traditionally used for relaxation, treating parasitic infections, burns, insect bites and spasms [100]. There is growing evidence to suggest that lavender EO may be an effective medicine in the treatment of several neurological disorders. Studies conducted on animals and humans have suggested that LNL is the active ingredient of lavender EO exhibiting anxiolytic, mood stabilizing, sedative, analgesic, anticonvulsive, anti-inflammatory, antitumor, antibacterial and neuroprotectiveACCEPTED properties.

LNL exhibits a variety of anticancer activities with distinct mechanisms. At a concentration of 25 µM, it has been found to reduce expression of the anti-apoptotic Bcl-2 and Bcl-xl proteins and increase the expression of the apoptotic activators Bax and Bak as well as the activity of caspase 3 and caspase 9, leading to apoptosis in glioma cells [101]. In addition, the protein expression of Sirtuin 3 (SIRT3) – which is overactive in several cancers – was significantly inhibited by LNL (25 µM). Besides, LNL has been found to inhibit the proliferation of breast, colorectal and liver cancer cells with IC 50 values of 224 M, 222 M, and 290 M, respectively [102]. LNL arrested most of the cells in the G1 phase. The same study remarked that LNL can also stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and ATNF-CCEPTEDα secretion, MANUSCRIPT which likely activates the antitumor immunity. Again, with a variety of cancer cell lines, cell death was observed with LNL treatment in the M range [103]. This was due to the inhibition of complex I and II activities of the respiratory chain, a decrease in GSH levels and an increase in the generation of ROS. In addition, LNL selectively diminished the growth of melanoma cells in comparison to healthy cells [104]. This selectivity was – at least partly – caspase-3-dependent, because the protein was expressed in melanoma cells but almost absent from normal keratinocytes. Moreover, LNL was found to be a pro-oxidant in tumor tissues but function as an antioxidant in liver tissue [105]. This dualism was dependent on the regulation of Nrf-2 and p21 proteins, which is an atypical property for liver cancer drugs. In comparison to another cancer drug, 5-FU, LNL was more cytotoxic towards U937 and HeLa cells with the IC 50 value of 3 and 11 M, respectively [106]. Interestingly, U937 cells accumulated to the G0/G1 phase, whereas HeLa cells accumulated in the G2/M phase. The cytotoxic effect was likely mediated through the up-regulation of cyclin-dependent kinase inhibitors (CDKIs) and the expression of the tumor suppressors p53, p21, p27, p16 and p18. It has also been found that LNL can reverse doxorubicin resistance [107] and, in combination with nanoparticles (NPs), significantly improves the cytotoxicity and apoptotic activity against carcinoma cells [108]. LNL-NP treatment promoted apoptosis in epithelial ovarian carcinoma cells by increased ROS generation, and the decrease in mitochondrial membrane potential, and increase, again, in caspase-3 levels. Moreover, LIN-NPs were able to decrease tumor size either alone or in a combination with PAC in a xenograft model in vivo . LNL (100 mg/kg) is an antidepressant, which acts through the monoaminergic system: most likely via noradrenergic and 5-HT1A receptors [95]. The antidepressant-like effect was observed in mice as an altered behavior in the forced swimming test (FST) and the anxiolytic-like activity in EPM [94]. A microarray analysis on the gene expression profiles from hypothalamus samples, taken from stressed rats, revealed that the inhalation of LNL restored the expression of 560 stress-induced genes in comparison to a normal status [109]. These genes were associated with synaptic transmission via neurotransmitters, anxiolytic neuropeptidesMANUSCRIPT like oxytocin and neuropeptide Y and several major histocompatibility complex (MHC) clas s I proteins, which are known to participate in neural development and plasticity. In mice, the anxiolytic activity of LNL was also supported by the light/dark test [110]. In addition, it reduced aggressive behavior and improved social interactions. Another study [111] demonstrated that the inhalation of (-)-LNL resulted in reduced blood flow in the anterior cingulate cortex and insular cortex, causing sedative and anxiolytic effects in healthy males. Their previous study with (-)-LNL had shown the involvement of glutamatergic transmission. In addition to anxiolytic and anti-depressant properties, LNL (single dose of 5, 10 or 20 mg/kg, i.p.) shows anti-nociceptive effects, as evidenced by the reversal of PAC-induced allodynia and hyperalgesia via the involvement of the peripheral opioid system [112]. Accordingly, LNL (50 mg/kg) (as well as linalyl acetate) evoked local anesthesia in vivo [113]. With various models of chronic inflammatory and neuropathic pain, LNL treatment significantly reduced mechanical hypersensitivity and edema in mice [114]. Moreover, the administration of (-)-LNL inhibited the biting response induced by IL-1β and TNF-α. LNL exhibits an anti-nociceptive effect through the suppression of COX-2 [84]. Via antagonism at the L-glutamate binding site of N- methyl-D-aspartate receptor, LNL (200 mg/kg) acted as an anticonvulsant in quinolinic acid induced seizures inACCEPTED vivo [115]. The terpene alleviated maximal electroshock-induced seizures in mice through the diazepam binding site of the GABA A receptor, as shown by a reversal of this effect by the receptor antagonist, PTZ, co-treatment [116]. Both the (+) and (-)-enantiomers showed similar potency and mechanism of action. Lastly, a double-blind, placebo-controlled randomized test with the inhalation of 0.5 ml of 1% linalool (total dose of 5 l) was able to reduce blood pressure and pulse rate in patients with carpal tunnel syndrome [117].

As a result of its radical scavenging activity, LNL has antioxidant and neuroprotective properties against H 2O2-induced oxidative stress, comparable to that of vitamin E or lipoic acid in terms of lipid peroxidation and oxidant-inducedACCEPTED genotoxicity MANUSCRIPT in the guinea pig brain [118]. Moreover, (-)- LNL and its antioxidant properties were found to be effective against oxygen-glucose deprivation/re-oxygenation-induced cortical neuronal injury i.e. in an in vitro model of ischemic stroke [119]. This was independent from the inhibition of n-methyl-D-aspartate (NMDA)-induced excitotoxicity but was mediated through the restoration of SOD and CAT activities. Additionally, (- )-LNL inhibited microglial migration induced by the chemokine (C-C motif) ligand 2 (CCL2). With regard to CCL2, it is known that elevated levels in glial cells are found – not only in brain ischemia and injuries – but also in epilepsy and AD. One study [120] evaluated the effects of LNL on aged, transgenic mice (a model of AD) and found that LNL (25 mg/kg every 48 h for 3 months) improved learning and spatial memory of the animals according to behavioral tests. Importantly, LNL showed a significant reduction in extracellular β-amyloidosis, tau hyperphosphorylation, astrogliosis and microgliosis in the hippocampus and amygdala. Furthermore, the inflammatory responses related to p38 MAPK, NOS2, COX-2 and IL-1β activities were reversed by the LNL treatment. The potential of LNL in the alleviation of AD symptoms was further highlighted in another study [121] where an AD like state was induced by A β1-40 injection into the bilateral hippocampus. Therein, the induced cognitive deficits were ameliorated by LNL (100 mg/kg, i.p.) treatments, as measured as behavior in the Morris water maze and step-through tests. The decrease in apoptosis was mediated through the suppression of activated cleaved caspases (caspase-3, caspase-9) and suppression of the oxidative stress activation via Nrf2/HO-1 signaling. In another study [122], D-galactose- and aluminum trichloride-induced cognitive defects in mice, representing those seen in AD, were alleviated by several mechanisms: LNL (100 mg/kg) restored levels of SOD, GPX, HO-1 and Nrf2 and protected against the increased activity of acetylcholinesterase (AChE) and the content of MDA. The study found that the decreased expression of synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus, were restored by the LNL treatment. In addition to neuroprotection, LNL (10, 20 and 40 mg/kg i.p.) exhibited protective properties against LPS and D- galactosamine-induced liver injuries in mice, manifested as a decrease in pathological liver damage, MDA content, MPO activity and serum alanine andMANUSCRIPT aspartate transaminases [123]. Furthermore, LNL caused serum and hepatic TNF-α and IL-6 levels to decrease, along with hepatic iNOS and COX-2 expression through the inhibition of NF-κB activity. The treatment with LNL increased bcl- 2 expression and inhibited caspase-3 and caspase-8 expression, thus, apoptosis. Moreover, LNL (10, 20 and 40 mg/kg i.p.) treatment reversed the increase in inflammatory TNF-α, IL-6, IL-1β, IL-8, MCP-1 and NF-κB levels induced by cigarette smoke in a dose-dependent manner [124], while in mouse models of chronic inflammatory and neuropathic pain, LNL inhibited LPS-induced TNF-α, IL-1β, NO, and PGE2 production [114]. This was further supported by a reduction in the inflammation in BV2 microglia cells through activation of the Nrf2/HO-1 signaling pathway. Besides, anti-inflammatory and analgesic effects were seen in nociceptive stimulus-induced inflammatory infiltrates and COX-2 overexpression [84]. LNL was also protective against t-butyl hydroperoxide (t-BOOH)-induced genotoxicity in a reverse mutation assay with Escherichia coli and oxyR mutants [25]. In the comet assay, in human hepatoma HepG2 and human B lymphoid NC-NC cells, LNL was effective against t-BOOH induced DNA damage in thr 0.01 g/ml range. LNL exhibited strongACCEPTED antimicrobial activity against periodontopathic and cariogenic bacteria [125], then against fluconazole-resistant Trichophyton rubrum with a minimum inhibitory concentration (MIC) value of 260 g/mL by causing cell leakage [126]. The LNL was effective against Microsporum species as much as ketoconazole [127]. It was also active on conidiogenesis and conidia germination. Last, this terpene showed antifungal activity against Candida spp. isolated from patients with oral candidiasis [128].

In summary, various in vitro and in vivo studies have shown that LNL has anti-tumor, anticonvulsant, anti-nociceptive, sedative, anti-depressant, anti-inflammatory, anti-oxidative, neuroprotective, hepatoprotective and anti-microbial properties. The CNS effects are likely to be mediated by neuropeptides, noradrenergic and glutamaergic systems, the 5-HT 1A receptor and altered blood flow in the anterior AcingulateCCEPTED cortex MANUSCRIPT and insular cortex.

Limonene Limonene (LIM, Fig. 2D) is occasionally the predominant terpene in Cannabis; for instance, in the 'girl scout cookie' drug chemotype, it comprised 56% of all terpenes [13], whereas in hops, it seems to be less abundant. However, it is also found in lemon rind and in other citrus (up to 97%), ajwain, Bupleurum gibraltarium (up to 96%), celery (up to 66%), ebolo (up to 70%), Canadian horseweed (up to 70%), and Bolivian coriander (up to 75%) essential oils. R-limonene and D-limonene are synthesized by two distinct TPSs in plants, but the terpene is usually present as a racemic mixture. It is used as a solvent in cleaning products, food manufacturing, perfumery and hygiene products and as well as an insecticide. Early studies with LIM have implicated anxiolytic features in mice by serotonergic action in the prefrontal cortex and dopaminergic function in the hippocampus, with a 5-HT 1A -dependent mechanism ([10] and references therein). Moreover, it is an immune stimulator via CD4/8 ratio normalization and has been shown to induce apoptosis in breast cancer cells in a Phase II clinical trial. It is non-sensitizing and non-toxic with an estimated human lethal dose of 0.5–5 g/kg. The anti-cancer properties of it has been known for two decades and have been evaluated in clinical trials. Of particular note, LIM is hydroxylated to perillyl alcohol (POH) by cytochrome enzymes, which can be further metabolized to perillyl aldehyde and perillic acid. Numerous studies have shown that POH is the most active compound against cancer. However, the current review deals with both separately, since routes other than oral administration may not transform it to perillyl derivatives, so it may work as a penetration enhancer for other molecules due to in vitro studies. The chemopreventive and chemotherapeutic activity against pancreatic, mammary, and prostatic tumors was reviewed in 1996 [129] and again in 2007, also introducing some other actions and the safety of LIM [130].

LIM can prevent skin tumorigenesis, as shown with a murine model [131]. The mechanism included the Ras signaling pathway: LIM decreasedMANUSCRIPT the expression levels of Ras and Raf and the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 in tumors. It also decreased the expression of anti-apoptotic Bcl-2 and increased the expression of the pro-apoptotic Bax protein. However, LIM restored the levels of reduced GSH, GPx, GSR, GSR and CAT, thus indicating that it may be protective towards healthy cells and tissues. In LS174T colon cancer cells, LIM suppressed the viability of the cells in a dose-dependent manner, causing apoptosis via caspase-3 and -9 activations and PARP cleavage [132]. Furthermore, it decreased the levels of p- Akt (Ser473), p-Akt (Thr308) and p-GSK-3β (Ser9) phosphorylation. The results suggested that the apoptosis was induced by the mitochondrial pathway and by suppression of the PI3K/Akt pathway. LIM exhibited synergistic action with berberine against gastric carcinoma cells by regulating the expression of the Bcl-2 and caspase-3 proteins [133]. In a high throughput gene expression analysis of HepG2 cells, LIM was found to regulate genes involved in apoptosis, signal transduction, cancer, the expression of kinases, inflammation, DNA damage repair and cell cycle control, thus exhibiting its anticancer activity through the interplay of these pathways [134]. The oral administration of LIM (2 g of limonene daily for 2 to 6 weeks) to cancer patients induced significant changes in the serum levels of several metabolites [135]. The metabolic analysis showed patterns that were related to the decreased levels ofACCEPTED cyclin D1 and adrenal steroids. LIM also regulated the genes linked to the glucose metabolism. Lastly, LIM may be a good target for the drug design, because a thiosemicarbazone derivative of LIM showed a lower value of growth inhibition (IC50 : 0.04-0.05 M) than PAC in a variety of cancer cells [136]. One derivative showed high selectivity against prostate cancer cells.

