Keywords

4.1 Introduction

Components from the plant Cannabis Sativa as well as synthetic derivatives developed by academic and industry researchers have been extensively studied as therapeutics in the past few decades. However, very few have successfully entered the clinical scenario, thus far. Numerous ongoing investigations are trying to decipher the potential of these chemical entities in the treatment of a wide variety of diseases.

A growing number of preclinical studies published in the last years highlight the therapeutic actions of these compounds in different experimental models. Therefore, medical efforts and patient hopes are quite high for the development of cannabinoids as pharmacological agents for metabolic, neurological, or oncologic diseases among others. Presumably, in the near future, this field will greatly benefit patients with otherwise difficult to treat disorders. It is noteworthy that in June 2018, the U.S. Food and Drug Administration approved the non-psychoactive phytocannabinoid cannabidiol (CBD, commercialized as Epidiolex®) for the treatment of seizures in children with Lennox–Gastaut and Dravet syndromes (Devinsky et al. 2018, 2019).

Cannabinoids are molecules that target the endocannabinoid system (ECS), which are involved in the regulation of numerous physiological and pathological processes. These compounds may bind or modulate one or various receptors that are part of ECS. Thus far, two G-protein-coupled receptors (GPCRs) have been identified as the two major cannabinoid receptors CB1 and CB2. CB1 is mostly found in the central nervous system, while CB2 is predominantly in the immune system among other organs and tissues (Matsuda et al. 1990; Herkenham et al. 1991; Demuth and Molleman 2006). Their endogenous ligands (endocannabinoids) and the enzymes implicated in their biosynthesis and degradation [(fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] are also part of this intricate system (Mechoulam et al. 1995, 1996; Beltramo et al. 1997; Fu et al. 2011; Marsicano and Chaouloff 2011). Whether additional cannabinoid receptors are part of the ECS still instigates a strong debate (Morales and Reggio 2017). Recent studies have shown that several cannabinoid ligands bind to the receptor GPR55 (Morales and Jagerovic 2016) and GPR18 (McHugh et al. 2010), supporting the idea that they may play an important role in ECS. Moreover, there is extensive evidence indicating that ECS also interacts with a number of established non-CB1, non-CB2 GPCRs, ion channels, and nuclear receptors (Pertwee et al. 2010; Morales et al. 2017; Morales and Reggio 2017).

4.1.1 Cannabinoid Classifications

Cannabinoid classifications have been established according to their pharmacology, their molecular structure, or their origin. Attending to the last criterion, cannabinergic compounds can be classified as endogenous (endocannabinoids), phytogenic (phytocannabinoids), and synthetic compounds.

4.2 Endocannabinoids

Endocannabinoids are endogenous lipidic molecules that bind to the cannabinoid receptors mediating retrograde neurotransmission (Wilson and Nicoll 2001). This family of compounds is formed by eicosanoids derived from arachidonic acid and other polyunsaturated fatty acids. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG, Fig. 4.1) are the first endocannabinoids discovered and are most abundant in the human brain (Basavarajappa 2007). AEA partially activates both cannabinoid receptors CB1 and CB2, whereas 2-AG fully activates both of them. (Di Marzo et al. 1994; Stella et al. 1997). Other endocannabinoids identified include 2-arachidonoylglyceryl ether (noladin ether, 2-AGE), O-arachidonoyl ethanolamine (virodhamine), and N-arachidonoyl-dopamine (NADA) (Fig. 4.1).

Fig. 4.1
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Structures of endogenous cannabinoids and synthetic endocannabinoid derivatives

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The endocannabinoid tone is sustained by enzymes that synthesize and degrade these eicosanoids. Due to the physiopathological implication of this machinery, diverse drug discovery approaches have explored the modulation of the endocannabinoid tone. Strategies such as inhibition of degrading enzymes, positive allosteric modulation of CB1 and/or CB2, and development of endocannabinoid mimetics with a lower affinity towards metabolic enzymes have shown promising results in preclinical models (Pertwee 2005; Di Marzo 2018). Medicinal chemistry programs have developed synthetic analogs of endocannabinoids with structural modifications at key positions following the aforementioned strategies. Instances of this approach are ACEA (arachidonyl-2′-chloroethylamide) or ACPA (arachidonylcyclopropylamide, Fig. 4.1), analogs of AEA with improved CB1 affinity (Hillard et al. 1999). (R)-(+)-Methanandamide (Met-AEA, Fig. 4.1), a methylated AEA derivative, displays the same functional profile at the cannabinoid receptors while being longer-lived because it is more difficult for FAAH to metabolize.

