Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review

Abstract

Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and recreational use has expanded their global market availability to meet local community demands. This scenario presents a complex challenge for clinicians, researchers, and industry, as the global appeal of therapeutic uses of CBD is growing more rapidly than the scientific evidence supporting its safety and effectiveness. Outcomes: A narrative review was conducted to discuss the best evidence regarding the pharmacological profile of CBD, its efficacy, and safety within the context of regulation and perspectives on the development of new cannabinoid-based drugs. Key articles addressing the various facets of this issue were selected for comprehensive analysis. Conclusions: Clinicians and researchers may face unique challenges in understanding the pharmacological profile of CBD and the prospects for developing its clinical indications, given the heterogeneity of clinical terminologies and the quality and composition of cannabis-based medical products available on the market. More basic and clinical research that complies with regulatory agencies’ testing guidelines, such as good manufacturing practices (GMPs), good laboratory practices (GLPs), and good clinical practices (GCPs), is needed to obtain approval for CBD or any other cannabinoid as a therapeutic for broader clinical indications.

1. Introduction

In the past two decades, there has been growing interest in the therapeutic uses of cannabidiol (CBD), one of more than 129 phytocannabinoids found in the cannabis plant. In contrast with Δ-9-tetrahydrocannabinol (∆9-THC), the primary component responsible for the psychotomimetic effects associated with the plant, CBD lacks these properties and is not associated with the reinforcement properties that may lead to abuse or misuse [1,2,3]. CBD also has a favorable tolerance profile across a wide range of doses [4] and has not been associated with changes in critical physiological parameters such as blood pressure, heart rate, or body temperature [2,5], garnering attention for its therapeutic applications due to its low side-effects profile [3,6].

In parallel with academic discussion and research, social perspectives toward the cannabis plant have undergone significant shifts, resulting in notable changes in legislation, public policy, and the marketing of cannabis and its derivatives in many countries [7,8]. Since the advancement of regulatory frameworks and the growth of the cannabis-derived products market over the past decade [8], there has been a marked increase in the variability of cannabinoid-containing products intended for both recreational and medical use [9,10,11]. However, the boundaries between these products are sometimes blurred, as in the case of “over-the-counter” CBD products [12,13,14,15].

Within the scope of products intended for medical purposes under medical prescription, there is currently a wide variability, including isolated (e.g., Epidiolex^®) or combined (e.g., nabiximols, Sativex^®, Mevatyl^®) phytocannabinoids of pharmacological grade purity, synthetic cannabinoids and their analogs (e.g., dronabinol and nabilone), CBD-enriched cannabis extracts that may not contain or contain traces (less than 0.3%) of THC (“broad spectrum”) or may contain THC in variable amounts (“full spectrum”), and the whole cannabis plant for medical use [16]. Although this variability can improve patient access [8], few of these products are pharmaceutical grade and have their applications supported by gold-standard evidence from randomized placebo-controlled clinical trials (RCTs) for the various indications they are currently used for, even when medically prescribed [17] (see Figure 1).

The only products that have demonstrated sufficient efficacy and safety for their approval as medications by regulatory agencies are Epidiolex^® for refractory childhood epilepsy in Lennox–Gastaut and Dravet syndromes and in tuberous sclerosis complex [18,19,20]. Also, Sativex^®, a 1:1 combination of THC and CBD, was approved to control spasticity and neuropathic pain in multiple sclerosis [21,22]. Additionally, there is still weak evidence of the efficacy of Δ9-THC and analogs for the relief of chemotherapy-induced vomiting and nausea and appetite stimulation in HIV wasting syndrome [21,23], although the FDA has approved these indications [17].

The high variability of marketed products, while beneficial for improving patient access, presents significant challenges for clinical decision-making in prescribing due to the broad variability of regulatory hurdles, pharmaceutical best practices, and quality control (difficulty in standardizing market cannabis-derived products regarding the quantity, proportion, and stability of phytocannabinoids) [8,17,24]. This complexity arises not only from the challenges of handling the plant’s botanical matrix but also because these marketed products often do not adhere to good agricultural practices (GAPs) and good manufacturing practices (GMPs), nor are they subjected to adequate pharmacovigilance controls through good laboratory practices (GLPs) [24,25,26,27]. These issues have several crucial implications for clinical practice, most notably the lack of effectiveness and safety concerns [28]. The variable amounts of ∆9-THC [11,27] and associated impurities in non-controlled products [29,30] can pose several risks to vulnerable populations such as children and adolescents and pregnant and lactating women [31]. This is particularly important regarding the long-term potential deleterious effects of ∆9-THC on neurodevelopment, the associated risk of onset of chronic psychiatric disorders such as anxiety, depression, and psychosis, as well as cognitive impairment and addiction [32,33].

