The Cannabis sativa L. plant contains over 100 chemical compounds that share a similar chemical structure (Crippa et al., 2018). Of these, at least 70 are cannabinoids, including seven cannabidiol acids (CBDA) and 11 tetrahydrocannabinolic acids (THC) (Perucca, 2017). With high pharmacological values, their potentialities and applications are not only limited to the biological activities of cannabinoids, but  also  defined  by non-cannabinoid compounds. Combining other cannabinoids with non-cannabinoid components could increase the beneficial effects of THC and reduce undesirable side effects (Pollastro et al., 2018).

The chemistry of Cannabis sp. is known to be very complex, capable of producing chemical structures that represent almost all different biogenetic classes (Pollastro   et   al.,   2018).    Chemical     characterization highlights the presence of various constituents, including flavonoids, spiroindanes, dihydro-stilbenes, dihydrophenanthrenes, lignanamides, steroids and alkaloids as well as carbohydrates, fatty acids and their esters, amines, phytosterols and cannabinoids (Andre et al., 2016; Pollastro et al., 2018). Some biological activities of cannabinoids are potentiated by the presence of terpenes and flavonoids due to a synergistic action (Pellati et al., 2018).

The effects of cannabinoid compounds are largely mediated by cannabinoid receptors CB1 and CB2, referred to as the endocannabinoid system (ECS). CB1, cloned in 1990 (Matsuda et al., 1990), is widely expressed in the central nervous system (CNS), where it probably mediates most of the psychotropic and behavioral effects of cannabinoids. CB2 is mainly expressed in peripheral tissues (Munro et al., 1993). Cannabinoid receptors belong to the class A protein G-coupled receptor (GPCR) family, which signal through heterotrimeric Gα and/or inhibitory G proteins, proteins involved in cell signal transduction, which is an important mediator of metabolic pathways (Begg et al., 2005; Balapal, 2017; Kumar et al., 2019; Lorenzen and Sakmar, 2019).

Probably additional receptors may contribute to the behavioral, vascular and immunological actions of Δ9 tetrahydrocannabinol (THC) and endogenous cannabinoids (Begg et al., 2005). In the search for new therapeutic treatments, it was found that cannabinoids can modulate transient potential receptors (TPR). These receptors modulate ion entry, especially Ca²⁺, mediating a variety of neural signaling processes. mplicated in temperature sensation, pressure, and pH, as well as in smell, taste, sight, and pain perception (Muller et al., 2019). Thus, it influences neuroplasticity, apoptosis, excitotoxicity, neuroinflammation and cerebrovascular degradation associated with stroke and trauma.

Phytocannabinoids and endogenous cannabinoids function as retrograde messengers that provide feedback on inhibition of excitatory and inhibitory transmission in the brain through activation of presynaptic CB1 receptors (Maroon and Bost, 2018). CBD, also known as “medical marijuana” represents the second most abundant phytocannabinoid in the Cannabis sp. Plant after the psychoactive tetrahydrocannabinol (Δ9-THC). Unlike THC, CBD is non-hedonic, that is there is no known abuse potential, no detectable psychoactive properties, and has low affinity for endocannabinoid receptors CB1 and CB2 (Pertwee, 2008).

In fact, CBD exhibits various therapeutic effects ranging from anti-inflammatory, antioxidant and neuroprotective to anticonvulsant, antiemetic and analgesic (Jiang et al., 2013; Zendulka et al., 2016; Hahn et al., 2017; Pollastro et al., 2018; Ostrovky et al., 2018). Thus, it acts on the endogenous cannabinoid system by influencing mood, motor coordination, cognition, pain and neuroinflammation (Devinsky, 2018; Chen, 2019).

Chronic cannabis use is associated with neuro-anatomical changes in the hippocampus. Studies suggest that CBD acts as a neuroprotective, as it may improve brain damage, including protection against hippocampal volume loss (Beale et al., 2018). Several anti-epileptic, anxiolytic drugs with better safety profiles have been approved in the last two decades. However, the vast majority of patients remain drug resistant, causing an increased risk of injury, premature death, psychosocial dysfunction and reduced quality of life.