The decreased systemic cytokine IL-6 and TNF-α, neo-vascularization and inhibition of endothelial P-selectin expression, all induced by a LIM treatment, were found to be important for wound- healing in murine models of chemically induced dermatitis and mechanical skin lesions [137]. Moreover, LIM (10 mg/kg/day, up to 15 days) exerted anti-hyperalgesic effects against mechanical hyperalgesia in the spared nerve AinjuryCCEPTED model of MANUSCRIPT neuropathic pain in rats [138]. In another study, LIM (25 mg/kg) presented antinociceptive activity in chemical nociception models in mice [139]. The study also noted that this action was likely independent of peripheral analgesia by the stimulation of opioid receptors. Nevertheless, D-LIM and POH showed anti-stress effects in female Wistar rats in terms of behavioral and physiologic parameters [140] . Therein, POH was less potent than LIM, which suggests that the metabolism of LIM extended the release of its active metabolite POH over the length of the experiments. When rats, with TNBS (2,5,6-trinitrobenzene sulfonic acid)-induced colitis were fed with LIM, it significantly lowered the serum concentrations of TNF-α [141]. The anti-inflammatory effects of LIM also included the inhibition of TNF α-induced NF-κB translocation in fibroblast cultures. Moreover, in elderly healthy subjects, to whom orange peel extract was given for 56 days, there were significantly fewer inflammatory markers – especially peripheral IL-6. In a cell model of osteoarthritis, LIM (85 µg/ml) inhibited IL-1β-induced NO production [15]. LIM also decreased the IL-1β-induced NF-κB, JNK and p38 activations and the expression of inflammatory iNOS and catabolic MMP-1 and MMP-13 genes; furthermore, it increased the expression of the anti-catabolic TIMP metallopeptidase inhibitor 1 (TIMP-1) and the activation of ERK1/2. Furthermore, D-LIM was protective against DOX-induced renal damage in rats [142]. The administration of DOX caused renal lipid peroxidation, and the depletion of GSH and anti-oxidant enzymes. Renal damage was evident in terms of elevated levels of kidney injury molecule-1 (KIM-1), urea and creatinine in blood. Furthermore, DOX caused an elevation of NF κB, COX-2, and iNOS and NO expression levels. However, D-LIM-treatment restored the levels of antioxidant enzymes, and significantly decreased the inflammatory response and the levels of kidney toxicity markers KIM-1 and urea and creatinine in the blood. Also, it reduced the expression of NF-κB, COX-2, and iNOS and NO. In another study, LIM was found to be a sedative and motor relaxant: a significant effect was detected with LIM (5 mg/kg) in OFT and muscle relaxation at the dose of 50 mg/kg. It can also increase the duration of sleep [14] and be an antidepressant [138]. Its derivative was found to be an anti-convulsant with GABAergic action [143]. LIM is also antispasmodic, manifested in the inhibition of ileum contraction [144], and exerts strong anti-viral activity against herpes simplex in monkey kidney ceMANUSCRIPTlls (RC-37) [98]. This was due to the direct interaction with free virus particles. Finally, a q HTS assay suggested that LIM agonizes the androgen receptor (AR) signaling pathway with an activity value of 28 µM in the MDA cell line (https://pubchem.ncbi.nlm.nih.gov/compound/22311#).

Briefly, LIM can promote wound healing and anabolism, while it can ameliorate stress, depression, inflammation, oxidative stress, spasms and viral infections. In addition, it shows a variety of anticancer and anti-tumor mechanisms. However, some of these effects may be due to its conversion to POH in the gastric system. Finally, its derivatives can be powerful anti-convulsants via GABAergic action.

Perillyl alcohol While present in Cannabaceae , Perillyl Alcohol (POH, Fig. 2E) is an abundant terpene in lavender, sage, and peppermint, and especially in the EOs of mints, cherries, citreous fruits and lemon grass. It is common ingredient in cleaning products and cosmetics. It is also a metabolite of LIM via hydroxylation by cytochromeACCEPTED P450 enzymes. It has no known toxicities. POH and its derivatives hold strong promises in cancer treatments, especially against brain tumors [145]. These are under many preclinical and phase I and II clinical trials. While it readily crosses the blood–brain barrier (BBB), it can give this property to its covalent derivatives like NEO212, which is a conjugate with temozolomide – a cancer drug in use against astrocytoma and glioblastoma multiforme. The novel drug was effective for the treatment of a broad range of temozolomide-resistant gliomas. POH, having both pro-oxidant and antioxidant properties, may be useful against malignant brain tumors – which often display elevated rates of oxygen consumption – but at the same time, POH could be protective toward tumor neighboring tissue [146]. In addition, POH is able to induce apoptosis in cancer cells without affecting the normal cells and can revert tumor cells back to a differentiated state. Nevertheless, in oral administrations,ACCEPTED it sh MANUSCRIPTows intestinal side effects. For this reason, clinical trials in Brazil exploited the intranasal POH delivery, which showed that long-term, daily chemotherapy was well tolerated and effective [147].

In addition to being effective against a variety of gliomas, POH shows potential against other cancer types as well. In particular, breast, skin and lung tumors could be treated, because administration through the skin or by inhalation is possible. Nonetheless, POH (250 µM) can induce apoptosis in lung cancer cell lines via increased caspase-3 activity [148]. Breakpoint cluster region protein– Abelson murine leukemia viral oncogene homolog 1 (BCR –ABL1) gene fusion is commonly found in leukemia. The Bcr/Abl protein is a constitutively activated tyrosine kinase that induces the expression of c-Myc via its downstream target Jak2. The constant over-expression of c-Myc leads to the unregulated expression of many genes, which are involved in G1/S phase transition, causing uncontrollable cell divisions and the avoidance of apoptosis. A previous study [149] found that POH activated the Myc-Ornithine decarboxylase (Myc-ODC) apoptotic pathway which is not protected by the Bcr/Abl anti-apoptotic mechanism in BCR–ABL1-transformed cells. A significant inhibition of ODC activity by POH was also found in another study [150]. This time, it was also found that the Ras/Raf/ERK pathway was suppressed by POH, which in turn limited the formation and progression of 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol- 13-acetate (TPA)-promoted tumorigenesis in Swiss albino mice skin. Moreover, POH (250 µM) impaired the regulation of the mevalonate- and the Ras-Raf-MEK-ERK pathways in U87 and U343 glioblastoma cells [151]. Furthermore, POH inhibited the post-translational prenylation of GTPase H-Ras and Ras-related C3 botulinum toxin substrate 1 (Rac1) by inhibiting enzymes down -stream in the mevalonate pathway. Thus, POH prevented them from being activated. Of particular note is that H-Ras is over expressed in many cancer types, while the inhibition of Rac1 may lead to the reversal of tumor cell phenotypes.

The expression of the translation repressor protein eIF4E-binding protein 1 (4E-BP1) and activation of the mTOR/4E-BP1 transduction pathway are dysreguMANUSCRIPTlated in a range of malignant cancers. 4E- BP1 is hypophosphorylated in quiescent cells, while the phosphorylation of 4E-BP1 causes its release from eIF4E, allowing cap-dependent translation to proceed. However, POH (400 M for 16 h) suppressed 4E-BP1 phosphorylation at Ser65 in prostate tumor cell lines, DU145 and PC-3, and in Caco2 adenocarcinoma cells [152]. Furthermore, 4E-BP1 phosphorylation at Thr37 was reduced by POH in DU145 cells. Thus, POH may promote cell quiescence. The mTOR/4E-BP1 pathway participates in the regulation of hypoxia-inducible factor 1-α (HIF-1α) protein levels. HIF-1α is known to be involved in angiogenesis, energy metabolism, cell survival and tumor invasion. POH (50 µM) was found to significantly moderate the increase in HIF-1α protein levels through the inhibition of the mTOR/4E-BP1 signaling pathway [153]. In vivo studies further confirmed the inhibitory effect of POH (three times a week for 40 days at a dose of 50 mg/kg) on the expression of HIF-1α proteins, leading to a decrease in the growth of HCT116 cells in a xenograft tumor model. Furthermore, POH (300 M) augmented the protein expression of p53 and p21, induced cell cycle arrest in the G1 phase and reduced cyclin D1, c-Myc, and Skp2 protein levels [154]. Another study confirmed the action of POH on p21 but also found that POH (1.0 mM) attenuated cell proliferation via up-regulation ofACCEPTED the expression of cyclin kinase inhibitor proteins and multiple tumor suppressor 2 (MTS-2) protein [155]. This resulted in the hypophosphorylation of retinoblastoma (RB), and thus subsequent G1 arrest.

An in vitro study [156] found that POH (400 M for 16 h) caused the rapid dissociation of the captured hTERT-mTOR-RAPTOR complex, which resulted in the decrease of telomerase activity. Polycyclic aromatic hydrocarbon-induced CYP1B1 activity was suppressed by POH (500 nM) [157]. Of particular note, CYP1B1 is known to be overexpressed in a wide range of tumors, especially as high levels of expression are observed in estrogen-mediated diseases. VEGF is up- regulated in many tumors and its contribution to tumor angiogenesis is well described. POH (100 µM), however, decreased the releaseACCEPTED of VEGF MANUSCRIPT from cancer cells, while, on the other hand, stimulated the expression of angiopoietin 2 (Ang2) by endothelial cells [158]. The results suggest that POH may suppress neovascularization and induce vessel regression in tumors. The AP-1 transcription factor is a dimeric complex that contains members of the JUN, FOS, ATF and MAF protein families. The AP-1 factor transduces the growth signals to the nucleus, leading to the expression of genes involved in growth and malignant transformation in many cell types. Thus, AP- 1 proteins are often considered as oncogenes, but recent studies have challenged this view: especially JUNB and c-FOS have been shown to possess tumor-suppressor activity. In breast cancer cells, POH was able to induce the expression of c-fos and c-jun genes and the phosphorylation of c- Jun [159]. In the experiments, these changes appeared concurrently with the transcriptional activation of an AP-1-dependent reporter gene. The results suggest that POH can alter the expression of AP-1 target genes, especially those with tumor-suppression activity. Hepatoma cells (HepG2, SMMC-7721 and MHCC97H) exhibit higher cell invasiveness and migratory capacity in comparison to normal liver cells (HL-7702). These properties were significantly suppressed by POH treatment with an IC 50 value of ~100 µM [160]. This occurred through the Notch signaling pathway and increased E-cadherin. A decrease of E-cadherin, and thus cellular adhesion, is known to promote tumor metastasis. The abnormal activation of Akt is commonly present in tumors; the dysregulation affects downstream processes, including the control of cell survival, proliferation, migration and angiogenesis. Akt activation via Ser473 phosphorylation was increased in DU145 cells by POH, suggesting that it may take control over the malignant events [152]. The Na/K- ATPase α1 subunit is commonly overexpressed in glioblastoma cells suppressing apoptosis [161]. Previously, the authors demonstrated by an enzyme kinetic study that POH is an Na/K-ATPase inhibitor. This time, they found that POH activated p38 and JNK in human glioblastoma cells, non- tumor monkey kidney and mouse astrocytes. An inhibitor of Src kinase abrogated the activation of JNK1/2 in U87 cells, suggesting that the NKA-Src is involved in this apoptotic mechanism. Furthermore, the inhibition of JNK1/2 reduced the apoptosis of in POH-treated glioblastoma cells, thus suggesting that JNK1/2 is involved in programmed cell death. Last, POH (500 nM) inhibited the expression and function of the androgen receptorMANUSCRIPT in human prostate cancer cells [162]. This was manifested in the inhibition of androgen-induced ce ll growth and the androgen-stimulated secretion of prostate-specific antigen and human glandular kallikrein in the human prostate cancer cell line LNCaP.

Ethanol use increases serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and hepatic MDA. Also, ethanol administration decreases hepatic reduced GSH content and the activity of various antioxidant enzymes. In a rat model, these changes were observed, while the ethanol treatment increased TNF-α production and NF κ-B activation. POH (50 mg/kg) treatment prior to ethanol treatment, however, effectively diminished these markers of acute liver injury, normalized endogenous enzymatic and non-enzymatic defense system, and down- regulated TNF-α and NF κ-B production [163]. Perillic acid, a metabolite of POH, was also found to exert anti-inflammatory features by suppressing pro-inflammatory IL-2 production in mitogenactivated T lymphocytes [164]. This happened via the ability of perillic acid to interrupt signaling in the Ras/MAP kinase pathway by depleting farnesylated Ras levels. POH (75 mg/kg) significantly suppressed the indicatorsACCEPTED of allergic airway inflammation, such as airway eosinophilia [165]. In addition, cytokine production in the thoracic lymph nodes of the mice was substantially suppressed. The results demonstrated that POH effectively suppressed antigen-induced immune responses in the lungs. Thus, POH holds potential for the treatment of immunologic lung disorders such as asthma. On the other hand, POH can activate innate immune responses in the pulmonary alveoli of mice, which manifest as increased splenocyte and cervical lymph node cell proliferation, IgM production, alveolar macrophages and IgA-producing lymphocytes [166]. However, negative changes in body weight or liver, brain and lung morphology were not found. Moreover, POH (25 µM) can reverse hypoxia/reoxygenation-induced injury in HK-2 cells by decreasing ROS levels, apoptosis and ER stress and ameliorating the cell viability via activation of the PI3K/Akt/eNOS pathway [167]. In a rat model of middle cerebral arteryACCEPTED occlusion, MANUSCRIPT oral POH (25 mg/kg once daily for 7 days) administration significantly attenuated neurological deficits and reduced infarct volume in a dose- dependent manner [168]. The POH treatment also inhibited oxidative stress and lipid peroxidation and increased the levels of GSH and CAT, GPx, and GSR enzymes. Moreover, POH suppressed the levels of inflammatory IL-1β, TNF-α, IL-6, COX-2, NOS-2 and NF-κB. In addition to this, a POH- dependent reduction of serum concentrations of IL-6 and TNF-α was observed in mice with chemically-induced skin lesions [137]. Finally, tissue regeneration was improved and neovascularization decreased. These factors accelerated the wound healing.

POH blocked formalin-, capsaicin-, and glutamate-induced orofacial nociceptive behavior in mice [169]. The action of POH was comparable to that of morphine in all tests. When 10 mg/kg POH was administered to stressed rats, a significant anti-stress action was evident, as measured by changes in behavioral and physiologic parameters [140]. Potentially, it could alleviate the symptoms of AD, since a previous study [170] found that POH decreased amyloid-β peptide-induced mitochondrial dysfunction and cytotoxicity in SH-SY5Y neuroblastoma cells. Moreover, POH exhibited antibiotic effect against Candida albicans [171] and Plasmodium falciparum in experimental cerebral malaria [172]. In a qHTS assay, POH was able to inhibit 15-LOX with an activity value of 12.6 µM https://pubchem.ncbi.nlm.nih.gov/compound/10819#

In summary, POH and its derivatives exhibit diverse anticancer and anti-tumor properties, especially against gliomas. It is an anti-inflammatory, antioxidant, hepatoprotective, nociceptive, anti-fungal and anti-parasitic agent. It may be effective against symptoms of AD.

Terpinolene Terpinolene (TPL, Fig. 3A) is also known as δ-Terpinene due to its close similarity to other terpinenes. It is sometimes the chief terpene found in a cannabis sample e.g. in the 'durban poison' drug chemotype (55%) [13]. It has been found in aMANUSCRIPT variety of plant sources such as sage, apple, cumin, lilac, tea tree and lemon, but it is primarily isolated from pine and fir trees.