When products are prescribed for clinical conditions without regulatory support regarding their efficacy and safety, and in the absence of proper pharmacovigilance control, GAPs, GMPs, and GLPs, patients may be exposed to interventions with an uncertain risk-benefit balance [8]. This can lead to unpredictable treatment failures, underreported medium- and long-term side effects, potential patient harm, and increased treatment costs [28].

Although some authors argue in favor of the therapeutic use of extracts from the perspective of pharmacological synergy between various phytocannabinoids and non-phytocannabinoid components (described as the “entourage effect”) [34], this hypothesis has proven to be too imprecise and nonspecific to designate the full potential of pharmacological interactions that can occur between these components in cannabis extracts [35,36,37]. Until the methodological and regulatory challenges associated with these products (along with other limitations related to this complex supply chain) are resolved, and evidence provided by RCTs is available [7,8], caution and prudence are necessary on the part of clinicians and stakeholders concerning prescription and regulation.

Therefore, the present review article explores the differences between purified CBD and cannabis extracts enriched with CBD, focusing on their efficacy, safety, and adherence to pharmacological gold standards. It also provides a narrative review of studies that support the rational decision-making of clinicians when prescribing CBD-based products, considering regulation and access concerns. By comparing these two forms, we aim to provide a comprehensive understanding that can guide healthcare providers, researchers, and consumers in making informed decisions about CBD products.

A non-systematic search was conducted in the PubMed, Embase, Web of Science, Scopus, and Lilacs databases to identify relevant studies in the field (including reviews and original studies) that enable a rational and evidence-based discussion.

2. Cannabis as Medication and Abuse Drug: Historical View of Market and Regulation Boundaries

Cannabis sativa L. (Cannabaceae) has been cultivated for millennia, serving diverse purposes, including fiber, food, religious, recreational, and medicinal uses [38,39,40,41]. While its therapeutic potential was acknowledged in ancient times, significant interest in its medicinal applications in the Western world emerged in the 19th century [40,41], leading to its inclusion in various official pharmacopeias, such as the British Pharmacopeia and the first Brazilian Pharmacopeia, where it was recognized for anti-inflammatory, analgesic, antiemetic, and anticonvulsant uses [8,38,39].

However, due to a lack of knowledge about its active components and inadequate standardization, there was high variability in therapeutic effects. Additionally, the rise of synthetic drugs in the early 20th century and concerns over cannabis abuse resulted in restrictive regulations in multiple countries [16,39]. Following strict classifications by the United Nations Conventions on Narcotic Drug Control (1961, 1971, 1988), cannabis was categorized as a Schedule I and IV substance, indicating significant control [39,42]. Despite this, it remains the most widely consumed illicit drug globally [7]. A comprehensive review of recreational cannabis policies is beyond the scope of this article.

In the past 60 years, following the isolation of key active components [43,44,45], scientific interest in cannabis has resurged, driven by preclinical and clinical research evidencing the therapeutic potential of specific phytocannabinoids [41]. This renewed interest has prompted international authorities to reconsider regulatory restrictions on cannabis for research and medicinal use [16,39]. In 2019, the WHO’s Expert Committee on Drug Dependence recommended removing cannabis from Schedule IV while retaining it in Schedule I, a suggestion adopted by the United Nations Commission on Narcotic Drugs in December 2020 [46,47]. This resolution reflects the UN’s recognition of cannabis’s medicinal potential.

Despite its reclassification, creating evidence-based regulations to address health risks and establish quality standards for cannabis products remains a challenge. As of March 2021, thirty-six countries had enacted regulatory measures for medical cannabis, varying significantly based on sociopolitical conditions—from access to registered cannabinoid medications to medical prescriptions for unregistered products [8]. Clinicians must navigate these complex regulatory frameworks, as they directly influence the safety, efficacy, and quality of cannabis-based products available for patient use.