4.3 Phytocannabinoids

To date, over 120 cannabinoids, termed “phytocannabinoids”, have been isolated from the Cannabis plant. These compounds bear a benzone-1,3-diol or a benzopyran ring and a hydrophobic alkyl chain. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD, Fig. 4.1) are the most abundant cannabinoids in the plant and the most widely studied. Other phytocannabinoids include cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC) (Fig. 4.1).

Phytocannabinoids exhibit different activities at the cannabinoid receptors CB1 and CB2 (Morales and Reggio 2017). Δ9-THC has been consistently shown to activate CB1 and CB2 with similar potency. Many of the therapeutic effects as well as the psychotropic outcomes of Cannabis Sativa are due to this phytocannabinoid. The non-psychoactive plant derivative CBD has also shown pharmacological potential in a wide range of pathologies (Mechoulam et al. 2007). Its functional profile at ECS is quite complex and is currently being investigated by diverse research groups (Morales and Reggio 2019) (Fig. 4.2).

Fig. 4.2
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Structures of the most abundant phytocannabinoids

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Synthetic cannabinoid derivatives have been developed in the search for improved therapeutics and often trying to dissociate CB1 and CB2 activity. Structure-activity relationship studies of phytocannabinoid analogs have helped to understand the molecular requirements for cannabinoid activity. Derivatization at pharmacophoric positions including the alkyl lipophilic chain, the phenolic, and the pyran ring has resulted in compounds with a cannabinoid selective profile. Widely studied synthetic phytocannabinoid derivatives include CP55,940, HU210, JWH133, and HU308 (Fig. 4.3). CP55,940 and HU210 are very potent CB1/CB2 agonists, whereas the deoxy and the methoxy-Δ9-THC derivatives JWH133 and HU308 are CB2 agonists with significant selectivity over CB1 (Huffman 2000). The only structural modification of Δ9-THC that has led to an approved drug, thus far, is nabilone (Fig. 4.3).

Fig. 4.3
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Structures of representative phytocannabinoid synthetic derivatives

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4.4 Synthetic Cannabinoids

The therapeutic relevance of ECS has prompted the identification of numerous synthetic cannabinoid scaffolds. Strategies for the development of cannabimimetic compounds include the design of drugs that selectively activate or block CB1 or CB2, molecules that can act as allosteric modulators or biased agonists of these receptors, inhibitors of the metabolic enzymes FAAH or MAGL, as well as the development of compounds acting at peripheral cannabinoid receptors (Morales and Jagerovic 2020). These synthetic cannabinoids aim to provide optimized therapeutic effects and pharmacokinetical profile, while reducing undesirable side actions.

As we will describe in the following sections, numerous synthetic compounds have been used as pharmacological tools or therapeutic agents in different disease models.

The best-known compounds of this synthetic family involve aminoalkyindoles, such as R-(+)-WIN55,212–2 (D’Ambra et al. 1992) and JWH-015 (Fig. 4.4), CB1/CB2 and CB2 agonists, respectively; arylpyrazoles, such as SR141716A (rimonabant) (Rinaldi-Carmona et al. 1994) or AM251 (Fig. 4.4), CB1 antagonist/inverse agonists; or indole-2-carboxamides such as ORG27569 (Fig. 4.4), identified as the first CB1 allosteric modulator (Price et al. 2005).

Fig. 4.4
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Structure of representative synthetic cannabinoids

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In the following sections, we will describe the ECS upregulation in diverse pathologies to provide an overview of the chemical entities evaluated in experimental disease models. Their potential for further drug development or their progress towards the clinic will be also discussed.