CBD can constitute up to 40% of cannabis extracts and is devoid of the typical psychological effects of cannabis when used as a recreational drug. Cannabidiol has a growing scientific relevance for medical applications and has been shown to be effective in diseases such as schizophrenia, anxiety, epilepsy and motor disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, neuropathic pain and seizure disorders in childhood, Lennox syndromes. Gastaut (LGS) and Dravet (Andre et al., 2016; Cheliah et al., 2018; Crippa et al., 2018; Thiele et al., 2018; Lorenzen and Sakmar, 2019). Thus, this article aims to conduct an integrative review on cannabidiol (CBD) and its potential benefits for human health.

Restrictions on publication date (last two years) and languages (English, Spanish, and Portuguese) apply. We used as criteria search strategy publication that involved administration of CBD in humans at least one pharmacokinetic measurement without criteria for age and gender.

Eligibility criteria

The studies were selected after the evaluation of titles and abstracts, strictly obeying the inclusion and exclusion criteria defined in the research. After identifying the most relevant studies, the complete publication was purchased and reviewed by the authors to determine eligibility for final inclusion. Inappropriate articles were rejected.

Data acquisition

Included articles were analyzed and the following data extracted: sample size, gender, route of administration, source and dose of CBD, and any pharmacokinetic details, where available.

Analysis

The analysis and data extracted from the selected studies were descriptive, allowing observing, counting, describing and classifying the data, in order to gather the knowledge produced about the theme explored in the review.

In this study a final sample  with  2,217  scientific  articles was used for the descriptor: cannabidiol. Thirsteen articles were found on the LILACS database, but four articles were selected; on the IBECS database, three articles were obtained (two selected); and from the MEDLINE 1,237 articles (53 selected) according to the inclusion and eligibility criteria (Figure 1). All studies included in the research were considered of good scientific quality and are described in Table 1, with their respective authors, methodologies, population, age group, administration, treatment (disease) and their respective results, and the conclusion of the study.

CBD is a non-psychotomimetic cannabinoid compound found in Cannabis plants; this effect is believed to be due to the action of CBD on the end ocannabinoid system. Elms et al. (2018) demonstrated that 91% of patients had decreased severity of posttraumatic stress disorder (PTSD) symptoms after CBD dosing.

Beale et al. (2018) conducted a long-term CBD treatment study on users of Cannabis sp. They compared heavy and light users to explore the influence of prior cannabis exposure on CBD treatment outcomes. They found that the volume of the left subicular complex (parasubiculum, presubiculum and subiculum) increased significantly from baseline to posttreatment by 1.58% (Cohen d = 0.63; 2.83% in parasubiculum), noting that the increase in the volume of the left subicular complex was driven by heavy users, particularly the marked growth that occurred on the left presubiculum, which  normalized posttreatment  volumes compared to those seen in mild users. Similarly, only heavy users showed a significant increase in entitlement. These results suggest that CBD may be a useful treatment and therapeutic complement to a number of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer's disease, and depressive disorder). Thus, the authors suggest a protective role of CBD against brain structural damage conferred by chronic use of Cannabis sp.

Chelliah et al. (2018) observed that topical use of CBD for Bullous Epidermolysis (EB) was effective in treating three subjects who benefited from topical CBD use, specifically observing a reduction in pain and blistering and rapid healing of wounds. However, the mechanism of action for the observed benefits still needs to be elucidated.

Generally, the most abundant cannabinoid present in Cannabis ruderalis Janisch (hemp) are cannabinoic acids such as cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), followed   by     their     decarboxylated     forms, cannabidiol (CBD) and cannabigerol (CBG) (Andre et al., 2016). Hahn et al. (2017) suggest that the use of CBD may be useful in the treatment of psychotic disorders, regardless of the concomitant use of Cannabis sp. CBD is highly lipophilic and has low oral bioavailability. The absorption rate of CBD is variable and undergoes extensive first-pass hepatic metabolism by CYP2C19 and CYP3A4 isozymes (Jiang et al., 2013; Zendulka et al., 2016).