Downstream of PI3K signaling, Akt is a regulatory protein involved in the metabolism, proliferation, cell survival, growth and angiogenesis, which is up-regulated in many cancers. In a previous study [173], 0.05% TPL was found to decrease the expression of Akt (but not Erk2) in myelogenous leukemia (K562) cells. In comparison, LNL was unable to down-regulate Akt. In another study [174], the proliferation of primary rat neurons and N2a neuroblastoma cells was significantly diminished after treatment with TPL (10 mg/L). However, the TPL treatment increased TAC in primary rat neurons, but not in N2a cells. Furthermore, TPL was not genotoxic to the normal cells. This was supported by another report [175], which revealed that TPL exhibited no genotoxicity against human primary lymphocytes either. Again, TPL treatment (10-75 mg/L) increased the cellular TAC levels (but not TOS levels). Moreover, the inhalation of TPL (0.1 mg) – via nasal absorption into the body – showed sedative effects in mice [176]. Analysis of the structure-function relationship of TPL (in the comparison to TPL analogs) revealed that the double- bond in the side-chain or pi bonds in the six-membered ring play important roles in the sedative effect. In addition,ACCEPTED TPL effectively prevented LDL-oxidation against copper-induced oxidation in human blood plasma preparations [177]. This protective effect may be beneficial toward atherogenesis and coronary heart disease. TPL has been shown to be a transdermal penetration enhancer for indomethacin, a non-steroidal anti-inflammatory drug (NSAID) in rats [178, 179]. An association of ineffective oral doses of TPL (3.125 mg/kg) and diclofenac (1.25 mg/kg) showed a synergistic anti-inflammatory and anti-nociceptive effect in mouse model of inflammatory hyperalgesia [179]. The TPL-diclofenac combination reduced neutrophils, macrophages and lymphocytes in the paw as observed by histological analysis. A possible mechanism of action of the analgesic effect might be mediated via 5-HT 2A receptors, since ketanserin - a antagonist of 5-HT2 receptors in rodents - completely reversed the antinociceptive effect. Importantly, this combination lacks the risk of gastric injury. ACCEPTED MANUSCRIPT

TPL show anticancer, antioxidant and anti-inflammatory properties along with efficiency against LDL oxidation, and sedative and penetration enhancing features. Also, it is anti-nociceptive via the 5-HT 2A receptor. γ-Terpinene In addition to cannabis and hops, γ-Terpinene ( γ-TPN, Fig. 3B) has been isolated from a variety of plant sources such as savories ( Satureja ) and thyme. Terpene is used as a flavoring agent and is not acutely toxic at least at 2 g/kg in rats [180]. γ-TPN (1.6-50 mg/kg) showed an anti-nociceptive effect in the formalin, capsaicin, and glutamate-induced pain models in rats [180]. When the animals were pretreated with naloxone, glibenclamide, atropine and mecamylamine in the glutamate test, they reversed the γ-TPN induced anti-nociception suggesting that the anti-nociceptive mechanism involves cholinergic and opioid systems. The study excluded the possibility of muscle relaxant activity or central depressant effects, which could otherwise explain the changes in the rat behavior. Another study [181] presented the anti-inflammatory and edema-relieving properties of γ-TPN in Swiss mice with carrageenan-induced paw edemas. Similar actions of γ-TPN were seen towards PGE2, bradykinin and histamine-induced inflammations. γ-TPN reduced pro-inflammatory cytokine IL-1β and TNF-α production and limited neutrophil migration into the inflamed site. In addition, γ-TPN possessed strong radical scavenging activity; it was able to trap approximately 1.2 radicals while protecting erythrocytes, methyl linoleate and DNA in vitro [182]. In comparison, this non-conjugated diene was superior to its conjugated counterpart α-TPN. Moreover, γ-TPN can inhibit LDL oxidation in synergism with Rutin – a common flavonoid glucoside in foods [183]. In addition, it prevents the lipid peroxidation with different mechanisms to those of vitamin E [184]. Lastly, γ-TPN suppressed the increase in the serum lipid concentrations in Triton WR1339-treated rats [185]. In summary, γ-TPN exhibited anti-inflammatory and anti-nociceptive features together with beneficial effects on the oxidation status and bloodMANUSCRIPT concentrations of LDL particles, and thus, possesses potential against cardiovascular diseases . Furthermore, studies have shown that γ-TPN has extraordinary ROS scavenging activity along with sedative, anti-nociceptive and anti- inflammatory properties. Furthermore, it is effective to lower LDL and lipid oxidation and the serum levels of lipids.

α-Terpinene α-Terpinene ( α-TPN, Fig. 3C) is found in cannabis and hops and is commonly used as a fragrance compound. It is found in allspice and many EOs e.g. from tea tree and Litsea ceylanica (20%), but it is usually produced industrially from α-pinene. α-TPN shows no embryofetotoxicity following the oral administration of 30 mg/kg to rats [186] and is also not mutagenic according to the Ames tests [187]. α-TPN shows good ROS scavenging activity, trapping approximately 0.7 radicals when protecting erythrocytes and 0.5 radicals when protecting methyl linoleate [188]. α-TPN is a strong antioxidant since it auto-oxidizes rapidly in comparison to many other compounds, preventing these from degradation. However, it can also form allergens by auto-oxidation according to a previous study [189]. α-TPNACCEPTED alone (at a dose of 1.0 ml/kg) increased longevity in mice infected with Trypanosoma evansi [190] . When combined with diminazene aceturate, it was able to cure nearly 60% of the infected animals. However, the daily oral administration of 0.5 ml/kg for 10 days induced memory deficits in rats accompanied by alterations in Na(+), K(+)-ATPase and NTPDase activity and DNA damage [191]. Taken together, even though α-TPN is a strong antioxidant and antibiotic, its use may not be recommended because of its serious adverse effects on brain health.

Terpineols α- and γ-terpineols (TOLs, molecular structure of α-terpineol is presented in Fig. 3C), and terpinen- 4-ol (T4OL, Fig. 3E) isomers are likely derived from their terpinene counterparts by hydration in plants. They are present in a varietyACCEPTED of plant sour MANUSCRIPTces such as tea tree oil, cajuput oil, pine oil, and petitgrain oils, lilacs, pine trees, lime blossoms and eucalyptus. T4OL is present at high concentrations (30–48%) in tea tree EO and at up to 29% in lavender EO [192]. They can be synthesized from more abundant terpenes limonene and pinenes.

α-TOL was tested against several cancer cell lines, of which it was most powerful against small cell lung carcinoma (IC 50 : 0.26 mM) [193]. In addition, the results showed that α-TOL is an NF-κB inhibitor, which was seen as NF-κB translocation and its reduced activity using two NF-κB assays. This led to down-regulation of the expression of several NF-κB-related genes such as IL-1β and IL1R1. γ-TOL significantly suppressed BEL-7402 cell proliferation in a dose-dependent manner (smallest dose tested: 40 mg/mL) [194]. It promoted apoptosis, visualized as morphological changes such as cell shrinkage, the deformation and vacuolization of mitochondria, nuclear chromatin condensation and fragmentation and the formation of apoptotic bodies. Furthermore, γ-TOL treatment accumulated the cells in the G1 or S phase and blocked cell proliferation . Similarly, T4OL showed anticancer activity in Hep-G2 hepatocellular carcinoma cells by inducing apoptosis and DNA fragmentation, and by the inhibition of cell migration and the accumulation of cells in the sub- G1 cell phase [195]. Anti-tumor effects were also observed in vivo with a mouse model, in which the administration of only 10 and 20 mg/kg of T4OL decreased the tumor weight and tumor volume in a dose-dependent manner. Moreover, in another study [196] using a xenograft model of ICR- SCID mice implanted with HCT116 cells, the local injection of 200 mg/kg of T4OL increased apoptosis and inhibited tumor growth, likely by caspase-3/7 pathway and through increased ROS generation by mitochondria. Furthermore, T4OL inhibited the proliferation of colorectal, pancreatic, prostate and gastric cancer cells (at the lowest concentration of 0.005%) either alone or in combination with various anticancer agents with notable synergism [197]. In a xenograft model, it (0.2%) reduced tumor volumes alone or in combination with other drugs. T4OL induced autophagy and apoptosis in human leukemic HL-60 cells and thus cell deaths with an IC 50 of 30 M via the activation of microtubule-associated protein 1A/1B-light chain 3 (LC3-I/II), Beclin-1 and Autophagy 5 (ATG5) proteins [198]. Finally, T4OL MANUSCRIPTshows anticancer and anti-tumor activities via the activation of caspases 9 and 3 and the cleavage of poly(ADPribose) polymerase (PARP), by decreasing the mitochondrial membrane potential (MMP) and XIAP protein and survivin levels, and by the elevation of the Bax/Bcl-2 ratio and lastly, by the increase in p53 levels [199].

T4OL (25 mg/kg i.p. or 10 ng intracerebroventricularly) exhibited anticonvulsant action as it inhibited PTZ-induced seizure via GABAergic system [200]. However, the anticonvulsant action exerted by the terpene alcohol was not reversed by flumazenil, a selective antagonist of the benzodiazepine site of the GABA A receptor, suggesting that T4OL does not bind to the classical benzodiazepine-binding site. Furthermore, T4OL decreased the sodium current through voltage- dependent sodium channels, thus, its anticonvulsant effect may be related to the changes in neuronal excitability. This could lead to a depressant effect in the central nervous system (CNS). Another study [201] showed neuronal excitability and voltage-dependent K + currents in the somatic sensory system where intact and dissociated neurons of rat dorsal root ganglia were inhibited. In turn, α- TOL, complexed with β-cyclodextrin, effectively reversed the effects of mechanical and TNF-α- induced hypernociceptionsACCEPTED without causing any defects in the force or motor coordination in mice [202]. Similar results were also observed upon carrageenan-induced local hypernociception, which was reversed by i.p. injection of 25 mg/kg of α-TOL [203]. The antinociceptive effects were reversed by naloxone or ondansetron-treatments suggesting an involvement of the opioid and 5-HT receptors [202]. These findings were supported by molecular docking studies. By using the acetic acid writhing reflex and formalin, glutamate, and capsaicin-induced nociception tests, the anti- nociceptive effects of α-TOL (25 mg/kg) were found in terms of reduced nociceptive behavior in mice [204]. However, this can also be, at least partly, because of the sedating properties α-TOL, which appear with an inhalation of the terpene [205].

α-TOL is a spasmolytic agent as Aa CCEPTEDconsequence MANUSCRIPTof its inhibitory effect on ileum contraction [144], but α-TOL (50 mg/kg) was able to induce gastric retention independently from the activity on the smooth muscle cells [206]. The mechanism of the latter rests on the cholinergic/nitrergic signaling in the vagus nerve. In turn, T4OL (with IC 50 of 170 µM) relaxed rabbit duodenum in vitro in a myogenic manner, which was mediated through calcium antagonism [207]. A similar action was found with isolated rat aortic ring preparations whose calcium influx through voltage-operated calcium channels was altered in the smooth muscle cells [208]. At mM concentrations, it reduced the contraction force in the isolated left atrium of rat hearts [209]. Conversely, at M concentrations, it caused a positive inotropic effect and extrasystole. It provoked the arrhythmia likely by its effects on intracellular Ca 2+ handling. However, in vivo , according to one study [210], intravenous bolus doses (1 to 10 mg/kg) of T4OL immediately and dose-dependently decreased the mean aortic pressure in conscious rats by a direct myogenic action. Nevertheless, NO plays a primary role in the induction of hypotension and vasorelaxation. Via activation of the NO-cGMP pathway, and the subsequent NO release from epithelial cells, α-TOL was able to induce these beneficial cardiovascular events with doses starting form 1 mg/kg in vivo and in M concentrations in vitro [211]. It remains to be determined whether α-TOL and T4OL share common mechanisms for smooth muscle cell relaxation.

After cerebral ischemia, induced by transient bilateral common carotid artery occlusion in male Wistar rats, α-TOL (100 mg/kg) was able to improve spatial memory and synaptic plasticity in the hippocampus [212]. This was likely and at least partly due to lowered levels of MDA and lipid peroxidation in hippocampus. Moreover, α-TOL (10 mg/kg) presented gastroprotective activity in two widely used models of gastric ulcers for the evaluation of anti-ulcerogenic drugs [213]. Furthermore, the data of the study indicated that its gastroprotective activity does not involve gastric acid secretion inhibition or an increase in prostaglandin synthesis. However, in LPS- stimulated human macrophages, T4OL and α-TOL suppressed the production of inflammatory IL- 1β, IL-6 and IL-10 [214]. The inhibitions were mediated via interference from the NF-kB, p38 or ERK/MAPK pathways. In a mouse experimental modelMANUSCRIPT of colitis, T4OL (10 mg/kg) inhibited NF- κB and nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation and the subsequent IL-1β secretion [215]. Of particular note, NLRP3 inflammasome is also an important player in chronic airway diseases such as asthma and chronic obstructive pulmonary disease. α-TOL and its derivatives were effective bronchodilators in a model of asthma in rats [216], and also down-regulated the levels of pro-inflammatory IL-4 and IL-17. In another study [217], an anti-inflammatory action of α-TOL (3.1 mg/L) on IL-6 segregation and the IL-6 receptor was found. This monoterpene alcohol also decreased the levels of pro-inflammatory IL-1β, IL-6, TNF-α, COX-2, and iNOS, and inhibited the activation of NF-κB, while it increased the expression of the anti-inflammatory cytokine IL-10 [218]. In addition, α-TOL was a strong antibiotic when tested against E. coli (MIC value of 0.78 L/mL) [219]. Moreover, it effectively killed periodontopathic and cariogenic bacteria in the mouth, suggesting that it could be used in toothpaste formulations, for instance [220]. Furthermore, α-TOL inhibited the growths of G. vaginalis with MIC value of 0.06 % (v/v) and C. albicans with MIC 0.125 % (v/v), which was comparable to the action of clotrimazole [218]. The antimicrobial features were confirmed in vivo (vaginal cavity of mice).ACCEPTED In turn, T4OL was effective against oral candidiasis with a dose of 50 µL of 40 mg/mL in a murine model [221]. It also suppressed the infection-induced secretion of the pro- inflammatory TNF-α and macrophage inflammatory protein 2-α (MIP-2) from macrophages. Finally, T4OL inhibited the growth of pathological fungi C. posadasii , mycelial H. capsulatum , and yeast-like H. capsulatum with MICs of 250 g/mL, 30 g/mL, and 10 g/mL, respectively, presumably by disturbing the fungal membranes and reducing the ergosterol content of cells [222].

In conclusion, studies have shown that all γ-TOL, α-TOL and T4OL may exhibit anticancer properties, but that only T4OL has been shown to be anti-tumorigenic. Both α-TOL and T4OL exhibit anti-inflammatory, spasmolytic, vasodilatory and antibiotic features. Whereas α-TOL shows potential against pain, spasms, asthmaACCEPTED and neurolog MANUSCRIPTical damages, T4OL is an anticonvulsant that acts via several different mechanisms.