4.5 Cannabinoids in Neuromodulation

ECS has a crucial role in mediating and modulating physiological responses in the central nervous system (CNS). ECS has been shown to be involved in synaptic plasticity and homeostatic processes in the brain. Therefore, it is not surprising that numerous reports have proved the dysregulation of cannabinoid receptor expression under specific neurological disorders providing a therapeutic scenario for the use of cannabinoids.

CB1 is one of the most abundant GPCRs in CNS, its expression is found particularly high in the basal ganglia, neocortex, hippocampus, and cerebellum CNS (Herkenham et al. 1991; Marsicano and Kuner 2008). The CB1 receptors are highly present at the presynaptic and axonal compartments, and thus their function is tightly associated with synaptic activity (Straiker and Mackie 2005). The activation of these receptors has been found to positively affect inwardly rectifying potassium channel conductance, while triggering a decrease in the N-type and P/Q-type voltage-operated calcium channel conductance and to reduce endocannabinoid production. This cascade of events leads to a decrease of neurotransmitter release at excitatory and inhibitory synapses conferring to CB1 the ability to modulate neurotransmission (Katona et al. 1999; Blázquez et al. 2011). Numerous investigations have demonstrated that the CB1 receptors exhibit neuroprotective effects against excitotoxicity induced by diverse stimuli (Marsicano et al. 2003). Therefore, multiple pathophysiological events, ranging from neurodegenerative disorders to memory deficits, have been associated with their actions (Kano et al. 2009; Di Marzo et al. 2015).

Moreover, the CB2 receptors, although initially thought to be peripherally restricted, have been found in particular brain regions offering a very promising therapeutic approach in certain neurological diseases. At a central level, the expression of these receptors is enhanced upon inflammation being mainly localized in the microglia (Fernández-Ruiz et al. 2015). Since neuroinflammatory alterations are associated with several neurological pathologies, the CB2 receptor agonists offer a promising therapeutic approach for the treatment of these disorders (Roche and Finn 2010; Navarro et al. 2016).

4.5.1 Cannabinoids in Epilepsy

Epilepsy is characterized by an imbalance between excitatory and inhibitory neurotransmitter release and abnormal neuronal electrical activity. Even though, antiepileptic drugs have been shown to limit seizures, over 30% of patients remain pharmacoresistant (Kwan et al. 2011). In this scenario, increasing research demonstrates that the exogenous modulation of ECS offers a promising and effective option for the treatment of refractory epilepsy (Rosenberg et al. 2015; Billakota et al. 2019). Although, the exact molecular mechanisms are still under investigation, the anticonvulsant potential of cannabinoids is supported by their neuromodulatory effects and their ability to inhibit hyperexcitability (Rosenberg et al. 2015).

Diverse phytocannabinoids, including Δ9-THC, Δ9-THCA (Δ9-tetrahydrocannabinolic acid, Fig. 4.5), Δ9-THCV (Δ9-tetrahydrocannabivarin, Fig. 4.5), CBD, and CBDV (cannabidivarin, Fig. 4.5), have shown anticonvulsant effects in different experimental models of seizures. Whereas, very few studies have been reported for the use of Δ9-THCA, Δ9-THCV, and CBDV, abundant data support the potential use of Δ9-THC and CBD for the treatment of epilepsy (Gaston and Friedman 2017).

Fig. 4.5
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Structures of phytocannabinoids Δ9-THCA, Δ9-THCV, and CBDV

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Most studies have supported the anticonvulsant potential of Δ9-THC, however, some experiments have revealed mixed or no effects (Rosenberg et al. 2015). Among cannabinoids, the non-psychoactive phytocannabinoid, CBD is currently the best hope for the treatment of refractory epileptic seizures. Its potent anticonvulsant actions have been widely demonstrated in in vitro and in vivo human studies leading to CBD’s approval for the management of seizures in children with Lennox–Gastaut and Dravet syndromes (Devinsky et al. 2018, 2019). Placebo-controlled clinical trials revealed that CBD is well-tolerated and does not present side effects on CNS or vital signs (Bergamaschi et al. 2011; Friedman et al. 2019).

