Phytocannabinoids: History
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Subjects: Pharmacology & Pharmacy
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Wiktor Bzdęga

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in adults in developed countries, with a global prevalence as high as one billion. The pathogenesis of NAFLD is a multifactorial and multi-step process. Nowadays, a growing body of research suggests the considerable role of the endocannabinoid system (ECS) as a complex cell-signaling system in NAFLD development. 

  • endocannabinoid system
  • endocannabinoid receptors

1. Introduction

The term “non-alcoholic fatty liver disease” (NAFLD) involves simple fat accumulation in the liver and may progress to steatohepatitis, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma (HCC) [1]. Over the past decade, the prevalence of NAFLD (nearly 30% in the general adult population) is increasing worldwide with each passing year due to sedentary lifestyles and the unlimited availability of fat- and calorie-rich diets in modern western society [2]. The incidence of NAFLD increases with age, with a tendency to occur in men before 50 years of age and women after 50 years of age [3]. NAFLD is considered the most frequent liver disease in the world, the second most common cause of liver transplantation, and a primary cause of the development of hepatocellular carcinoma. Given these facts and the lack of effective treatment, NAFLD is a relevant problem for all health systems. Unsurprisingly, the pathogenesis of NAFLD is associated with fat deposition in the liver. Particularly, increased accumulation of triacylglycerols (TAG) is characteristic of NAFLD development. Steatosis occurs as a result of the imbalance between lipid storage (from accelerated free fatty acids (FFA) influx and de novo synthesis) and hepatic lipid clearance (decreased oxidation of FFA in the liver and decreased synthesis of low-density lipoproteins (VLDLs)). The complex and multifactorial process of NAFLD development was explained initially by the “two hits” model. The “first hit” included hepatic steatosis as a consequence of metabolic syndrome and excessive TAG deposition in hepatocytes. The “second hit” seemed to be necessary to develop non-alcoholic steatohepatitis (NASH) from NAFLD. However, this model was too simple to fully describe the complexity of NAFLD. In 2010, Tilg and Moschen proposed the “multiple hit” model, suggesting that different risk factors such as insulin resistance, adipocytes dysfunction, nutritional factors, gut microbiota, and genetic and epigenetic factors act simultaneously on both intrahepatic and extrahepatic pathways, which finally leads to steatosis or inflammation [4]. The previous model assumed that NAFLD always precedes inflammation. According to the “multiple hit” model, depending on which signaling pathways are activated by risk factors, hepatic lipid overload or NASH development may occur [5]. Currently, there are only a few specific pharmaceutical strategies available to treat NAFLD. However, none of them is ideal. Many of the promising results from rodent studies on phytocannabinoids and the endocannabinoid system (ECS) have fueled hopes of implementing novel therapeutic approaches and targets in humans. In our review, we aim to discuss the latest reports describing the changes in the ECS and its components on the development and progression of NAFLD. Furthermore, we will summarize the clinical studies analyzing the effects of natural cannabinoids in NAFLD treatment.

2. Phytocannabinoids

The Cannabis sativa plant is rich in a broad spectrum of phytochemicals including cannabinoids, terpenoids, sterols, and flavonoids. Phytocannabinoids (natural cannabinoids contained in the Cannabis plant) are considered to be the most active ingredients of marijuana that may be found in the human body of all the above mentioned. Most of the phytocannabinoids are found in female Cannabis inflorescence [6].

Among many phytocannabinoids found in Cannabis, the most studied agents are Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and tetrahydrocannabivarin (THCV) [7].

There are plenty of Cannabis sativa varieties (cultivars) existing, and each one has an individual combination of bioactive compounds. In this case, especially important is the proportion of THC:CBD:THCV, which is the cause of the unique and different pharmacodynamic and medicinal properties of various Cannabis extracts [8]. Cannabis also contains a large number of acidic precursors of the aforementioned molecules, respectively: Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and tetrahydrocannabivarinic acid (THCVA). These compounds may reveal interesting therapeutic properties, such as attenuation of body weight gain and amelioration of glucose-insulin homeostasis in a mouse model of HFD-induced obesity after administration of THCA [9]. However, the current knowledge in the field of phytocannabinoid acids is limited and requires further examination [10]. Therefore, the effect of medicinal Cannabis should be considered as the “entourage effect” of cannabis as a whole [6]. When analyzing the effects of the individual phytocannabinoids presented in our review, their complex pharmacology should be considered. The different effects on the response of several phytocannabinoids studied in vivo are possibly related to the competition and displacement of endogenous cannabinoids, with the different centers (orthosteric and allosteric) and with the biased signalling of cannabinoid target receptors [8]. Additionally, phytocannabinoids interact with each other. For instance, CBD has the ability to antagonize THC effects by CBR1 and non-CB1 receptor mechanisms of action. However, CBD may also potentiate some THC effects in an additive or synergistic fashion [11].

Promising research results regarding clinical application of cannabinoids in many morbidities and increasing acceptance of the clinical use of marijuana and its derivatives has led the pharmaceutical industry to research new compounds based on Cannabis [12]. This was accompanied by a growing awareness of the role of the endocannabinoid system in our body. Currently, THC and CBD are the two major active compounds of Cannabis. Table 1 provides a summary of the main opposing characteristics of these substances that account for the differential effects exerted on the human body.