Geraniol Geraniol (GOH, Fig. 4A) is used in perfumes and as a flavoring agent, and also as a preservative, insect repellent and attractant. It is the chief component of palmarosa oil and the second most abundant in rose oil, as well as being found in citronella oils (lemon grass) and Geranium . Actually, it is found at least in 160 plant EOs (references in [223]) including cannabis and hops. GOH is important in the biosynthesis of other terpenes. The LD 50 value of GOH is 3.6 g/kg in rats [224]. To date, experimental evidence supports the therapeutic or preventive effects of GOH towards different types of cancer (reviewed in [225]). The anticancer mechanisms include the Ras-ERK and AKT- mTOR signaling, altering the Bcl-2/Bax ratio, regulation of AKT-mTOR, cyclins A, B, D and E and CDK1 and CDK4, as well as p21Cip1 and p27Kip1, AMP-activated protein kinase (AMPK), PCNA, mutant p53 and c-Fos. Furthermore, GOH suppresses angiogenesis via the downregulation of VEGF [226].

GOH suppressed skin inflammation through a variety of mechanisms [225]. It inhibited the expression of COX-2, NF-κB, TNF-α, IL-6, IL-1β and pp38. Moreover, it restored the levels SOD, GSR, GPx, GST, CAT, GSH and NO and reduced MDA content. It showed beneficial attributes towards hyperglycemia and diabetic cardiac complications alleviating cardiac ischemia and oxidative stress in streptozotocin-induced diabetic rats [224, 227]. Mechanisms of action of GOH on the impaired vascular reactivity of aortic rings isolated from diabetic rats or in rats with metabolic syndrome were revealed: it was able to block both voltage-dependent and receptor operated calcium channels in an endothelium-independent pathway [227]. Another study implicated a possible cardioprotective effect using an in vitro model of normal neonatal rat ventricular cardiomyocytes, in which hypoxia-reoxygenation stress was introduced [228]. The addition of 5 M of GOH to the cell culture was able to decrease the MANUSCRIPTendogenous production of ROS in the stressed cardiomyocytes. GOH treatment also increased phosphorylated AMPK levels implicating the reconstitution of energy homeostasis. In another study [229], mice were fed for three weeks with feed supplemented with 25 mmol of GOH per kg, and beneficial effects were found. Plasma lipid levels were reduced, which was likely due to upregulation of the acetyl-CoA carboxylase 1 (ACACA) enzyme, which is the rate-limiting enzyme in fatty acid synthesis. In addition, cholesterol synthesis was reduced due to a decrease in cholesterol 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) protein levels and catalytic activity. The mRNA levels of LDL and VLDL receptors were upregulated, which suggests the enhanced uptake of these lipoprotein particles from the serum. Chronic inflammation is a key player in atherosclerosis. A study [230] found that hamsters fed an atherogenic diet supplemented with 100mg/kg of GOH showed reduced remodeling of the heart and aorta tissues in comparison to the control group, because GOH was able to enhance the free radical scavenging, and also due to its anti-inflammatory effects.

In a rat model of colitis, GOH (250 mg/kg) replenished the depleted antioxidant capacity and showed anti-inflammatory action by inhibiting the colon contents of PGE2 and IL-1β and suppressed immunologicalACCEPTED responses, possibly via Wnt/GSK-3β/β-catenin, p38MAPK, NF κB, and PPAR γ signaling pathways [231]. In turn, in dextran sulfate sodium-induced colitis mouse model, GOH (30 mg/kg) strongly improved the histological signs of colitis [232]. Furthermore, this terpene alcohol significantly reduced COX-2 expression in the gut wall as well alleviated colitis-associated dysbiosis. Moreover, the administration of 120 mg/kg of GOH reduced systemic inflammation, as evidenced by a significant decrease in the IL-10, IL-17, TNF α, and IFN γ levels. Independently from that, another study [233], using the same colitis model, confirmed the effect of GOH on the TNF-α, IL-1β, IL-6 and COX-2 levels. Furthermore, the study found that GOH reduced the activity of MPO and the amount of iNOS in the colon tissue. Not surprisingly, these effects were dependent on the activity of I κBα and the degradation of NF-κB. The pre-treatment with GOH also ameliorated the reduction in the amount of reducedACCEPTED GSH and SOD MANUSCRIPT activity and the lipid peroxidation and reduced the nitrite levels in colon tissue. These three studies together strongly suggest that GOH could be useful in the treatment of inflammatory bowel disease.

Rats received 250 mg/kg/day of GOH for four weeks after traumatic spinal cord injury introduced by a surgical procedure [234]. The observed regeneration at the injury site by the GOH treatment was mediated through the modulation of NF-κB and p38 MAPK, which likely involved the actions of TNF α and IL6. Furthermore, the inflammatory response, oxidative stress, and caspase-9 and -3 activities were significantly suppressed. In addition, the regeneration of liver tissue was evidenced by another study [235], in which, soon after partial hepatectomy, TNF α and IL6 gene expressions were up-regulated in the GOH-treated groups. Also, alanine transaminase levels were diminished. The action of GOH was similar to that of Silymarin – a drug used for the treatment of cirrhosis. Again, in vivo , GOH (12.5 mg/kg) exhibited protective effects, this time against the acute lung injury induced by the administration of LPS [236]. Acute respiratory distress syndrome, a disease that causes morbidity and mortality in critically ill patients, is characterized by chronic inflammation, pneumonia, interstitial edema, sepsis and increased apoptosis. However, GOH treatment for ill mice ameliorated pathological injuries and pulmonary cell apoptosis, and MPO activity and increased the production of IL-1β, IL-6, and TNF-α. In vitro , GOH reversed the effects of LPS by reducing the iNOS and COX-2 levels and the expression of Toll-like receptor 4 (TLR4), thus preventing NF-κB-dependent actions. The apoptosis was alleviated by the altered Bcl-2/Bax ratio and the reduced Caspase-3 expression. In mice, ovalbumin-induced allergic asthma was attenuated by treatment with 100 mg/kg of GOH [237]. The terpene alcohol administration reduced the levels of pro-inflammatory IL-4, IL-5 and IL-13, increased the innate immunity, promoting interferon-γ in the bronchoalveolar lavage fluid, and reduced the amounts of ovalbumin-specific IgE in the serum. Furthermore, GOH increased the production and activation of Nrf2 and the subsequent expression of the antioxidant enzymes glutamate-cysteine ligase, SOD and glutathione S-transferase, while decreasing the formation of MDA in the lungs. MANUSCRIPT GOH with both oral and i.p. administration of 12.5 mg/kg reduced writhing behavior induced by acetic acid in mice [223]. Furthermore, a 12.5 mg/kg i.p. injection reduced paw licking time in the formalin test, and in the glutamate test with 50 mg/kg administration, suggesting the involvement of glutamatergic mechanisms. This was supported by an experiment in which a non-selective NMDA receptor antagonist, dizocilpine, produced similar results. The opioid antagonist naloxone failed to reverse the anti-nociceptive activity of GOH, suggesting a non-opioid pathway for the mechanism of action. Of particular note, involvement of GABAergic mechanisms cannot be excluded. Nevertheless, GOH potentially ameliorated the symptoms and progression of AD in mice [238] and Drosophila [239]. In mice, AD symptoms were induced by the chronic intake of neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid. This led to an increase in apoptotic cells in the nigrostriatal region, neurodegeneration and motor impairment in mice. However, GOH (100 mg/kg) treatment ameliorated these effects, evidenced by improved motor behavior and altered levels of Bcl2, Bax and cytochrome-C [238]. The loss of dopaminergic neurons in a transgenic Drosophila model was reversed by exposure to 10 M of GOH. Furthermore, the experiments resulted in a significantACCEPTED delay in the loss of climbing ability, improved overall activity and lowered oxidative stress in the brains of the flies [239]. Neuropathy, in turn, is a result of several environmental factors such as medications, diabetes, traumatic injuries and chronic alcohol consumption. However, it can be also induced by acrylamide in an experimental mouse model. A previous study [240] showed that the adverse changes induced in the model, such as oxidative stress, can be reversed. This was seen as the ability of GOH (100 mg/kg) treatment to normalize the levels of antioxidant enzymes, NO and GSH in the sciatic nerve and cortex and cerebellum brain regions, and decreased the levels of MDA and cytosolic calcium in the same brain regions. Furthermore, AChE activity was reduced. GOH was an anti-depressant for chronically stressed mice [241]. The three-week administration of GOH (20 mg/kg/day) facilitated depressive behaviors in both the forced swimming and tailACCEPTED suspension MANUSCRIPT tests. Furthermore, the treatment normalized the levels of stress induced pro-inflammatory cytokine IL-1β. The induced neuroinflammation was reduced, probably by inhibition of the NF-κB pathway and NLRP3 inflammasome expression. Lastly, according to qHTS assays, GOH agonized the estrogen receptor α (ER-α) signaling pathway with an activity value of 2.2 µM and inhibited 15-LOX with a concentration of 7.9 µM (https://pubchem.ncbi.nlm.nih.gov/compound/637566#) while its cis-isomer agonized TRPA1 at 11.7 µM (https://pubchem.ncbi.nlm.nih.gov/compound/643820#).

In conclusion, GOH possesses potential for the treatment of several diseases and conditions; these include cancer, colitis, inflammation, diabetes, cardiac dysfunction, atherosclerosis, tissue injuries, allergic asthma, pain, PD, neuropathy and depression.

Nerolidol Nerolidol (NOH, Fig. 4B) is herbivore and pathogen-induced volatile in plants, but it is regularly found across the planta, including Cannabaceae, and makes up 74–95% of the total terpenes in paper bark tea tree oil. It is found in the EOs of the ginger family (up to 90%), Siparuna (90%) , Myrceugenia (90%), Piper claussenianum (83%), Melaleuca quinquenervia (87%), New England peppermint tree (80%), Salvia (72%) and in neroli, from which it got its name. NOH is commonly used across industries e.g. in cosmetics, cleansers and as a food flavoring agent. In early studies, it was found to possess sedative effects (reviewed in [10] & references). As more recently reviewed [242], NOH has also been shown to possess anti-oxidant, anti-bacterial, anti-fungal, broad-spectrum anti-parasitic, anti-nociceptive, anti-inflammatory, anti-ulcer and anticancer properties. In addition, it has shown great promise for the treatment of neurodegenerative diseases featuring anti- cholinesterasic, antioxidant, anti-nociceptive, anti-inflammatory and anxiolytic activities, as reviewed in 2017 [243]. Because of the low acute toxicity (dermal LD 50 in rabbit higher than 2000 mg/kg and oral LD in rats 5 g/kg and mice 10 g/kg) it may have great clinical potential. 50 MANUSCRIPT NOH exerts an anxiolytic effect without altering the motor coordination in mice [244]. In comparison to diazepam (1 mg/kg), it produced the same effect in EPM with the administration of 50 mg/kg, in open field tests (OFT) with 25 mg/kg, and did not affect motor coordination by the rotarod test with any concentration tested. In addition, NOH (daily three doses of 12.5 mg/kg) significantly suppressed the sub-convulsive PTZ-induced progression of kindling [245]. Additionally, NOH ameliorated depression and memory impairment, as indicated by improved behavior in the tests. These behavioral observations were associated with up-regulated neurotransmitters and decreased oxidative stress. A previous study [246] demonstrated the anti- nociceptive activity following the oral administration of 200 mg/kg of NOH, which was possibly via the GABAergic system and anti-inflammatory activity due to the suppression of TNF-α and IL- 1β. In a rat model of PD, a daily dose of 50 mg of NOH was able to reverse rotenone-induced loss of dopaminergic neurons in the subcortical nuclei and striatum [247]. Also, this sesquiterpene alcohol ameliorated the decrease in the activity of antioxidant enzymes, decreased glial activation, and expression of IL-1β, IL-6, and TNF-α in midbrain tissues and COX-2 and iNOS in the striatum region. In the mouse hippocampus, a single dose of 25 mg/kg of NOH was found to be effective against oxidative stressACCEPTED in neuronal cells, comparable to ascorbic acid [248]. This was at least in part due to the increase in the protein levels of SOD and CAT. Furthermore, the sedative effects in terms of behavior in OFT were comparable to that of diazepam. NOH-loaded nanospheres were able to alleviate Trypanosoma evansi infection-induced memory impairment in terms of mice behavior [249]. In addition, the treatment was able to prevent oxidative stress and alterations in Na +, K+-ATPase and AChE activities caused by the infection. Using the same model for the mouse liver, heart and blood, the authors demonstrated that the use of NOH and NOH-loaded nanospheres resulted in similar effects, ameliorating the oxidative stress and inflammation via the inhibition of TNF α, IL-1β and TLR4 [250]. According to high throughput data, NOH inhibited LPS-induced production of TNF-α (with an activity value of 2.0 µM) and IL-12p40 (7.6 µM) (https://pubchem.ncbi.nlm.nih.gov/compound/5284507#ACCEPTED MANUSCRIPT). It also inhibits the activity of 15-LOX (12.6 µM). It showed antimalarial activity against Plasmodium falciparum trophozoite (0.12 µM) (https://pubchem.ncbi.nlm.nih.gov/compound/5356544#). Furthermore, it is an agonist (36 µM) operating in the AP-1 signaling pathway (https://pubchem.ncbi.nlm.nih.gov/compound/8888#). In summary, NOH is a sedative, anti-oxidant, bactericide and fungicide featuring broad-spectrum anti-parasitic, anti-nociceptive, anti-inflammatory, antidepressant, anxiolytic and anticancer properties. It has also shown great promise for the treatment of neurodegenerative diseases and protection against environmental stress in the kidney, liver, brain, blood and epithelia. Borneol Borneol (BOH, Fig. 4C) is found up to 14% in cannabis cultivars [251] and can be found in several species of Artemisia, Blumea and Kaempferia and Dryobalanops and EOs of many medicinal herbs, such as valerian. It has low toxicity: the oral LD 50 of BOH is 3000–5800 mg/kg in rodents and 3200 mg/kg in rabbits. BOH has been and is still used in traditional Chinese medicine formulations as a drug enhancer and to mitigate the effects of heart disease. Indeed, it may play a role in the control of heart disease because of its anticoagulant and fibrinolytic effects [252]. It also ameliorates ischemic stroke with an ED 50 value of 0.36 mg/kg [253]. This occurs via suppression of the expression of TNF-α, iNOS, IL-1β and COX-2. BOH is well known for its BBB permeability enhancing effect, reviewed in [254]. Mechanisms of BBB permeability involve the modulation of ABC transporters, including permeability glycoprotein P-gp, tight junction proteins, and the enhancement of vasodilatory neurotransmitters. For instance, it enhances the delivery of classical cancer drugs cisplatin [255] and PAC, restoring its efficacy against multidrug-resistant cancers [256].