The proposed mechanisms of CBD anti-epileptogenic actions include the activation of TRPV1 channels (Bisogno et al. 2001), blockage of T-type voltage-gated calcium channels (VGCC) (Ibeas Bih et al. 2015), and modulation of GPCRs including the cannabinoid receptors CB1 and CB2 (Wallace et al. 2001, 2002), GPR55, the adenosine receptors A1 and A2 (Gaston and Friedman 2017), and the serotonin receptors 5-HT1A and 5-HT2A (Sourbron et al. 2016).

Synthetic cannabinoids have also been tested in preclinical seizures models (Rosenberg et al. 2015). FAAH inhibitors such as URB597 and AM404 (Fig. 4.6) did not exert significant anticonvulsant actions in animal models. Likewise, the CB1 antagonists, including SR141716A and AM251 (Fig. 4.4), were not successful in the assessed models. CB1 agonists, such as WIN55,212–2 (Fig. 4.4) and ACEA (Fig. 4.1), showed anti-seizure effects, although proconvulsive effects were reported in a low percentage of cases (Rosenberg et al. 2015). In fact, one study suggested that the CB1 agonists may exhibit proconvulsant effects at high doses via TRPV1 activation (Manna and Umathe 2012).

Fig. 4.6
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Structures of FAAH inhibitors tested in epilepsy experimental models

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In summary, the activation of ECS exerts anti-epileptic effects whereas inhibition of the endogenous cannabinoid machinery does not prevent seizures in reported epilepsy models.

4.5.2 Cannabinoids in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that is defined by the progressive deterioration of cognition and memory caused by the formation of β-amyloid plaques and neurofibrillary tangles. Alteration of ECS has been identified in animal models and human postmortem samples in the AD brain, especially in the hippocampus and cerebral cortex brain regions severely affected by this disease. AD patients experience a loss of the neuronal CB1 receptors (Ramírez et al. 2005), while significant upregulation of the CB2 receptors in microglial cells has been extensively reported (Benito et al. 2003; Aso and Ferrer 2016; López et al. 2018). Additionally, increased 2-AG and elevation of FAAH enzymes have also been associated with the progression of AD pathogenesis (Benito et al. 2003).

The enhanced 2-AG levels along with the increased CB2 receptors expression in microglial cells have been proposed to exert protective effects against β-amyloid-induced neuroinflammation and neuronal injury (Benito et al. 2003; López et al. 2018). However, the CB1 receptor downregulation in the hippocampus and basal ganglia may contribute to the destructive inflammatory process experienced by the AD patients (Ramírez et al. 2005). Increased FAAH activity in astrocytes has been associated with the formation of more arachidonic acid, which eventually leads to pro-inflammatory effects.

The exogenous modulation of ECS has shown promising results in preclinical AD models. On the one hand, CB1 activation has been reported to prevent amyloid β-induced neurotoxicity in vitro (Milton 2002; Benito et al. 2003; Ramírez et al. 2005) and to improve memory deficits and cognitive impairment in diverse animal models (Van Der Stelt et al. 2006; Haghani et al. 2012; Aso et al. 2012). Moreover, the activation of the CB2 receptors has been reported to attenuate the inflammation associated with AD modulating Aβ aberrant processing (Aso and Ferrer 2016). On the other hand, the inhibition of the endocannabinoid enzymes, FAAH and MAGL, has also been proposed as a potential therapeutic strategy for AD (Benito et al. 2012).

Among the cannabinoids tested in AD experimental models, the most promising results come from the phytocannabinoids Δ9-THC, CBD, or combinations of both (commercialized as Sativex®) (Fernández-Ruiz et al. 2015). These molecules, and the Δ9-THC synthetic derivative nabilone (Fig. 4.3), have been shown to counteract specific pathological hallmarks of AD, such as tau and β-amyloid aggregation, leading to cognitive and behavioral improvements. The few clinical trials performed so far confirmed the results observed in the animal models of the disease.Footnote 1 However, more controlled trials are needed to evaluate the efficacy of cannabinoids in the management of the different stages of this neurodegenerative disease.