3. Phytocannabinoids, Synthetic Cannabinoids, and Non-Cannabinoid Compounds Derived from Cannabis That Hold Therapeutic Potential

Currently, research has identified that, aside from Δ9-THC and CBD, which are well-documented and widely studied, the cannabis plant comprises roughly 565 constituents across 23 classes of compounds. These include more than 129 cannabinoids, 120 terpenoids (comprising 61 monoterpenes, 52 sesquiterpenes, and 5 triterpenoids), 26 flavonoids, 11 steroids, among others [48,49,50].

Perhaps the most well-known class of compounds in cannabis is the phytocannabinoids. These are a group of terpene-phenolic compounds produced through the plant’s secondary metabolism in trichomes of female inflorescences [51], many of which directly modulate the endogenous endocannabinoid system [48]. These naturally occurring cannabinoids are distributed among 10 subclasses, including Δ9-THC and Δ8-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabidinol (CBND), cannabicyclol (CBL), cannabitriol (CBT), cannabielsoin (CBE), and other miscellaneous types (30 known) [52].

In the plant, phytocannabinoids can usually be present in either acidic or neutral forms. The acidic forms are synthesized in the plant via enzymes (e.g., cannabidiolic acid (CBDA) produced by CBDA synthase), while neutral forms are created via decarboxylation from exposure to light or heat [48,49,51,52]. Besides Δ9-THC and CBD, various other phytocannabinoids, including cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN), produce pharmacological effects of potential therapeutic relevance [37,51]. Many phytocannabinoids also have chiral centers in their molecular structures [53]. This means there could be one or more additional enantiomers, mirror images with unique three-dimensional shapes, and potentially different physiological effects [54].

It is important to distinguish that, in addition to cannabinoids derived from plants, numerous synthetic cannabinoids have been created and studied. These encompass pharmaceutical grade compounds that resemble the chemical structure of naturally occurring phytocannabinoids found in cannabis plants, like dronabinol (an oral synthetic Δ9-THC formulation) and ZYN002 (a synthetic CBD gel for transdermal application). Most cannabinoids and their derivatives originate from natural sources through the cultivation of cannabis. However, their content can vary significantly due to a range of influences, including soil characteristics, climatic factors, and inherent challenges associated with the extraction and purification of phytocannabinoids of therapeutic interest. Consequently, the interest in obtaining cannabinoids through chemical synthesis has been growing among an increasing number of researchers [55].

However, the notion that cannabinoids are the only components with therapeutic properties in cannabis has been changing in recent years. This is due to increasing scientific interest in investigating the therapeutic contributions of terpenes and flavonoids. Terpenes are lipophilic organic compounds abundant in the plant’s oils, responsible for its characteristic aroma. Their distribution in the cannabis plant can vary substantially depending on the chemovars [56] and on the conditions and duration of drying and storage [57]. Due to their therapeutic properties in other plants [58], terpenes are being investigated as potential contributors to the therapeutic value of the cannabis plant [59]. Also, flavonoids constitute a broad group of bioactive compounds known for providing color and protection against UV radiation. Their role in cannabis is not yet fully understood, and the literature on this topic remains scarce [60].

4. Cannabinoid Drug Development

4.1. Phytotherapy and the ‘Medical Cannabis’ vs. ‘Single Molecule’ Approach

Given the diverse array of compounds derived from cannabis and their synthetic counterparts that interact with the endocannabinoid system to produce therapeutic effects, two primary paths have emerged over the past decades for cannabinoid drug development. These paths reflect extensions of traditional pharmacological drug development as proper medications versus botanical-derived drug development within the context of alternative and complementary medicine (ACM) [61,62].

The first path involves a strategy of single-molecule purity standards for phytocannabinoids extracted from the plant matrix or synthetic cannabinoids and their analogs [61]. The second path involves a broader strategy of products directly derived from the plant that may contain various phytocannabinoid compounds across a wide spectrum of distribution and concentration and also under different designations, such as “medical cannabis”, “cannabis-based medicines”, or “cannabis-based products” [61,62]. For a comparison, see Table 1.