Like camphor (which is the corresponding ketone of this alcohol), BOH is a potent TRPM8 agonist, evidenced by the increased TRPM8 influx Ca 2+ currents at M concentrations in whole cell assays [257]. Moreover, it antagonized TRPA1 receptor, asMANUSCRIPT camphor does, but with an IC 50 of 0.3mM in whole cell assays [258]. The analgesic efficacy of topical BOH was found in a randomized, double- blind, placebo-controlled clinical trial with 122 patients experiencing postoperative pain [259]. Using mouse models of pain, it was found that the analgesic effect was mediated independently from TRPA1- or GABA A-receptors. It was found that the TRPM8 channel was the molecular target of BOH, which evoked downstream glutamatergic mechanisms in the spinal cord, while another study [260] found that hyperalgesia was alleviated by the enhancement of GABAergic transmission in the spinal cord. The analgesic effects on mechanical hyperalgesia and neuropathic pain were gained in mice following the oral administration of 125 mg/kg or intrathecal injection of 15 g of (+)-BOH. Indeed, yet another study [261] found that both (+)-BOH and (-)-BOH were powerful positive modulators of GABA A receptors, but not at the benzodiazepine binding site. It potentiated the action of low concentrations of GABA by more than 1000%. The efficacy was at least equivalent to that of the anesthetic etomidate and much greater than that of diazepam or 5-α- pregnan-3α-ol-20-one [261]. In addition, BOH inhibited nicotinic acetylcholine receptors and the effect was more potent than that of lidocaine, suggesting potentially strong local anesthetic properties [262]. TheACCEPTED anti-nociceptive properties of BOH (5 mg/kg) have been demonstrated by a variety of mouse models of pain (acetic acid, formalin, hot plate, and grip strength tests) [263]. The rotarod test revealed no defects in motor coordination, implicating that the behavior was truly due to the anti-nociceptive effects. Finally, the dose of 50 mg/kg was similar to that of 20 mg/kg of indomethacin on the acetic-acid-induced writhing test and it was comparable to morphine in a hot plate test [264]. The tests were controlled with rotarod and grip strength tests.

BOH (1.0 mg/kg) exerted neuroprotection and promoted the recovery of neurological and sensimotor functions by diminishing the loss of dendritic spines after permanent ischemic stroke [265]. Furthermore, BOH significantly decreased the infarct volume by a reduction in the expression levels of iNOS and TNF-ACCEPTEDα. In a rat MANUSCRIPTmodel of global cerebral I/R, BOH improved the ultrastructure of neurons and intracellular calcium content in both the cortex and hippocampus and reduced apoptosis by decreasing the expression of p53 and caspase-3 [266]. BOH increased neuron autophagy in the hippocampus, likely by the regulation of Unc-51 like autophagy activating kinase (ULK1), a kinase involved particularly in autophagy. In another study [267], BOH (0.003 µM) reduced neuronal injury, nuclear condensation, ROS generation, iNOS expression and a loss of mitochondrial membrane potential, which were first induced by oxygen-glucose deprivation/reperfusion. Moreover, BOH inhibited caspase-related apoptotic signaling pathway, release of pro-inflammatory factors, I κBα degradation and blocked NF-κB p65 nuclear translocation. Moreover, (-) and (+) BOH treatment (100 µM) protected SH-SY5Y cells against A β- induced toxicity [268]. It reduced ROS generation by up-regulating the expression of HO-1 and Nrf2, while it reduced apoptosis by altering Bcl-2/Bax ratio. In vitro , in RAW 264.7 macrophages, BOH reversed LPS-induced increase in the levels of inflammatory factors including NO, TNF-α and IL-6, while in vivo , it lowered the endotoxic fever induced by LPS in rats [269]. In LPS- induced acute lung injury mouse model, BOH (20 mg/kg) mitigated pulmonary inflammation in terms of inflammatory infiltration, histopathological changes, cytokine production and pulmonary edema [270]. Furthermore, BOH significantly reduced the phosphorylation of NF-κB/P65, I κBa, p38, JNK, and ERK, suggesting that BOH suppressed inflammation through inhibition of the NF- κB and MAPKs signaling pathways. In a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis, BOH (0.09% in diet) notably decreased IL-1beta and IL-6 mRNA levels [271]. In a mouse model of peritonitis, BOH (25mg/kg) reduced leukocyte migration induced by the inflammatory agent carrageenan [264]. The efficiency was comparable to that of aspirin (200 mg/kg).

The oral administration of BOH (25 mg/kg/day) for four weeks significantly attenuated fasting blood glucose, glycated hemoglobin, urea, alanine aminotransferase, aspartate aminotransferase, MDA concentration and the atherogenic index in diabMANUSCRIPTetic rats [272]. Furthermore, BOH reversed the increase in body weight and improved plasma insulin, cellular contents of glycogen and antioxidant enzymes and GSH. In an NO-deficient animal model of hypertension, BOH (50 mg/kg) reversed increased levels of the structural modification in proteins and triglycerides and improved liver health in terms of alterations in proteins, lipids, and glycogen in the liver [273]. In a cell model of oral submucous fibrosis, BOH possessed anti-fibrosis activity due to its inhibitory effects on fibroblasts' mitosis, collagen and TIMP-1 production [272]. This indicates that BOH could be useful in the treatment of Crohn’s disease. On the other hand, BOH was found to improve wound healing in rats by reducing MPO activity and increasing the collagen production [274]. Furthermore, BOH showed synergistic effects with several drugs independent from its penetration enhancement feature. These included G2/M arrest by curcumin [275] and bisdemethoxycurcumin [276]. It fortified the effect of edaravone against DSS-induced colitis by polarizing macrophages via the JAK2-STAT3 signaling pathway [277]. It induced apoptosis together with curcumin in human melanoma cells [278], and exhibited DNA protection in HepG2 cells and on plasmid DNA against Fe 2+ -induced damage [279]. In the qHTS assay, BOH targeted H2A histone family member X (H2AX) with an activityACCEPTED value of 1.6 µM (https://pubchem.ncbi.nlm.nih.gov/compound/1201518#). Antipyretic, anti-nociceptive, antioxidant, anti-inflammatory, neuroprotective and DNA preserving actions can be attributed to BOH, which also improves the efficiency of other drugs either by its permeability-enhancing properties or independently from that.

α-Bisabolol

Bisabolol (BISA, Fig. 4D) is widely used in the cosmetics industry. BISA was sometimes the second most abundant terpene (17%) out of the 200 analyzed samples of cannabis [13] and is present in hops (at levels of up to 16%) [3]. In addition to cannabis and hops, this unsaturated monocyclic sesquiterpene alcohol – also known as levomenol – is found in EOs from the candeia tree, salvia, Plinia, Eremanthus andACCEPTED cat's claw . It MANUSCRIPT is the main constituent in some Eos; for instance, more than 80% of the EO from Myoporum crassifolium (a figwort from the Pacific islands) is BISA. Yet another rich source of BISA is chamomile oil, which is mainly composed of (-)-α-BISA [280]. BISA is safe at a daily dose of 200 mg/kg for four weeks via dermal administration on rats without any adverse effects. The LD 50 for acute toxicity for rats and mice is around 15 ml/kg. It results in notable, in the order of 10-100 times, enhancement in the permeability of other drugs. Furthermore, it is anti-mutagenic in bacteria, mammalian cells and drosophila [281, 282]. The BH3-interacting-domain death agonist (BID) is a pro-apoptotic protein belonging to the Bcl-2 family. BISA may induce apoptosis by direct interaction with BID. Furthermore, BISA also interacts with the kisspeptin receptor 1, which is associated with tumor mobility and invasiveness. These actions of BISA, especially against pancreatic cancer, have been recently reviewed [283]. In addition to pancreatic cancer, BISA was effective against breast cancer in HER-2/neu transgenic mice model [284]. Therein, 10 mg/mouse of BISA downregulated fibroblast growth factors FGF (involved in angiogenesis) and anti-apoptotic survivin (Birc5). Moreover, BISA was effective against leukemia, including Imatinib-resistant cases, with IC 50 of 14 M in vitro [285]. In another study [286], glioma cells, which were again treated with BISA, showed decreased viability, which coincided with the increase of ecto-5'-NT/CD73 activity. However, this was reversed following pretreatment with an A 3 antagonist, suggesting that the A3 receptor is involved in the anti-proliferative effect of BISA. Besides, BISA also exerted its anticancer feature by inducing pores in mitochondria and lysosomes [287]. BISA was able to activate the pro-apoptotic caspases-8,-9,-3 and promoted expression of Fas, as well down-regulating the expression of the anti-apoptotic protein Bcl-2 [288]. The translocation of Bax, Bak and Bid suggested the involvement of the mitochondrial pathway. Again, apoptosis of endothelial cells was induced by BISA, as evidenced by the release of cytochrome c from the mitochondria, a reduction of the Bcl-2/Bax ratio and the activation of caspase 3 [289]. In turn, at a non-apoptotic concentration (0.25 M), BISA showed a differentiating effect, resulting in growth inhibition, a reduction of invasiveness and tubule stabilization. The results also suggested that BISA could be effective inMANUSCRIPT reducing angiogenesis in a variety of tumors. Novel derivatives of BISA also showed anticancer properties: they prevented the progression of pancreatic cancer via the inhibition of AKT in vitro [290]. Finally, it is a potential adjuvant in formulations containing 5-aminolevulinic acid, indicating effectiveness for the photodynamic therapy treatment of oral cancers [291].

In contrary to the pro-apoptotic effects, BISA (5 µg/ml) was found to be anti-apoptotic and antiamyloidogenic against A β25-35 -induced neurotoxicity in PC12 cells [292]. The treatment with BISA caused a reduction in the levels of A β-induced chromosomal damage and apoptosis, similar to the standard drug donepezil (50 µg/ml). Furthermore, in a PD-model of Drosophila , BISA – administered as a food supplement at a concentration of 5 M – was effective against rotenone- induced mortality, locomotor deficits and a high level of oxidative stress [293]. BISA (7.7–31 g/ml) suppressed the ROS production induced by either corpusculates of Candida albicans or N- formyl-methionyl-leucyl-phenylalanine in a concentration-dependent manner [294]. Moreover, a previous study [295] showed that BISA was able to decrease oxidative stress and inflammatory events associated withACCEPTED the gastric lesions induced by ethanol. Furthermore, at 100 mg/kg it was protective against indomethacin-induced ulcers by increasing the bioavailability of gastric sulfhydryl groups and altering the activity of MDA, MPO, SOD and CAT and the nitrite amount in favorable manners [296]. Likewise, BISA (100 mg/kg) was nephroprotective in an I/R model of acute kidney injury; BISA was able to reverse I/R-induced alterations in diuresis, water intake, urinary osmolality, plasmatic creatinine, urea and uric acid, creatinine clearance, proteinuria and microalbuminuria [297]. Moreover, it reduced KIM-1 levels and restored favorable TBARS and GSH levels in kidney tissue. Also, BISA (30 mg/kg) was able to decrease LPS-induced inflammation in the lung tissue by altering MAPK signaling and the phosphorylation levels of ERK1/2, JNK, and p38 [298]. Another study [299] indicated that BISA, in part, exerts its anti- inflammatory effects by downregulatingACCEPTED the expressi MANUSCRIPTon of iNOS and COX-2 genes through the inhibition of NF-κB and AP-1 (ERK and p38) signaling. In vitro and in vivo models of skin inflammation, induced by LPS or 12-O-tetradecanoyl-phorbol-13-acetate (TPA), demonstrated that BISA can decrease the production of the pro-inflammatory cytokines TNF-α and IL-6 [300]. In a recent clinical trial, BISA ameliorated atopic skin [301]. Another clinical trial found it useful for vascular leg ulcer treatment [302].

BISA exhibits anti-nociceptive effects in vivo with a single dose of 25 mg/kg; it was especially effective in pain related to inflammation [303]. It also suppressed the inflammation in relation to leukocyte migration, protein extravasations, the amount of TNF-α and neutrophil degranulation. Again, a 25 mg/kg (i.p.) dose of this monocyclic terpene alcohol significantly reduced nociceptive behavior in various tests, including both phases of the formalin test [304]. It was more effective than the whole fraction of EO of Stachys lavandulifolia (56.4% of BISA). Pretreatment with BISA- nanocapsules (200mg/mL) was also effective against corneal nociception, which was induced by topical application of 5M of NaCl [305]. On the other hand, a molecular docking study [306] indicated that BISA is not a TRPV1 agonist (note: both agonist and antagonist may alleviate pain) but may induce a modulatory influence on other vanilloid receptors. The study further suggested that the anti-nociceptive effects are not mediated through binding at α2-adrenoceptors, since yohimbine did not reverse it. The anti-nociceptive effects of the oral (100 mg/kg) or topical administration (50 mg/mL) of BISA were achieved in terms of changes in behavior in various rodent models of pain, including formalin- or cinnamaldehyde-induced orofacial pain [307]. With a variety of tests, the authors found that the effect may be – at least in part – effective through TRPA1 antagonism. In addition, BISA (0.5 mM) decreased peripheral nerve excitability in terms of the compound action potential characteristics [308]. Thus, the effect of BISA might be caused by an irreversible blockade of voltage-dependent sodium channels. Of particular note is the fact that this does not exclude the involvement of TRPV1 currents. Interestingly, BISA also inhibited ACh- induced α7 receptor-mediated currents (IC 50 3.1 M) [309]. It is a little bit surprising that the inhibition of the α7-nAChRs agonism would provokeMANUSCRIPT the seen anti-nociceptive and anti- inflammatory actions. Nevertheless, in EPM, BISA (1 mg/kg) showed anxiolytic-like and sedative properties with involvement of GABAergic but not serotoninergic systems [310]. Of particular note, these sedative properties may party explain the anti-nociceptive like behavior seen in previously- mentioned behavioral studies. Taken together, the anti-nociceptive effect of BISA is likely to be mediated by a variety of mechanisms, but the exact mechanisms still need to be elucidated. Finally, BISA is a vasodilator [311] and relaxant of smooth muscles in the trachea [312]. This may be mediated through the inhibition of voltage-dependent Ca 2+ channels.