Synthetic cannabinoids with diverse pharmacological profiles have also been tested in AD preclinical models. For instance, CB2 agonists, such as the naphthoylindole, JWH-015 (Fig. 4.4), or the phytocannabinoid derivatives, JWH-133 (Fig. 4.3), and HU-308 (Fig. 4.3), have been shown to reduce plaque aggregation, thereby exerting anti-inflammatory effects (Aso and Ferrer 2016). Likewise, CB1/CB2 mixed agonists including WIN55,212–2 (Fig. 4.4) and HU-210 (Fig. 4.3) have been demonstrated to have the ability to reduce pro-inflammatory markers and improve cognitive performance in the AD models (Ramírez et al. 2005; Martín-Moreno et al. 2011). Although, more studies need to confirm these effects, endocannabinoid reuptake inhibitors, such as VDM11 (Fig. 4.7) or MAGL inhibitors such as JLZ184 (Fig. 4.7), can decrease amyloid neurotoxicity (Van Der Stelt et al. 2006; Chen et al. 2012).

Fig. 4.7
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Structure of endocannabinoid reuptake inhibitor VDM11 and MAGL inhibitor JLZ184

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It has been extensively demonstrated that the pleiotropic activity of cannabinoids can target several crucial processes associated with AD. This includes neuroinflammation, β-amyloid and tau aberrant processing, excitotoxicity, or oxidative stress. In a multifactorial disease, such as AD, this offers a promising strategy. Hopefully, results from more clinical trials will shed additional light into this research such that AD patients worldwide can soon benefit from cannabinoid therapy.

4.5.3 Cannabinoids in Parkinson’s Disease

Parkinson’s disease (PD) is a long-term degenerative disorder that mainly affects motor coordination, although non-motor symptoms also appear with the progression of the disease. One of the main pathological hallmarks of PD is cell death in the basal ganglia, especially of dopaminergic neurons.

As in the previously mentioned neurological disorders, ECS has been shown to be abnormally regulated in this pathology. For instance, the upregulation of the CB1 receptors has been shown in the basal ganglia of experimental models of PD (Stampanoni Bassi et al. 2017). Moreover, a loss of the neuronal CB2 receptors was detected in the postmortem tissues of PD patients due to the degeneration of nigrostriatal dopaminergic neurons (García et al. 2015).

Pharmacological cannabinoid strategies to manage PD include activation of CB2, to control inflammatory events, and blockage of CB1 receptors, to improve akinesia and reduce motor inhibition. Since one of the main characteristics of PD is high oxidative stress, the experiments reported so far in the PD models have been focused on the use of antioxidant phytocannabinoids. The evaluation of Δ9-THC (Lastres-Becker et al. 2005), CBD (Lastres-Becker et al. 2005; García-Arencibia et al. 2007; García et al. 2011), and Δ9-THCV (García et al. 2011) in animal models revealed their ability to reduce parkinsonian motor symptoms. In fact, clinical trials to assess the potential of CBD, nabilone, or Cannabis oils in the PD motor and non-motor symptoms are currently ongoing.Footnote 2

Synthetic cannabinoids such as the potent CB1/CB2 receptor agonists WIN55,212–2 (Price et al. 2009; More and Choi 2015) and CP55,940 (Jimenez-Del-Rio et al. 2008) or the AEA synthetic derivative AM404 (García-Arencibia et al. 2007) have been shown to provide neuroprotection in the PD models.

Even though further clinical research is required, the knowledge gained in this field and ongoing clinical efforts point towards a cannabinoid-based neuroprotection for the treatment of PD.

As thoroughly reviewed by others, cannabinoids have been shown to impact many other neurological disease models, such as multiple sclerosis (MS), traumatic brain injury (TBI) or amyotrophic lateral sclerosis (ALS), as well as mental disorders including schizophrenia, anxiety, or depression (Kendall and Yudowski 2017; Aymerich et al. 2018; Ibarra-Lecue et al. 2018; Friedman et al. 2019). Moreover, symptoms associated with these diseases can also be treated with cannabinoid-based medicines, for instance, Sativex® is used for the symptomatic relief of pain and spasticity in adults suffering from MS (Giacoppo et al. 2017).

Even though much more research needs to be conducted, the modulation of ECS is a great therapeutic opportunity for the treatment of several neuropsychiatric and neurodegenerative disorders.