Ostrovsky et al. (2018) obtained interesting results on the efficacy of CBD as a therapeutic complement in reducing seizures in patients with Lennox-Gastaut Syndrome   (LGS),  uncontrolled with other drugs. Among the results presented there was a significant improvement in the control of epileptic seizures with CBD, assuming remarkable recognition as the first randomized controlled trial to study a cannabinoid specifically for LGS.

Chen et al. (2019), for reviewing the efficacy, safety, pharmacology and pharmacokinetics of pure plant-derived CBD (CBD, Epiolex) in the treatment of Dravet Syndrome (DS) and  Lennox-Gastaut Syndrome (LGS), observed that ingestion of CBD formulation significantly reduced seizures as a complement to standard antiepileptic therapies in patients ≥ 2 years-old.

In their double-blind, placebo-controlled study, Devinsky et al. (2018) treated patients with LGS.  In this study, a mean percentage reduction in the frequency of seizures during the treatment period was observed: 41.9% in the group using20 mg of cannabidiol, 37.2% in the group with 10 mg, and 17.2% in the group. placebo group (Table 1).

Chelliah et al. (2018) observed that topical use of CBD in patients with epidermolysis bullosa produced faster healing, fewer blisters and reduced pain. According to Crippa et al. (2018), cannabinoid receptors (CB1 and CB2) are highly prevalent in the human nervous system. THC has a well-documented mechanism of action via cannabinoid receptors; however CBD has a relatively low affinity for binding to CB1 and CB2 receptors, which may inhibit THC binding to CB1 cardiac receptors.

Recent findings indicate that some cannabinoid effects are not mediated by CB1 and CB2 receptors, and in some cases there is compelling evidence to implicate additional receptors in these actions (Muller et al., 2019). Thus, for Begg et al. (2005), transient potential receptor (TRP) may imply endothelium-dependent vasodilatory effect and presynaptic inhibition of glutamatergic neurotransmission in the hippocampus. TRP are a group of membrane proteins involved in transducing chemical and physical stimuli in neurons. These receptors modulate the input of ions, mainly Ca²⁺, mediating a variety of neural signaling processes implicated in sensation of temperature, pressure and pH, as well as in smell, taste, vision and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the search for new treatments for these disorders, it has been found that cannabinoids can modulate a subset of TRP channels (Muller et al., 2019).

CBD is used as an antiepileptic drug and several mechanisms have been established to reduce excitability and neuronal transmission such as: inhibition by g-aminobutyric acid; modulation of intracellular calcium by transient potential receptors (TPS) such as TRPM8, TRPA1, TRPV1 and TRPV2, G protein-coupled GPR55 receptor (Muller et al., 2019). The chemistry of Cannabis sp. is known to be very complex, its potentialities and applications are not only limited to the biological activities of cannabinoids, but also defined by non-cannabinoid compounds (Pollastro et al., 2018). According to Andre et al. (2016), several biological effects have been attributed to Cannabis sp., including   anti-inflammatory,   antimicrobial,   neuroprotective   and   antiproliferative activities. In particular, studies show that flavonoids, canflavins A and B have an anti-inflammatory action and their molecular targets have been identified as prostaglandin E2 synthesis found in the microsomal fraction (mPGES-1) and 5-lipoxygenase (5- LO) (Wertz et al., 2014) and finally, flavonoids can also modulate pharmacokinetics of some cannabinoids by inhibiting liver enzymes P450 (Andre et al., 2016). Dihydrostilbenoids represent another class of polyphenolic substances isolated from Cannabis sp., of which canniprene is the main representative and exerts anti-inflammatory activity by inhibiting the production of eicosanoid proinflammatory drugs (Alledrone et al., 2017; Pollastro et al., 2018).

Cunetti et al. (2018) evaluated the use of CBD in patients with chronic pain and as a result, cannabidiol showed good tolerance and no adverse effects were observed. Bravo et al. (2018) were successful with their patients, who responded well to CBD treatment by treating Dravet's Syndrome (DS), genetic epilepsy.

Hoch et al. (2019) performed a systematic review and randomized controlled trials (RCTs) to analyze the efficacy and safety of Cannabis sp. in patients with mental disorders. According  to  the  authors,  THC  and CBD-based medications, administered as adjuncts to pharmacotherapy and psychotherapy, were associated with improvements in various symptoms of mental disorders, but did not produce remission.