BISA is a broad-spectrum anti-parasitic drug. It shows effectiveness towards Acanthamoeba castellani in vitro [313], Trypanosoma evansi in vitro and in vivo [314] and Leishmania tropica in a hamster model [315]. Furthermore, it powerfully inhibited Aspergillus fumigatus Af239 growth via microsomal ∆24-sterol methyltransferase – a crucial enzyme in the ergosterol biosynthetic pathway [316]. This makes it potential fungicidal agent against other fungi too. Indeed, α-BISA showed antifungal activity against Microsporum gypseum, Microsporum canis, Trichophyton violaceum, Nannizzia cajetani,ACCEPTED Trichophyton mentagrophytes, Epidermophyton floccosum, Arthroderma gypseum, Trichophyton rubrum and Trichophyton tonsurans [317]. The results of this study showed that BISA presented a modulatory synergistic effect for some antibiotics such as gentamicin. It is also effective against multidrug-resistant bacteria [318]. In addition, it efficiently inhibited spore germination.

In short, BISA exhibits anticancer and anti-tumor activities, mainly via pro-apoptotic mechanisms. In contrast, its anti-apoptotic function may protect healthy cells and be neuroprotective. Moreover, it participates in gastro- and nephroprotection, mainly via its anti-inflammatory mechanisms, and is anti-nociceptive, likely via a number of mechanisms. Finally, it is anxiolytic and a broad-spectrum antibiotic. ACCEPTED MANUSCRIPT

Bisabolenes α-, β- and γ-bisabolene (Fig. 4E) are found – in addition to in cannabis and hops – in a wide variety of plants including cubeb, lemon and oregano. Various natural derivatives of bisabolenes can function as pheromones in a variety of insects e.g. in fruit flies. They are also produced by several fungi, but their biological role in fungi remains unknown. β-Bisabolene has a balsamic odor and is approved in Europe as a food additive. β- and γ-bisabolenes have so far been found to possess anticancer properties. In a previous study [319], γ-bisabolene (10 µM) showed anti-proliferative and apoptosis-inducing features in neuroblastoma cells. Pathways included the CK2 α-p53 pathway in mitochondria-mediated apoptosis, and the phosphorylation of ERK1/2, protein phosphatases 1 (PP1), and p53. γ-Bisabolene also decreased the phosphorylation of histone deacetylase 2 (HDAC2), and p53 was found to be acetylated, which enhances the expression of p53-regulated apoptotic genes [320]. Besides, β-bisabolene (1.12 g/kg i.p. twice in week for 2 weeks) showed anti-tumor properties; it was effective in reducing the growth of transplanted 4T1 mammary tumors in vivo by inducing apoptosis [321]. In seizure models in zebrafish (30 min 23 µM) and mouse, bisabolene inhibited PTZ-induced seizures [322]. However, the neuromodulatory action remains unknown. Moreover, β-bisabolone showed a synergistic bactericidal activity with ampicillin against resistant Staphylococcus aureus [323]. In summary, bisabolenes may show some anticancer, antitumor, anti-convulsive and anti-bacterial features.

β-elemene β-elemene (ELE, Fig. 5A) is found in wild hops from Lithuania at levels of up to 14% [3] and in notable amounts in the medical cannabis cultivar 'bedropuur' [324]. It contributes to the floral aromas of many plants and is used as a pheromone by some insects. It is also found in the Chinese medical herb Rhizoma zedoariae , which has been used for its alleged properties to improve blood circulation and alleviate pain. MANUSCRIPT The efficacy of ELE in cancer treatments was reviewed in 2013 [325] and 2017 [326]. In 2013, a meta-analysis of thirty-eight trials revealed that chemotherapy supplemented with ELE was significantly associated with an improved response in the treatment of various tumors and leucopenia when compared with chemotherapy alone [325]. However, these pooled reports did not show an improved survival rate of ELE plus chemotherapy in comparison to chemotherapy alone. A recent (2017) meta-analysis, which included eleven randomized controlled trials (765 patients), suggested that ELE (injections) might enhance the effectiveness of radiotherapy in cancer treatments [327]. Recent studies (reviewed in 2017 in [326]) have shown that ELE possesses an anti-proliferative effect on cancer cells by promoting apoptosis, cell cycle arrest and necrosis. Furthermore, it was also able to induce protective autophagy in some cancerous cell lines and was less cytotoxic to normal cells in comparison to other chemotherapeutic agents. ELE may be effective against cancer cells of multiple origins, including endocrine, urinary, reproductive, digestive, immune, respiratory, nervous and integumentary systems. Because ELE is non-toxic towards normal cells, it is highly promising for the treatment of cancer [328]. ELE suppresses proliferative signaling,ACCEPTED such as via the MAPK and PI3K/Akt/mTOR pathways, induces cell death, up-regulates growth suppressors, deactivates invasion and metastasis, interacts with replicative immortality and attenuates angiogenesis. ELE is also a potential target for the drug design, for instance, an isopropanolamine derivate improved its anticancer profile and aqueous solubility [329], whereas Furoxan-based NO-donating ELE hybrids were found to improve the anticancer efficacy and were more anti-proliferative against three cancer cell lines when compared to the parent compound ELE [330]. IC 50 values of the derivatives were in the nM range. The mechanisms were G2 cell cycle arrest and the induction of apoptosis by deactivation of the PI3K/Akt pathway. It also suppressed tumor growth in a xenograft mouse model at a dose of 60 mg/kg.

Recent studies suggest that ELE isA protectiveCCEPTED again MANUSCRIPTst atherosclerosis in vivo and in vitro . In the early development of atherosclerotic lesions, monocytes are recruited by active endothelial cells. This makes the inhibition of monocyte-endothelial cell interactions a potential target in the prevention of atherosclerosis. In vitro , ELE inhibited monocyte adhesion and transendothelial migration through the suppression of the NF-κB-dependent expression of cell adhesion molecules and through prevention of the activation of the MAPK signaling pathway [331]. Also, it protected the endothelial cells from hydrogen peroxide-induced cell injury and decreased the generation of ROS. In a rabbit model of atherosclerosis, the placebo group was fed an atherogenic diet prior to balloon angioplasty-induced endothelial injury, which showed an increase in the thickness of the atherosclerosis lesion and increased levels of TC, TG, and LDL-C [332]. ELE treatment, however, reversed these effects and reduced the infiltration of macrophages. In vitro , this aliphatic monocyclic sesquiterpene (0.1 mM) decreased the levels of TNF-α and IL-6. Furthermore, ELE can increase the survival rate of human umbilical vein endothelial cells in vitro ; this is likely due to its capability to decrease the MDA content and increase TOC, SOD, CAT and GPx activities [333]. Moreover, in a flow culture, ELE reduced the migration of vascular smooth muscle cells, but not endothelial cell migration. In vivo , it inhibited smooth muscle cell proliferation and migration and thus, neointima formation after vascular injury. In ApoE -/- mice, ELE inhibited the atherosclerotic lesion size and increased the stability of plaques by alleviating vascular oxidative stress and preventing pro-inflammatory cytokine production [334]. Last, ELE-coated stents promoted endothelialization after stent implantation, while it inhibited the proliferation of vascular smooth muscle cells [335]. A case study [336] demonstrated that the injection of ELE during bronchoscopy resulted in the inhibition of the proliferation of fibroblasts and in lower airway granulation; thus, the results suggested a new way to treat airway stenosis. In addition, in a clinical trial [337], all patients with diagnosed chylothorax experienced a resolution of symptoms with 1-5 injections of ELE to the pleural cavity. In one study [338], which used a model of liver fibrosis in rats, ELE was administered via i.p. injections into rats for 8 weeksMANUSCRIPT (0.1 ml/100 g bodyweight per day) and was found to downregulate the CCl 4-induced levels of plasma endotoxins, serum TNF-α, and hepatic CD14 expression. This alleviated the development of the hepatic fibrosis. In a model of MS, the treatment of C57 mice with ELE significantly delayed the onset of autoimmune encephalomyelitis by improving Th17 and Treg balance [339]. The treatment drastically reduced the IL-17, IL-6, IL- 23 levels and RAR-related orphan receptor γ t (ROR γt) expression and upregulated the Forkhead box P3 (Foxp3) expression in both the periphery and inflamed spinal cord. In macrophage cells (RAW264.7), the expression of IL-6, TNF-α and IL-1β, induced by LPS, was significantly suppressed by a treatment with ELE (10 µg/mL) via the inactivation of β-catenin [340]. Furthermore, ELE fought effectively against LPS-induced expression of iNOS and IL-10, thus intensifying the before-mentioned anti-inflammatory effects.

In summary, ELE holds potential for the treatment of cancer, atherosclerosis, MS, airway and liver fibrosis and other diseases in which excessive ROS production and inflammation play roles. Fenchone ACCEPTED In addition to cannabis and hops, fenchone (Fig. 4B) is found in fennel, olive leaves, flowering parts of Lavandula stoechas while its EO can contain 30% of fenchone. Fenchone is used as a flavoring agent in foods and in perfumery. Traditionally fennel products are used for the improvement of food digestion and the prevention of flatulence. Biological effects of fenchone per se have so far been limited to two studies. First, fenchone was able to inhibit carcinoma progression in vivo by inducing cell cycle arrest in the S phase [341]. Furthermore, 60 mg/kg fenchone reduced tumor volume and mass and increased the survival rate of treated animals. Second, fenchone was found to augment wound healing in rats [342]. It also showed anti-inflammatory and antimicrobial activities and increased collagen synthesis. Lavender EO, containing fenchone (30%), α-pinene (23%), Camphor (16%), Camphene (7.8%), significantlyACCEPTED protected MANUSCRIPT against the increase of blood glucose and increased the antioxidant enzyme activities, and thus protected against oxidative stress in alloxaninduced diabetes in rats [343].

Fenchone derivatives exhibit antimicrobial features. Fenchone and fenchyl alcohol significantly reduced C. albicans biofilm formation [344]. Notably, fenchyl alcohol at a concentration of 0.01% clearly inhibited hyphal formation by downregulating biofilm-related genes. Furthermore, fenchyl alcohol reduced C. albicans virulence in a Caenorhabditis elegans nematode model, whereas the N- acyl derivative of fenchone was found to be effective against Mycobacterium tuberculosis H37Rv in vitro [345]. Moreover, derivatives bearing a sulfonamide functional group were found to have comparable activity to ethambutol and possess lower cytotoxicity. Aminoethyl substituted 2-endo- fenchol was studied as a scaffold for the synthesis of a series of 31 amide structures and in vitro , some of these presented promising antimicrobial activity with concentrations of 0.2 g/ml with low cytotoxicity [346].

Pulegone In addition to Cannabaceae , pulegone (PUL, Fig. 5C) is widely present in the Mentha genus e.g. in Mentha pulegium, from which PUL gets its name, and in Calamintha nepeta (lesser calamint) oil, which contains PUL up to 85% [347]. It is also found in Agastache formosanum oil and rosemary for instance. This monoterpene ketone is used as a flavoring agent and in perfumery. It is claimed to possess antispasmodic, emmenagogue, diaphoretic, diuretic and CNS strengthening properties. The biological activities of the oil includes but is not limited to antimicrobial, antioxidant and anti- inflammatory, anti-ulcer and insecticidal properties, while PUL per se shows antimicrobial, anti- parasitic, anti-inflammatory, spasmolytic, antidiarrheal, central depressant, anti-nociceptive, antipyretic and antihistaminic features. Indeed, PUL is a potent histamine receptor 1 antagonist with similar action to mepyramine and dexchlorpheniramine [348]. This could also explain the spasmolytic activity. MANUSCRIPT Ambulation in ICR mice was promoted by PUL intake [349]. When dopamine receptor antagonists were co-administered with PUL, the effect of PUL on ambulation was diminished. A pretreatment with the dopamine depletor reserpine produced no subsequent sensitivity to the effect of PUL. These results suggest that the dopaminergic system is involved in the ambulation. Conversely, in another study [350], PUL was found to cause a notable decrease in the ambulation of mice. Besides, it increased pentobarbital-induced sleeping time, suggesting that it is a depressant in CNS. Interestingly, it also augmented the latency of PTZ-induced convulsion. The same study yet showed that PUL is an anti-nociceptive molecule and its action was not blocked by naloxone – a non- selective opioid receptor antagonist. In another study [351], employing mouse behavioral tests, PUL was found anxiolytic and psychostimulant. Only Verapamil, a drug that blocks voltage-dependent calcium channels, decreased the PUL-induced psychostimulation. Its anxiolytic-like actions were not mediated through the benzodiazepine site of the GABA A receptor. However, PUL may have adverse effects on mammalian heart function since it may have an effect on Ca 2+ homeostasis and causes negative inotropism in the mammalian myocardium [352]. Moreover, the mainACCEPTED constituents of the C. nepeta oil (limonene, menthone, pulegone, menthol) were tested against variety of microorganisms; while PUL showed antimicrobial activity, particularly against all of the Salmonella species, limonene and menthone were inactive in this respect [353]. It also inhibited the growth of Aspergillus flavus at 0.8 mg/mL (https://pubchem.ncbi.nlm.nih.gov/compound/442495#). The sub-chronic toxicity of PUL was investigated in rats for 28 days [354]. The daily exposure to the dose of 80 mg/kg of PUL induced atonia, decreased blood creatinine content and terminal body weight, and caused histopathological changes in the liver and in the white matter of cerebellum. With higher doses, in long-term studies with rodents, PUL showed no carcinogenic properties, but increased the incidence of various tumors and nephropathy in males as well other non-neoplastic lesions in the liver [355]. Taken together, even though PUL exhibits a varietyA CCEPTEDof beneficial MANUSCRIPTproperties, it also exhibits adverse effects for heart, renal and liver functions, and may therefore not be suitable as a pharmaceutical in high doses for longer term use. α-Phellandrene α-Phellandrene ( α-PA, Fig. 5D), in addition to C. sativa and H. lupulus , is found also in Eucalyptus phellandra , from which it got its name. α-PA has also been isolated from the oil of water fennel and Canada balsam oil and Schinus terebinthifolius (rose pepper) fruits. The phellandrenes are used in fragrances and are approved as flavoring agents in the EU. It has been reported that α-PA modulates immune responses in mice. A previous study [356] demonstrated that α-PA (25 mg/kg) increased the phagocytosis of macrophages from blood samples, promoted the natural killer cell activity of splenocytes and increased B- and T-cell proliferation. In another report [357], α-PA induced autophagy in human liver tumor cells (J5) by regulating mTOR and LC3-II expression, p53 signaling and NF-κB activation. In addition, α-PA (50 mg/kg) was able to prevent carrageenan-induced neutrophil accumulation, inhibit leukocyte rolling adhesion and the production of the pro-inflammatory cytokines TNF-α and IL-6 in vivo [358]. These results point out that α-PA is an anti-inflammatory agent acting via the modulation of neutrophil migration and mast cell stabilization. In mouse leukemia cells (WEHI-3), α-PA induced the production of ROS, diminished mitochondrial membrane potential and released cytochrome c, apoptosis-inducing factor (AIF) and endo G from the mitochondria [359]. These together led to G0/G1 arrest and apoptosis of these cancer cells. α-PA (3.1 mg/kg) exhibited anti-hyperalgesic effects against mechanical and cold hyperalgesia, and was anti-depressive in SNI rats [360]. Pretreatments with naloxone, glibenclamide, l-arginine, atropine or yohimbine reversed the anti-nociceptive effect of α-PA, implicating that the mechanisms of action involve the glutamatergic, opioid, nitrergic, cholinergic and adrenergic systems. Oral administration for up to 15 days of α-PA (10 mg/kg) significantly obtunded hyperalgesia in a spared nerve injury model of neuropathic pain and inhibite MANUSCRIPTd sensitivity to a cold stimulus [138]. In addition, α-PA is a potential fungicide. It was effective against (plant pathogen) Penicillium cyclopium by disrupting the integrity of the fungal cell membrane [361]. Thus, it may also be effective against some human pathogens. In addition, its metabolite 5-p-menthene-1,2-diol exhibited antibacterial and anti-candidal properties, comparable to standard antimicrobial agents [362]. Thus, it may be useful in antibiotic drug design in the future. Lastly, qHTS assays suggest that α-PA could be an antagonist (~50 µM) of the farnesoid-X-receptor (FXR) and an agonist (~50 µM) of the antioxidant response element (ARE) signaling pathway (https://pubchem.ncbi.nlm.nih.gov/compound/442482#). Taken together, α-PA is a pro-apoptotic, immunomodulatory, anti-inflammatory, anti-nociceptive, anti-depressive and anti-microbial terpene. β-eudesmol In addition to cannabis and hops [363], β-eudesmol ( β-EOH, Fig. 5E) is present in Atractylodes lancea and ZingiberACCEPTED (gingers), for example. A. lancea is used in traditional Chinese medicine to ease gastrointestinal problems, eliminate pathogens and treat headaches, body aches, fever and blocked nasal passages. β-EOH exhibits pro-apoptotic, anti-proliferative and antitumor properties. β-EOH inhibited the proliferation of human lung (A549) and colon (HT29 and Caco-2) cancer cells in vitro [364]. It also inhibited the cell adhesion and migration of A549 and HT29 cells. In a human cholangiocarcinoma xenograft mouse model, β-EOH (100 mg/kg for 30 days) reduced tumor size by 92% and lung metastasis by 95% [365]. The survival time of the xenograft mice was prolonged by 64% compared with untreated controls. In HL60 cells, β-EOH induced apoptosis by the cleavage of caspase-3, caspase-9 and poly (ADP-ribose) polymerase, and by the downregulation of Bcl-2 expression [366]. Involvement of the mitochondria was evidenced by the release of cytochrome c and decreased membrane potentialACCEPTED and the activation MANUSCRIPT c-Jun N-terminal kinases (JNK) in β-EOH treated cells . Moreover, β-EOH inhibited the growth of several cancer cell lines with IC 50 values ranging from 17 to 25 g/ml [367]. Again, increased caspase-3 activation promoting mitochondria mediated apoptosis was found.