4.6 Cannabinoids in Cancer

The ability of Cannabis to prevent nausea and vomiting, stimulate appetite, and reduce pain has been widely demonstrated. Therefore, cannabinoids have been successfully used in the treatment of specific cancer chemotherapy side effects (Abrams and Guzman 2015).

A few decades ago, dronabinol (Marinol®) and nabilone (Cesamet®) were approved to treat emesis and nausea induced by antitumor agents (Tramèr et al. 2001). However, they are only prescribed in certain countries upon failure of conventional anti-emetics (Sharkey et al. 2014).

Extensive research has demonstrated the palliative potential of cannabinoids for cancer patients. For instance, Δ9-THC acts as an appetite stimulant increasing food intake in rodents. Clinical trials confirmed this orexigenic effect in the management of cancer anorexia (Jatoi et al. 2002; Berry and Mechoulam 2002; Walsh et al. 2003). Moreover, the ability of cannabinoids in reducing chemotherapy-induced pain has also been reported. Δ9-THC and synthetic analogs have shown to act as potent analgesic drugs in diverse clinical trials highlighting their beneficial role in the treatment of cancer pain (Campbell et al. 2001; Iversen and Chapman 2002; Mantyh et al. 2002). Actually, Sativex® can be currently prescribed in certain countries to reduce pain in adults with advanced tumors (Pertwee 2009; Fallon et al. 2017).

Preclinical data indicate that peripheral neuropathies associated with cancer treatment can also be ameliorated upon cannabinoid administration (Guindon et al. 2014). Synthetic agonists such as the aminoalkylindole WIN55,212–2, diminishes mechanical and cold allodynia in rodent models of paclitaxel (Pascual et al. 2005), vincristine (Rahn et al. 2007), and cisplatin-evoked neuropathy (Vera et al. 2007). Moreover, CBD is able to reduce doxorubicin-induced cardiomyopathies (Hao et al. 2015) and cisplatin-induced nephrotoxicity (Pan et al. 2009).

Besides their palliative potential, cannabinoids have exhibited antitumor effects in numerous in vitro and in vivo experimental models of cancer (Guzmán 2003; Chakravarti et al. 2014; Velasco et al. 2016). Since the early 2000s, a growing body of research has evidenced the potential of cannabinoids in the reduction of tumor growth and progression in diverse cancer models (Galve-Roperh et al. 2000; Guzmán et al. 2002; Guzmán 2003; Carracedo et al. 2006; Sarfaraz et al. 2008; Velasco et al. 2012).

ECS alterations have also been detected in cancer physiopathology. Abnormal expression of the ECS components in neoplasms compared with healthy tissues has been detected (Guzmán 2003; Caffarel et al. 2006; Malfitano et al. 2011; Velasco et al. 2012). These data can be tumor type-specific and therefore, studies need to determine how ECS is regulated in each cancer type (Malfitano et al. 2011; Velasco et al. 2016). In specific cancer types, such as glioblastoma (Schley et al. 2009) or specific breast tumors (Qamri et al. 2009; Caffarel et al. 2010), increased CB2 receptor levels have been shown. Other tumors, including gastric carcinoma (Miyato et al. 2009) or rhabdomyosarcoma (Oesch et al. 2009) are characterized by the overexpression of the CB1 receptor. Upregulated expression of both CB1 and CB2 has also been detected in acute myeloid leukemia (Joseph et al. 2004) malignant astrocytomas (Stella 2010), pancreatic cancer (Carracedo et al. 2006), and hepatocellular carcinoma (Giuliano et al. 2009) among others. Levels of endocannabinoids, AEA and 2-AG, have also been shown to differ between cancer cells and their normal counterparts in specific tumors (Bifulco et al. 2006). Upregulation of the putative cannabinoid receptor, GPR55, has also been observed in cells of diverse cancer types including breast adenocarcinoma, squamous skin cell carcinoma, or gliomas (Oka et al. 2010; Andradas et al. 2011; Leyva-Illades and Demorrow 2013; Pérez-Gómez et al. 2013). GPR55 expression has been shown to correlate with proliferation and thus, it has been proposed as a novel oncology biomarker with a potential prognostic value (Henstridge et al. 2011). Expression of GPR55-CB2 heterodimers has also been reported in human tumors (Moreno et al. 2014; Balenga et al. 2014).