The standard approval process for medicines in Western medicine follows the model of isolated compounds that have been systematically developed into medications [61]. As will be discussed further, this branch of medication development possesses characteristics that facilitate studies following the principles of evidence-based medicine, which are necessary for approval by regulatory agencies for specific therapeutic indications based on efficacy and safety criteria.

However, this path underwent a significant shift with the legalization of medicinal use of botanical cannabis, initially in some states of the United States and subsequently in other countries worldwide [8]. This is a significant example in medicine where market access to a drug for medical use occurred through legislation rather than formal approval by regulatory agencies, and where the botanical model was preferred over the single-molecule and pharmacological standard model [61].

In this regard, advancements in understanding the plant’s matrix concerning the variability of its active components through the acquisition of different phenotypes via various selection, cultivation, and extraction methods have led to renewed interest in using the plant as raw material for various therapeutic subproducts in recent decades [62,63,64]. Thus, marketed cannabis-based products, encompassing oils and extracts, as well as the inhalation and decoction of specific parts of the plant, have become designated forms of its therapeutic use again, often overlapping with recreational use as permitted in some countries and allowed by some regulations [35].

4.2. Critical Evaluation of the ‘Entourage Effect’ and the ‘Medical cannabis’ Concept Through a ‘Single Molecule’ Approach Perspective

In this context, the ‘Entourage Effect Hypothesis’ [65] has gained new contours within the concept of more than a synergistic therapeutic potential in the context of cannabis phytotherapy [63,66,67], and is cited for advocating the therapeutic use of these products based on theorizing their potential benefits [34,63] without, however, emphasizing the importance of controlled studies to evaluate their safety and effectiveness properly [35,37,68].

Some authors have already pointed out the inconsistency of the validity of this hypothesis within the pharmacokinetic and pharmacodynamic frameworks, considering the great difficulty in controlling multiple variables to support, in fact, a hyper-synergistic pharmacological effect between cannabinoids and non-cannabinoids [35,36,37]. This hypothesis also includes several limitations, including the current lack of clarity regarding which compounds contribute to the effect, which pharmacodynamic effects of cannabis are influenced, and whether this phenomenon can be leveraged to enhance cannabinoid therapeutics rather than adverse effects [61,69].

As such, the results obtained under the scope of this hypothesis have been controversial, with inconsistent results in both the few controlled preclinical [70,71,72] and clinical [73] studies that have examined it [74].

Furthermore, while significant progress has been made in recent years in decomposing the active principles of cannabis and their therapeutic potential [21,49,75], scientific literature also provides solid evidence regarding the health risks of cannabis use as a drug of abuse, concerning the risk of developing chronic psychiatric disorders such as depression and anxiety [76], psychosis [77], cognitive impairment, and the risk of car accidents [78], particularly for younger populations [79]. There is also data in the literature showing that exposure of young people to cannabis-based product advertisements increases the risk of cannabis use disorder [80]. Together, these data raise concerns that have not yet been addressed in the literature about how the increased circulation of these products on the market may affect the recreational use and abuse of cannabis [7,81].

Thus, the very concept of “medical cannabis” becomes extremely fragile in terms of an imbalance of risks and benefits [33]. On one hand, it serves the growing billion-dollar market and advertising of these products well, making them attractive to patients and the general public given the argument that if it is natural, it cannot be harmful [82]. On the other hand, it generates methodological inconsistencies at the research level by creating heterogeneity of terms and products [10,26,61], also involving additional concerns related to contamination with heavy metals, mycotoxins, pesticides, and other impurities [27,29,30]. Consequently, research and clinical decision-making become complex, increasing uncertainty about the effectiveness and safety of these treatments for patients and heightening clinicians’ responsibility for outcomes [17].

Combined, these factors may explain, at least in part, the delay in delivering robust and definitive clinical evidence of the safety and efficacy of cannabis-based medicines, as well as in developing interventions with a favorable cost–benefit balance [62]. Additionally, they contribute to the difficulty for clinicians in adequately reconciling and educating their patients’ expectations about these therapies [17]. From a retrospective perspective, this could indicate a similar path to the devaluation and loss of credibility of phytocannabinoid and cannabis-based medicines research as occurred in the nineteenth century [39].