β-EOH showed an anti-inflammatory action via suppression of the calcium ionophore A23187- induced caspase-1 activation in mast cells [368]. In addition, it inhibited the production of IL-6 and suppressed the activation of p38 MAPK, NF-κB and caspase-1, and the expression of receptor- interacting protein-2. It is known that stem cell factor (SCF) participates in allergic reactions through the differentiation and migration of mast cells. The treatment of rat peritoneal mast cells (RPMCs) with β-EOH (2 µM) markedly suppressed SCF-induced mast cell migration and morphological alterations in a concentration-dependent manner [369]. β-EOH also reduced SCF induced F-actin formation, the activation of Fyn kinase, Rac1 GTPase and p38 MAPK, and the expression of TNF-α and intercellular adhesion molecule-1. Also, in PC-12 cells, it induced neurite outgrowth in 100 M concentrations with the involvement of phosphoinositide-specific phospholipase C (PI-PLC) and MAPK [370]. Taken together, β-EOH may have a regulatory role via the MAPKs in mast cell-mediated inflammatory and allergic diseases and neuronal differentiation. It also inhibited superoxide production in A549 cells [364].

β-EOH (50 mg/kg) prevented convulsions and lethality induced by maximal electroshock or an organophosphate [371]. When the CA1 pyramidal layer of hippocampal slices was studied, β-EOH reduced the high potassium (8.5 M)-induced electrographic seizure activity. It was also able to reverse the neuromuscular failure, which was confirmed by another study [372] in which β-EOH completely blocked the neuromuscular junction at 200 M concentration. With the patch-clamp technique, it was shown that β-EOH blocked the nACh channels in both the open and closed conformations, and accelerated the desensitization of nAChR. Thus, β-EOH could be useful as a muscle relaxant in anesthesia. A previous report [373] demonstrated that the stimulation of TRPA1 by β-EOH (0.14 ppb in drinking water) increasedMANUSCRIPT appetite and weight gain in vivo . β-EOH significantly elevated plasma levels of ghrelin – a peptide hormone, which is known to control appetite. Also, gastric vagal nerve activity (GVNA) was increased, which was eliminated by treatment with a TRPA1 inhibitor (HC-030031). In vitro , it activated human TRPA1 with an EC 50 value of 33 ± 0.38 M. Besides, β-EOH has been reported to stimulate gastric emptying and small intestinal motility by inhibition of the dopamine D2 and 5HT 3 receptors [374].

In conclusion, β-EOH is a molecule with anticancer, anti-inflammatory and anticonvulsive properties, and can stimulate neurite outgrowth, appetite and gastric emptying at low concentrations.

Other terpenes found in cannabis and hops Isopulegol (Fig. 6A), which differs from menthol only by a single extra double bond, presented depressant- and anxiolytic-like effects when it was administered to male mice with the i.p. dose of 25 mg/kg [375]. The effect was similar to that of diazepam (1 mg/kg), but without the loss in general motor activityACCEPTED in the OFT. However, the overall sedative effect was likely due to a similar mechanism of action to that of benzodiazepine i.e. the positive modulation on GABAergic receptors. This was supported by another study [376]. In the study, isopulegol (100 mg/kg) significantly protected animals against PTZ-induced convulsions and related mortality. It also significantly prevented the increase in lipid peroxidation and reversed the PTZ-induced loss of CAT activity and GSH in the hippocampus of mice. Moreover, isopulegol presents significant gastroprotective effects in both ethanol- and indomethacin-induced ulcer models [377]. The results showed that the effects appear to be mediated, at least in part, by endogenous prostaglandins and K(ATP) channel opening. Furthermore, isopulegol restored GSH levels. Lastly, isopulegol derivatives have been created with different properties, especially to enhance the transdermal penetration [378]. ACCEPTED MANUSCRIPT

Isoborneol (Fig. 6B), a geometric isomer of borneol, protected SH-SY5Y neuroblasts against oxidopamine-induced apoptosis at low µM concentrations [379]. Oxidopamine is neurotoxic research chemical, which selectively destroys dopaminergic and noradrenergic neurons in the brain. Thus, isoborneol could be an ameliorative supplement for the treatment of PD. It is also a potent inhibitor of herpes simplex virus type 1 [380]. Isoborneol and its acetate ester were effective inhibitors of the motility of mice after inhalation; this sedative effect was mediated by positive modulation of the GABA A receptor [261]. However, borneol produced a stronger effect.

The efficacy of sabinene (Fig. 6C), a major constituent of carrot seed oil, was studied in silico against the drug target L-asparaginase [381]. This bicyclic monoterpene yielded the lowest the docking score in comparison to ciprofloxacin, eucalyptol and cinnamaldehyde, suggesting that sabinene could be a safe alternative in the treatments of infections e.g. caused by multidrug-resistant Salmonella . Moreover, sabinene (0.6 µL/mL) demonstrated a strong anti-inflammatory activity through the iNOS inhibition [382]. Another bicyclic sesquiterpene that includes a rare cyclopropane ring, 3-carene (Fig. 6D), and its pyrazole derivatives, may act in cell differentiation and maturation, and exhibit beneficial effects on bone health. First, it was supported by an in silico study [383], in which Sphingosine-1-phosphate receptor 1 (S1P1) agonism was found. Secondly, at a low concentration such as 5 M, it significantly stimulated the activity and expression of alkaline phosphatase, an early phase marker of osteoblastic differentiation, in mouse osteoblastic MC3T3- E1 subclone 4 cells [384]. The stimulatory effect of 3-carene on the mineralization might be associated with its potential to induce the protein expression/activation of the MAPKs, osteopontin and type I collagen. If the effects are mediated through S1PR1 signaling, as previously suggested in an in silico study, it may also have a role in endothelial cell migration and vascular maturation. S1PR1 is known to be involved in tumor angiogenesis and typical lesions in MS. These facts together make 3-carene and its derivatives attractive S1PR1 agonist/antagonist. Furthermore, along with α-pinene, 3-carene was the most potent inhibitorMANUSCRIPT of AChE out of 17 screened bicyclic monoterpenoids [385]. Of particular note, AChE inhibitors are used to treat neurodegenerative conditions like AD, Lewy Body Dementia, PD and schizophrenia. Last, it showed antispasmodic activity against oxytocin-induced contraction in the Wistar rat uterus at concentration of 2.2 µg/ml (https://pubchem.ncbi.nlm.nih.gov/compound/26049#). -cadinene (Fig. 6E) is a potent larvacide against common malaria, dengue and filiriasis vectors [386]. In addition, it and its derivatives were found to be effective fungicides against various infectious fungi [387]. In addition, it exhibited high antimicrobial activity against Streptococcus pneumonia [388] . Finally, it inhibited the growth of ovarian cancer cells via the induction of caspase-dependent apoptosis and cell cycle arrest in the G0/G1 phase in a dose-dependent manner [389]. Selinene (Fig. 7A), which is present in Callicarpa macrophylla (57%) and in cannabis in moderate amounts (up to 9%) [390], exhibited strong anti-inflammatory, analgesic, and antipyretic activity, comparable to those of the standard drugs: ibuprofen, paracetamol and indomethacin [391]. Valencene (Fig. 7B), a close molecular relative to cadinene and selinene, possesses various biological effects such as anti-allergic and anti-melanogenetic activity. In addition, it had desirable effects on the skinACCEPTED lesions in a mice model of atopic dermatitis [392]. Valencene significantly ameliorated the symptoms and restored the decreased expression of filaggrin (filament aggregating protein). Furthermore, it reduced the serum levels of IgE, IL-1β, IL-6, and IL-13. In vitro , it reversed the TNF-α and IFN-γ-induced expression of many pro-inflammatory chemokines including CCL17, CCL22, CXCL8, GM-CSF, and I-CAM through the blockade of the NF-κB pathway. On the other hand, it increased the expression of the skin barrier protein, involucrin – which was likely the reason for the observed reduction on itching behavior in mice. Copaene (Fig. 7C), which contains two 6-member rings fused together with cyclobutane ring, significantly reduced the cell proliferation of several cell lines at the concentration of 200 mg/l [393]. In addition, it was anti-mutagenic and antioxidant by increasing TAC levels at concentration of 50 mg/l. Copaene is also known for its actionsACCEPTED in plant-inse MANUSCRIPTct interactions. Farnesol (Fig. 7D), an acyclic sesquiterpene and the simplest alcohol that can be directly made from farnesyl-pyrophosphate (FPP), is also a structural isomer of nerolidol (Fig. 4B). It participates in the quorum sensing of several species and is used for its anti-allergic and antibiotic properties. It plays multiple roles in both cell proliferation and apoptosis, and thus, in cancer [394]. Furthermore, it has roles in embryonic development, prenylation of proteins – and thus the protein trans-localization and fate, endoplasmic reticulum stress and the subsequent expression of the related genes and levels of some hormones. Moreover, farnesol was neuroprotective and anti-nociceptive in acrylamideinduced neuropathy in mice by the suppression of reactive gliosis and related inflammatory events [395]. In detail, farnesol supplementation (100mg/kg) showed a remarkable improvement in gait performance, neuromuscular function and fine motor coordination, reversed the adverse changes in the GSH, lipid peroxidation, protein carbonyl, hydroxide, hydroperoxide and nitrite levels, and alleviated the histological aberrations and reactive gliosis. The last one occurred by the downregulation of Glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule-1(Iba-1) in the cortex, hippocampus and striatum. Lastly, farnesol, at least partly, reversed the acrylamide-induced increase in the levels of TNF-α, IL-1β and iNOS. Furthermore, in obese mice, farnesol limited weight gain by the inhibition of adipogenesis through the up-regulation of AMP-activated protein kinase, an increase in the expression of uncoupling protein 1 and PPAR γ coactivator 1 α, and the browning of white adipose tissue [396]. In addition, farnesol was cardioprotective in rats; a dose of 1 mg/kg/day significantly decreased infarct sizes [397]. The effect was mediated through the increased protein geranylgeranylation but independent from the antioxidant effect of farnesol. Farnesene, an aliphatic hydrocarbon derived from FPP (lacks the – OH group in comparison to farnesol (Fig. 7D)), is present in both cannabis and hops in low to moderate amounts and probably functions as a herbivore repellent since it is also an insect alarm pheromone. It is neuroprotective against H2O2-induced neurotoxicity in vitro [398]. It suppressed the H 2O2-induced cytotoxicity, genotoxicity and oxidative stress in the newborn rat cerebral cortex cell cultures. Myrcenol (Fig. 7E), an alcohol derivativeMANUSCRIPT of myrcene, which is present at least in hops, is an insect pheromone and a sedative by the allosteric modulation on GABA A receptor expressed in Xenopus oocytes [399]. The same study found, interestingly, that beer itself induced the same effect on GABA A receptors, and furthermore, the pentane extract of the beer, hop oil and myrcenol potentiated the action of GABA on the receptor. When myrcenol was injected into mice, it increased the sleeping time induced by pentobarbital. β-Ocimene (Fig. 8A), which differs from MYR only by the positions of double-bonds, is found in taget EO (up to 70%) and thyme EO (up to 44%). β-ocimene and myrcene synthases shares 92% amino acid identity. β-ocimene is also commonly found in cannabis at moderate concentrations (up to 23% in “white super skunk” drug chemotype [13] and is often the second most abundant terpene in 'mostly sativa' phenotypes [400]). It contributes to the distinct sweet herbal scent of cannabis plants. However, little is known about ocimene, apart from the fact that it is common pheromone of honeybees and moths and participates to insect-plant and even plant-plant interactions [401]. These, common properties of closely related terpenes may indicate similar actions and potentials in biomedicine; however, these are yet to be discovered. Linalyl acetate (Fig.ACCEPTED 8B), the acetylation product of LNL, coexists usually with LNL; however, the enzyme responsible for the acetylation reaction has not yet been identified. Linalyl acetate decreased locomotor activity, and increased sedation and anti-nociceptive activity in rodents [402]. In addition, it, with the administration of 100 mg/kg, it was a mitigating agent for acute cardiovascular events induced by tobacco, while 1 mg/kg was able to decrease lactate dehydrogenase activity, vascular contractility and NO levels in mice [403]. Lastly, when added together with limonene, it exhibited toxicity effect against neuroblastoma cells [404]. Since linalyl acetate is converted to LNL with oral administration [405], its effects may be actually due to LNL. However, other routes of administration could have different effects. Bergamotene (Fig. 8C) was present as the predominant terpene with 30% proportion in floral EO of Eugenia klotzschiana [406]. Several studies with EOs from differentACCEPTED plant sourc MANUSCRIPTes have shown antioxidant, anti-inflammatory, broad-spectrum antibacterial and anti-parasitic activities (not referred herein). However, these data are limited to EOs in which bergamotene is only one of the terpene constituents; thus, more studies with purified bergamotene are needed. A bicyclic sesquiterpene alcohol (-)-Guaiol (Fig. 8D) is known to possess antibacterial activity. It is present in 'liz lemon' drug chemotype (11%) [13] and can be found in volatile fractions of many medicinal plants e.g. in Ferula ferulaeoides (37%) and Guaiacwood Oil (40–72%) [407]. Guaiol also shows inhibition against aphids at low concentrations, but, maybe more importantly, guaiol inhibited non-small cell lung cancer in vitro and in vivo in terms of tumor volume [408]. The study indicated its involvement in the cell autophagy and apoptosis triggered by the regulation of the expression of RAD51 and subsequent double-strand breaks via H2AX phosphorylation. It shows low toxicity and no sensitization, which is indicated by its use in perfumery. Yet three bicyclic terpenes co-exist with Guaiol, namely, β-elemol (Fig. 8E), bulnesol (Fig. 9A) and the precursor molecule guaiene (Fig. 9B). Indeed, guaiol and guaiene co-exist in notable amounts in 'bedropuur' drug cultivar, thus, in a cannabis based medicine: Bedrocan [324]. γ-elemene is sometimes present in hop EOs in relatively high proportions (up to 14.0%) [3]. However, the literature is limited to EOs, which contains γ-elemene, and thus nothing can really be said about the medicinal potential; however, hop EO is likely the richest source of γ-elemene. p-Cymene (Fig. 9C) is sometimes a significant component of terpene fraction of C. sativa and H. lupulus . Cymene exhibit a range of biological activity including antioxidant, anti-inflammatory, anti-nociceptive, anxiolytic, anticancer and antimicrobial effects [409]. Of particular note is that p- cymene is readily formed during prolonged storage of EOs or upon heating from other monoterpenes such as myrcene and terpinenes. Fenchol (Fig. 9D), an isomer of borneol, is present in medical cannabis cultivars up to a proportion of 5.2% [251]. Nothing is known about the physiological effects of humulene-1,2-epoxide (Humulene epoxide II [Fig. 9E]) either, even if it was found (up to 7.9%) in the aqueous extracts of 10 cultivars of the “aroma”-type H. lupulus [93]. The same study found an unidentified terpene (upMANUSCRIPT to 9.7%); thus, these two, along with other terpenes, can be present in beer in notable concent rations and contribute to the health effects of moderate beer consumption [410].