Table 1. Comparison of selected features of tetrahydrocannabinol (THC) versus cannabidiol (CBD).
Feature THC CBD Reference
Interaction with receptors:
a) CB1R
b) CB2R		 + (partial agonist)
- (weak antagonist)		 - (negative allosteric modulator)
- (inverse agonist)		 [13][14][15]
Psychoactive effect Yes No [16]
Appetite stimulation Yes No [16]
Cardiovascular stimulation (inducing tachycardia and hypertension) Yes No [16]
Anticonvulsant effect Yes No [16]
Therapeutic indications approved by the FDA 1 Anorexia associated with weight loss in AIDS 3 patients
Nausea and vomiting associated with anticancer chemotherapy
Multiple sclerosis spasticity		 Lennox-Gastaut syndrome
Dravet syndrome		 [17][18][19][20]
Formulations available on US pharmaceutical market Nabilone (trade name Cesamet) synthetic THC analog aviable as oral capsule
Dronabinol (trade name Marinol)—synthetic formulation of the main THC constituent enantiomer found in Cannabis: [(−)-trans-Δ9-tetrahydrocannabinol] as an oily resin in capsules		 Epidiolex®—pharmaceutical formulation of CBD as an oral solution [18][19][20]
Combination drugs available on US 2 pharmaceutical market Nabiximol (trade name Sativex)—oral spray standardized in composition, formulation, and dose, delivering of 2.7 mg THC and 2.5 mg CBD per dose. [21]

1 FDA, Food and Drug Administration; 2 US, United States; 3 AIDS, Acquired Immunodeficiency Syndrome.

3. Effects of Prolonged Cannabis Use in the Context of NAFLD and its Comorbidities

Progressive legalization of marijuana across the world allowed researchers to observe its interesting properties in encouraging or counteracting many metabolic and psychiatric diseases. Although Cannabis use is generally considered an unhealthy, addictive habit, there is growing strong evidence that it can be protective against the development of metabolic disturbances leading to hepatic steatosis and its progression.

This is a particularly interesting fact because dysregulation of the endocannabinoid system is undoubtedly one of the most important factors in the development of NAFLD. Moreover, Cannabis use is expected to increase over the coming years as a new therapeutic agent for many disorders.

On the other hand, it is well documented that chronic cannabis use (CCU) has been associated with metabolic disturbances ascertained as detrimental factors leading to NAFLD development. Firstly, CCU is undoubtedly linked with increased appetite and calorie overconsumption [22][23]. What is more, this appetite dysregulation is augmented by a higher intake of highly-palpable, unhealthy foods that are rich in refined sugar and fat [24][25][26]. On the other hand, a multitude of studies analyzing the metabolic effects of CCU observed plenty of beneficial effects that could counteract the development of NAFLD. It has been shown that prolonged Cannabis use is linked with decreased prevalence of insulin resistance [27][28] and hyperlipidemia and metabolic syndrome [29][30], as well as decreased frequency of diabetes mellitus occurrence [25]. In the aspect of CCU and obesity, an overwhelming majority of studies have shown a decreased prevalence of obesity among marijuana users. However, one study showed increased visceral adiposity in Cannabis smokers, but this study considered only 30 cannabis smokers [31][32][33]. Mounting evidence indicates that current or past marijuana use is associated with a lower risk of NAFLD development, regardless of the presence of metabolic risk factors [31][34][35][36]. At first glance, this association is contradictory to the role of ECS in NAFLD development. Although it is clearly proven that increased endocannabinoid tone in liver and brain relates to obesity and metabolic syndrome and contributes to the development of NAFLD, the complex effects and impact of phytocannabinoids in relation to NAFLD pathophysiology are not yet fully clear (Figure 1).

Jcm 10 00393 g001 550
Figure 1. The opposite metabolic effects of chronic Cannabis use (CCU).

One of the possible mechanisms responsible for the positive influence of Cannabis use on the prevalence of NAFLD and other metabolic diseases may include the antagonistic action of CBD and THCV on CB1R [37][38]. Additionally, CBD has been described as acting as a negative allosteric modulator of CB1R in HEK 293A and in STHdhQ7/Q7 cells, two model systems that highly express CB1R [26]. Antagonism of CB1R improves the insulin sensitivity of hepatocytes [39], decreases intrahepatic triglyceride synthesis [40], and decreases secretion of very-low-density lipoprotein (VLDL) [41]. Diminished IR may contribute to improved hepatic steatosis, hepatomegaly, and metabolic syndrome by restoring the optimal hepatic glucose metabolism and decreasing liver fat accumulation [42].

Moreover, the anti-inflammatory effects of phytocannabinoids should be emphasized, as they can inhibit secretion of pro-inflammatory cytokines (TNF-a, IL-6) and adipokines (leptin) and lead to the upregulation of inflammatory mediators such as cell transcription factor (NF-kB) [43]. Excessive inflammatory response plays a robust role in NAFLD development and progression to NASH [44]. CBD has been shown to alleviate liver inflammation induced by a high fat-cholesterol (HFC) diet in mice by inhibition of NF-kB and can likewise restrain NLRP3 inflammasome activation, which both lead to a reduction in inflammatory response [45][46][47]. Another possible mechanism that is involved in the beneficial properties of Cannabis is development of tolerance and down-regulation of CB1R from repetitive THC use. THC should theoretically induce or worsen NAFLD by its agonistic role regarding CB1R. However, it has been proven that repetitive use of THC may result in decreased CB1R density, which may contribute to a dose-dependent inverse relationship between marijuana use and NAFLD occurrence [14][29][48]. Finally, the most important factor is that Cannabis is a source of not only THC, CBD, and THCV but also various other phytocannabinoids such as cannabidivarin (CBDV), cannabigerol (CBG), cannabigerovarian (CBGV), cannabigerolic acid (CBGA), and cannabinol (CBN). The therapeutic potential of these compounds remains largely unexplored. Thus, there is a need for further research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove’ [14][49].

This entry is adapted from the peer-reviewed paper 10.3390/jcm10030393

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