Even if further research is required to clarify the intricate role of this complex system in the course of oncological processes, there is no doubt that cannabinoids are useful drugs for the management of cancer and related symptoms.

As in previously described diseases, thus far, preclinical and clinical studies on cannabinoids as antitumor agents have been mainly focused on understanding the mechanism of action of Δ9-THC and CBD (Pellati et al. 2018; Hinz and Ramer 2019). Δ9-THC has shown antiproliferative effects in diverse cancer types including glioblastoma, prostate, breast, colon, pancreatic, lymphoma, or lung among others (Fowler 2015; Fraguas-Sánchez et al. 2016). Mechanisms of this antitumor action include the CB receptor-dependent and independent pathways (Powles et al. 2005). Moreover, CBD has been widely proved to reduce tumor growth via proapoptotic actions in numerous cancer cell lines (Hinz and Ramer 2019). The anticancer effects of CBD have been suggested to be mediated by several targets, including COX-2, 5-LOX, PPARγ, TRPV2, mTOR, and the p38 MAPK pathway (Ligresti 2006; Hinz and Ramer 2019). Clinical trials are trying to unravel the antitumor potential of phytocannabinoids (such as Δ9-THC) alone or in combination with benchmark chemotherapeutic agents in different types of cancer. Guzmán et al. developed the first clinical trial to further explore the antitumor actions of cannabinoids in cancer patients. This pilot trial investigated the effects of Δ9-THC on nine patients with recurrent glioblastoma multiforme. The preliminary results attained from this study suggest a reduction in tumor growth upon Δ9-THC administration (Guzmán et al. 2006). Ongoing clinical trials are trying to decipher the potential antitumor role of cannabinoids.Footnote 3

Even if phytocannabinoids are in the forefront towards the clinic, many other cannabinoids with antitumor properties have been reported in the literature (Morales and Jagerovic 2019). For instance, the well-known aminoalkylindole WIN55,212–2 is able to decrease cell proliferation and migration in models of different cancer types, hepatocellular carcinoma (Xu et al. 2015), neuroblastoma (Müller et al. 2017), myeloma (Barbado et al. 2017), renal carcinoma (Khan et al. 2018), prostate (Morell et al. 2016), or gastric cancer (Xian et al. 2016) among them.

Moreover, it is worth highlighting the anticancer potential of cannabinoid quinones. Oxidized derivatives of phytocannabinoids cannabidiol (HU-331, Fig. 4.8), Δ8-THC (HU-336, Fig. 4.8) and cannabinol (HU-345, Fig. 4.8) were effective in reducing tumor growth in mice cancer models (Kogan et al. 2004). However, their biological activity was attributed to their quinone structure independently of their cannabinoid character, since they do not modulate the cannabinoid receptors (Kogan et al. 2006, 2007). Para- and ortho- quinones of chromenopyrazoles were also reported as antitumor agents (Morales et al. 2013, 2015). These compounds were able to reduce cancer proliferation through mechanisms that involve the cannabinoid receptors. For instance, para-quinones PM49 (Fig. 4.8) was able to reduce prostate cancer in vitro and in vivo (Morales et al. 2013). 1,4-naphthoquinone derivatives, such as 3a (Fig. 4.8), have also been reported to inhibit tumor proliferation. GPR55 has been proposed as the target through which they exhibit their antitumor effects (Badolato et al. 2019).

Fig. 4.8
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Structures of quinones related to cannabinoids with reported antitumor potential

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Currently, the use of cannabinoids is limited to the management of chemotherapy-induced side effects. Nevertheless, the aforementioned preclinical data clearly evidence the antitumor potential of cannabinoids. Hopefully, further clinical data can soon confirm the therapeutic potential of cannabinoids in the treatment of cancer.