Discussion

The terpenes reviewed herein show very low acute toxicity: typically, acute oral LD 50 values are around 5000 mg/kg or higher e.g. for β-caryophyllene, myrcene, limonene, terpinolone, pinenes, nerolidol, ocimenes and fenchone [411]. This means that a good therapeutic index (LD 50 of 1%) is achieved with the administration of 50 mg/kg of these terpenes – a typical amount for the biological activity for terpenes reviewed herein. Even lower effective doses were regularly met in vivo , for instance caryophyllene oxide with the dose of 12.5 mg/kg showed analgesic and anti-inflammatory activity [65]. Limonene (10 mg/kg/day) exerted anti-hyperalgesic effect on neuropathic pain [138] and it was also a sedative at the dose of 5 mg/kg [14]. 10 mg/kg perillyl alcohol was able relieve stress [140]. 1 mg/kg of terpenen-4-ol decreased blood pressure [210], while α-terpineol induced hypotension and vasorelaxation at 1 mg/kg [211]. Furthermore, geraniol was anti-nociceptive at 12.5 mg/kg [223],ACCEPTED while nerolidol, at the same dose, ameliorated depression and memory impairment in mice [245]. Moreover, borneol ameliorated ischemic stroke with ED 50 value of 0.36 mg/kg [253], and was neuroprotective and reduced infarct volumes (1.0 mg/kg) [265], while α- bisabolol showed antitumor effect at 10 mg/mouse [284], and anti-nociceptive and anti- inflammatory effect with a single dose of 25 mg/kg [303, 304]. Lastly, α-phellandrene (3.1 mg/kg) was effective against mechanical and cold hyperalgesia, depression [360], and 10 mg/kg neuropathic pain (pared nerve injury model) [138]. Nonetheless, terpenes are not mutagenic; actually, some are even anti-mutagenic such as bisabolol [281, 282], myrcene [24] and copaene [393]. These facts together make them safe for biomedical use. In early animal studies [205], miceA CCEPTEDexposed to the MANUSCRIPT inhalation of terpene odors in ambient air for 1 h experienced profound effects on activity levels; linalool caused a decrease in motility of 73% at a plasma concentration of 27 nM, while pinene showed a 14% increase at trace concentrations and terpineol a 45% reduction at 34 nM. A double-blind, placebo-controlled and randomized tests with the inhalation of 0.5 ml of 1% linalool (total dose of 5 l) was able to reduce blood pressure and pulse rate in patients with carpal tunnel syndrome [117]. Moreover, in a double-blind, randomized and controlled therapeutic set-up, inhalation of EO had significant effects on physiologic craving of inhalant-drug-addicted persons [412]. In vitro , β-eudesmol ( β-EOH) activated human TRPA1 with EC 50 value of 33 ± 0.38 M, but more importantly, it increased the ghrelin concentration in rodents with supplementation of 0.14 ppb in drinking water [373]. That is comparable to the concentrations found in beer. This high activity in vivo increasing appetite was not only due to the previously mentioned mechanism, but β-EOH has also been reported to stimulate gastric emptying and small intestinal motility by the inhibition of the D 2 and 5HT 3 receptors. Thus, one terpene can have notable effects through the cumulative effect of multiple pathways. Then, multiple constituents of Cannabis and Humulus preparations can have additive or synergistic effects. For instance, experiments with different combinations of six to eight major terpenes, showed both synergistic and antagonistic effects on each other in cholinergic system [413]. Aromatherapy has been suggested to provide a potentially effective treatment for a range of psychiatric disorders by double blind, controlled and randomized studies [414]. Sedative, antidepressant, anxiolytic and analgesic effects are most commonly reported. In turn, in mice, the inhalation of 27 mg linalool or 23 mg linalyl acetate decreased the motility of normal mice and reversed caffeine-induced over-agitation. I.p. administration of 0.050–0.1 ml/kg of EO of Eugenia caryophyllata (clove), comprised of 77% eugenol and 10% β-caryophyllene, suppressed tonic electroshock-induced convulsions and mortality in mice. In rats, 0.3 mg/kg of Tagetes minuta (Asteraceae) EO (containing mostly ocimene) displayed anxiolytic and antidepressant effects, while in chickens, administration of 0.04– 0.45 mg/kg of the EO exhibited anxiogenic effects.

It is claimed that terpenes, together with THC or CBD,MANUSCRIPT evoke a so-called ‘entourage effect’, which means that the terpenes could have synergistic acti ons with these cannabinoids [10]. Especially, myrcene is claimed to induce strong synergistic sedative/immobilizing action with THC – or ‘cough lock’ as recreational cannabis users refer to it. However, this review did not found any support for this or for the ‘entourage hypothesis’ in general. Thus, it may also possible that minor cannabinoids explains the most of different subjective effects. Especially, CBD is known to antagonize psychotomimetic action of THC among its other properties in its own right [415]. In addition, there are several other cannabinoids with distinct physiological effects. Cannabinoids; cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), 9- tetrahydrocannabivarin ( 9-THCV), cannabivarin (CBV) and cannabidivarin (CBDV) among other less abundant cannabinoids has been shown to act – not only on the classical cannabinoid receptors, CB1 and CB2 – but also on other receptors like PPAR γ, 5HT 3A , A 1A adenosine receptor, α2 adrenergic and on a variety of TRP channels and the non-classical cannabinoid receptors G protein-coupled receptors GPR55 and GPR18 [416]. Thus, it is yet unknown whether different chemotypes of cannabis show their different effects through this complex interplay or by the support of terpenes. However, if the terpenes contributeACCEPTED to the sedative effects of cannabis, then limonene [14], terpinolene [176], nerolidol [249], bisabolol [310], isopulegol [375], borneol [261], linalool, linalyl acetate and ocimene [414] may be the more probable candidates. Of particular note is also that myrcene is readily converted (e.g. via oxidation and upon heating) to citral, nerol, polymeric products, terpinenes, linalool, geraniol, limonene and especially to p-cymene [417]. It is not known which terpenes (or other molecules) are responsible for the sedative effects of hops, and there is no evidence that humulene would have sedative properties either. Thus, the sedative mechanisms of these plants are yet to be elucidated.

However, the case of β-caryophyllene (BCP) is especially interesting. The Ki value of BCP is 150 ACCEPTED MANUSCRIPT nm, while it agonizes CB2 with an EC 50 value of 1.9 M [30]. Because it is fat-soluble, the EC 50 would be achieved by a consumption of 5 mg of BCP (by a human with 70kg body weight and 20% fat). Further, this would correspond to the consumption of 200 mg dry C. sativa inflorescence (assuming that 4% of the dry weight is terpenes and that 64% is BCP) [13]. Interestingly, BCP does not seem to share any obvious structural similarities with other CB2 agonists such as JWH-015 JWH-133 or AM-1241, indicating a distinct molecular mechanism for the agonism. Thus, synergistic or at least additive effect may be possible when combined with other CB2 agonists – like THC. CB2 agonists are known to suppress neuroinflammation and especially microglial activation. Thus, BCP alone or in combination with cannabinoids or other drugs has potential for the treatment of neurological disorders in which microglial over-activation plays a role such as MS, AD, PD, Huntington's disease, bipolar disorder, depression and schizophrenia. Indeed, BCP (25 mg/kg/day) attenuated the neurological damage in CNS in a mouse model of MS [43] and in a rat model of PD, BCP (50 mg/kg/day) reduced oxidative stress, neuroinflammation, glial activation and the loss of dopaminergic neurons [45].

The production of EOs may be viable with cannabis and hop cultivars. By preventing pollination field-cultivated hemp yields 18 l/ha of EO ([11] refs therein). In comparison, lavender can produce 17 l/ha of EO on its third year of cultivation [418]. Because the synthesis of both cannabinoids and terpenes share common enzymatic pathways, the drug and landrace chemotypes produces a higher proportion of terpenes too, in comparison to hemp cultivars. If we assume that a female cannabis drug chemotype produces 500 g/m 2 inflorescence and contains 3% terpenes, this would yield 150 kg/ha. In turn, hops can produce up to 137 l/ha of EO [419]. In comparison, rosemary produces 60 kg/ha and thyme 20–100 kg/ha of EO [418]. Thus, we can conclude that cannabis and hop can produce EO in comparable or even higher amounts with other high yielding plant sources. Terpene profiles vary greatly between the chemotypes and could be further optimized by selective breeding. Thus, especially, the production of humulene, humulene epoxide II, myrcene, β-caryophyllene, limonene, ocimene, bisabolol, elemene, farnesene an dMANUSCRIPT terpinolene could be worthwhile. Conclusions Terpenes are widely used in industry, perfumery, as food additives and in traditional medicines. They show low toxicity and high bioavailability and readily cross the skin and BBB. They have a good therapeutic index i.e. they are well tolerated without side effects and the therapeutic effects are gained far before the lethal dose. Many terpenes exhibit high selectivity over receptors such as TRP channels, and dopaminergic and GABAergic receptors. Only β-caryophyllene show high affinity to cannabinoid receptors and the CB2 agonism holds great potential to treat a variety of neuroinflammatory diseases. The additive and synergistic action of terpenes with other drug molecules, and the improved penetration of other drugs by either adjuvant or covalent fusion have been already gained, but little is known about how they affect together with cannabinoids and the resinous part of hops. Per se they exhibit, especially, antibiotic, anti-inflammatory, anti-antioxidant, anticancer and anti-tumor activities. They show anticancer activity often by pro-apoptotic action, but are non-toxic for healthy cells or tissues – they are rather neuro-, hepato-, and nephroprotective. However, the pharmacokineticsACCEPTED and pharmacodynamics of many terpenes are yet to be studied, as well more placebo-controlled double-blind human trials with pure terpenes are needed.

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ACCEPTED ACCEPTED MANUSCRIPT Fig. 1. Molecular structures of A) myrcene, B) β-caryophyllene, C) caryophyllene oxide and D) humulene.

Fig. 2. Molecular structures of A) α-Pinene, B) β-Pinene, C) linalool, D) limonene and E) perillyl alcohol.

Fig. 3. Molecular structure of A) terpinolene, B) γ-terpinene, C) α-terpinene, D) α-terpineol and E) terpinen-4-ol.

Fig. 4. Molecular structures of A) geraniol, B) nerolidol, C) borneol, D) bisabolol and E) bisabolene.

Fig. 5. Molecular structures of A) β-elemene, B) fenchone, C) pulegone, D) α-phellandrene and E) β- eudesmol.

Fig. 6. Molecular structures of A) isopulegol, B) isoborneol, C) sabinene, D) 3-carene and Δ-cadinene.

Fig. 7. Molecular structures of A) selinene, B) valencene, C) copaene, D) farnesol and E) myrcenol.

Fig. 8. Molecular structures of A) β-ocimene, B) linalyl acetate, C) Bergamotene, D) (-)-guaiol and β- elemol.

Fig. 9. Molecular structures of A) bulnesol, B) guaiene, C) p-cymene, D) fenchol and E) humulene-1,2- epoxide.

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“Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus”

by Tarmo Nuutinen

- The current, comprehensive review presents terpenes found in cannabis and hops. - Cannabaceae plants Cannabis sativa L. and Humulus lupulus L. are rich in mono- and sesquiterpenes - Some terpenes are relatively well known for their potential in biomedicine and have been used in traditional medicine for centuries - A wide variety of terpenes’ medicinal properties are supported by numerous in vitro, animal and clinical trials - Because of the very low toxicity, these terpenes are safe and well-tolerated and have good therapeutic index

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