Kenyon et al. (2018) evaluated the effects of CBD pharmaceutical grade synthetics on a variety of cancer patients. Results showed a reduction in circulating tumor cells in 92% of the 119 cases studied. Poleg et al. (2019) have noted growing interest from researchers about cannabinoids, especially CBD, either as monotherapy or as an additional treatment for the main symptoms and comorbidities of Autism Spectrum Disorder (AED).

The National Academy of Sciences, Engineering and Medicine claims that there is substantial evidence for the effectiveness of Cannabis sp. in the treatment of chronic pain in adults, there is moderate evidence of improvement in short-term sleep disorders in patients with chronic pain (Romero-Sandoval et al., 2018). Cannabis sp. has been used for centuries in many cultures to treat a wide range of medical conditions. More recently, therapeutic considerations have gone beyond plant extract to explore and produce more pharmacologically refined compounds (Hua et al., 2016).

Cannabis sp. induces its analgesic and mood-enhancing effects through cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals mainly through adenylyl cyclase Gi inhibitory heterotrimeric G protein. Activation of CB1-Gi signaling pathways has the potential to treat various neurological disorders and, therefore, is crucial to understand the mechanism of CB1 deactivation of Gi (Basavarajappa, 2017).

Cannabinoids are currently used to reduce pain and nausea that often accompany cancer. Several cannabinoids have been shown to exert anti-proliferative and pro-apoptotic effects on various types of cancer, both in vitro and in vivo (Massi et al., 2013). Thiele (2018) suggests that the mechanism of action of CBD is related to modulation of TNF-α (Tumor Necrosis Factor alpha) release by inhibiting adenosine reuptake.

Some biological activities of cannabinoids are reinforced by the presence of secondary metabolites in Cannabis sp. extracts, as in cases of sleep and anxiety disorders (Russo et al., 2011). This effect has been attributed to a close interaction between cannabinoids and terpenes, resulting in a synergistic action (Russo et al., 2011). Terpenes are able to increase blood-brain barrier permeability and can also interact with neurotransmitter receptors, contributing to cannabinoid-mediated analgesic and psychotic effects (Andre et al., 2016).

Some biological activities of cannabinoids are reinforced by the presence of secondary metabolites in Cannabis sp. extracts, as in cases of sleep and anxiety disorders. This effect has been attributed to a close interaction between cannabinoids and terpenes, resulting in a synergistic action. Terpenes are able to increase blood-brain barrier permeability and can also interact with neurotransmitter receptors, contributing to cannabinoid-mediated analgesic and psychotic effects.

All studies included in the research were considered of good scientific quality and are described in Table 1. CBD is a non-psychotomimetic cannabinoid compound found in Cannabis plants. This effect is believed to be due to the action of CBD on the endocannabinoid system. There is a growing interest of researchers in cannabinoids, especially CBD, either as monotherapy or as an additional treatment for the main symptoms and comorbidities of Autism Spectrum Disorder (AED). The National Academy of Sciences, Engineering and Medicine claims that there is substantial evidence for the effectiveness of Cannabis sp. in the treatment of chronic pain in adults. There is moderate evidence of improvement in short-term sleep disorders in patients with chronic pain.

Cannabis sp. has been used for centuries in many cultures to treat a wide range of medical conditions. More recently, therapeutic considerations have gone beyond plant extract to explore and produce more pharmacologically refined compounds. Cannabis sp. is a complex plant capable of producing over 480 chemical entities that represent almost all different biogenetic classes. Cannabidiol (CBD) is considered the non-psychoactive component of the plant and has a multitude of pharmacological activities. There is scientific evidence that CBD can be used as a useful treatment for different therapeutic conditions such as schizophrenia, anxiety, epilepsy and motor disorders such as Parkinson's disease, among others CBD and phytocannabinoids have potential health benefits for human health.

The authors would like to thank the CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico –Grant N° 42935/2018-5) by the financial support.

The authors have not declared any conflict of interests.