4.7 Cannabinoids in Metabolic Disorders

ECS has been recognized to play a crucial role in the regulation of metabolic events, particularly in energy balance, food intake, and lipid metabolism (Scherma et al. 2014; Williams et al. 2015). This system has shown dysregulation in metabolic pathologies including obesity. For instance, the increased levels of circulating endocannabinoids (Blüher et al. 2006; Matias et al. 2006) and upregulation of the CB1 receptors have been observed in obese rodents and human obesity (Murdolo et al. 2007; Pagano et al. 2007). In this disorder, ECS dysregulation has been reported, not only in CNS but also at the peripheral level, in diverse organs including the pancreas, liver, and adipose tissues.

It is well-known that ECS activation induces orexigenic effects (Rossi et al. 2018), therefore, the inhibition of the CB1 receptors has been considered as a potential strategy for the management of obesity and metabolic syndrome. In fact, the CB1 antagonist/inverse agonist rimonabant (SR141716A, Fig. 4.4, commercialized as Acomplia®), was approved in certain European countries in 2006 for the management of obesity (Després et al. 2006). The anti-obesity effects of this drug were accompanied by the undesired effects such as depression, anxiety, headache, and suicidal thoughts forcing its withdrawal from the clinic, a couple of years later. Numerous research projects from academia and the pharmaceutical industry were centered on the development of CB1 receptor antagonists, however, the psychiatric side effects of rimonabant led to a significant decrease in the continuation of this approach (Serrano et al. 2012; Silvestri and Di Marzo 2012; Sharma et al. 2015; Yadav and Murumkar 2018; Amato et al. 2019).

Other pharmacological strategies targeting ECS, but without severe psychiatric side effects, have been attempted. Peripherally restricted CB1 antagonists, such as URB447 and AM6545 (Fig. 4.9), have shown promising results in the control of fat intake and obesity (DiPatrizio et al. 2011; Argueta and DiPatrizio 2017).

Fig. 4.9
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Structures of CB1 antagonists URB447 and AM6545 and FAAH inhibitor BIA 10–2474

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Moreover, molecules acting preferentially via the CB2 receptors have shown efficacy in a rat model of alcoholic hepatic steatosis by decreasing the liver/body weight ratio and hepatic triglyceride content (Lotersztajn et al. 2008, 2011). The inhibitors of the enzymes involved in the degradation of endocannabinoids, such as FAAH inhibitors, has also shown potential for the regulation of energy balance (Balsevich et al. 2018). However, this approach should be taken with caution, since the FAAH inhibitor BIA 10–2474 (Fig. 4.9) caused severe neurotoxicity in a phase I clinical trial probably due to off-target effects (Van Esbroeck et al. 2017).

Despite the clinical failures obtained so far, ECS still represents a very promising pharmacological target to treat metabolic disorders.

4.8 Conclusions

It has been widely demonstrated that compounds targeting ECS, particularly CB1 and/or CB2, have therapeutic potential for the clinical management of numerous diseases. These include neurological disorders, metabolic pathologies, cancer, or symptoms such as inflammatory and neuropathic pain. However, just a few of these diseases can be treated with cannabinoid-based medicines currently (Table 4.1).

Table 4.1 Representative cannabinoids that have been reported to exhibit therapeutic potential in specific diseases
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Even though CB1/CB2 agonists are in the forefront of clinical research for neuroprotection or cancer treatment, there is an increasing interest in exploiting novel pharmacological approaches (Picone and Kendall 2015). CB2 selective agonists or peripherally restricted CB1/CB2 agonists exhibit a promising therapeutic potential for treating various pathologies, while avoiding the adverse psychotropic effects related to the modulation of CB1 in the brain (Dhopeshwarkar and Mackie 2014). CB1 and/or CB2 antagonists or inverse agonists, as well as, allosteric cannabinoid ligands are also emerging and may prove useful in the treatment of certain diseases (Picone and Kendall 2015; Vemuri and Makriyannis 2015). Biased cannabinoid agonists can also fine-tune the therapeutic effects, while minimizing side effects associated with other receptor pathways (Morales et al. 2018; Al-zoubi et al. 2019). Even though phytocannabinoids are way closer to the bedside, some of the aforementioned synthetic cannabinoids may provide advantages in the treatment of specific pathologies. Nonetheless, more preclinical and especially clinical research needs to be done in this field.