Analogous to cannabis and cannabinoids, other medications have also been isolated from sources that potentially included greater risks to humans, such as acetylsalicylic acid from willow bark, opioids originating from poppy, and bradykinin and captopril derived from the venom of the Bothrops jararaca snake. Although the in natura use of these examples may seem less reasonable today in Western medicine, this is due to the development of products with sufficient quality standards to be reproducible and widely tested for their safety and efficacy, thus being considered regulated medications [83].

Having discussed the differences between the terms “medical cannabis”, “cannabis-based medicines”, “cannabis-based products”, and the concept of cannabinoid-based medications, we will proceed with a description of the properties and indications of CBD at a pharmacological purity level.

5. CBD: From Isolation to Therapeutic Applications

CBD was first isolated from the cannabis plant in 1940 [43]. For the next two decades, research primarily focused on its isolation, with its precise chemical structure elucidated in 1963 by Israeli researchers led by Raphael Mechoulam [44]. During the 1960s, Mechoulam’s team also clarified the structure and stereochemistry of Δ9-THC and other major cannabinoids [45], setting the stage for subsequent research into their pharmacological properties (see Figure 2).

Until the 1970s, few pharmacological studies on CBD were conducted, suggesting it lacked the psychotomimetic effects associated with Δ9-THC [84]. Early studies from this period indicated that CBD did not mimic cannabis effects, leading to the belief that it was an inactive cannabinoid. This view changed as research revealed significant variations in the effects of different cannabis extracts that could not be explained solely by differing Δ9-THC levels [85,86]. This led to the hypothesis that other cannabinoids, especially CBD, might influence Δ9-THC’s effects.

In this context, a Brazilian team led by Elisaldo Carlini began investigating the effects of CBD and other cannabinoids [87]. Their research suggested that CBD had distinct pharmacological effects, including anticonvulsant properties in animal models [88,89], prompting the first placebo-controlled studies in patients with refractory epilepsy [90,91] and raising the hypothesis of using isolated CBD for the treatment of this condition.

Subsequent research showed that CBD could inhibit or enhance Δ9-THC’s effects in animals, depending on their ratio and dosage [92,93]. Studies on humans found that high oral doses of Δ9-THC induced anxiety and psychotic symptoms, which were mitigated by co-administration of CBD [1].

These findings have been crucial in understanding the varied effects of marijuana across populations and suggest that CBD possesses its own pharmacological properties. Subsequent research has explored these effects extensively, resulting in the current understanding that CBD exhibits a wide range of actions and potential therapeutic uses, particularly in neuropsychiatric conditions [94,95].

Despite the increase in studies on CBD and Δ9-THC in the 1970s, interest in CBD’s therapeutic profile waned in the following decades. However, some groups, particularly the Brazilian teams led by professors Carlini and Zuardi, continued to investigate the anticonvulsant [91,96,97,98], anxiolytic [1,99,100,101] and antipsychotic [102,103] properties of CBD in preclinical and clinical studies [94].

A renewed interest in cannabinoid research emerged after the identification of cannabinoid receptors CB1 and CB2 in the brain and peripheral tissues [104,105] and the discovery of endocannabinoids such as anandamide [106], 2-arachidonoyl-glycerol (2-AG), and its degradation enzymes [107]. These findings suggested the existence of an endocannabinoid system, prompting studies into the pharmacological activities of endocannabinoids as retrograde synaptic messengers [108,109,110], their synthesis on demand from postsynaptic membrane phospholipids [111], and their degradation by the enzymes FAAH (fatty acid amide hydrolase) and MAGL (monoacylglycerol lipase), respectively, in presynaptic neurons [111,112,113,114].

These discoveries led to investigations into how disruptions in the endocannabinoid system could be involved in mental conditions like anxiety and psychotic disorders, and its interaction with other neurobiological processes in the brain [115,116,117,118]. This ushered in a new era of research into the therapeutic properties of cannabis constituents, including CBD’s anxiolytic, antipsychotic, and anticonvulsant effects, through its interactions with the endocannabinoid system and other brain sites [119,120,121].

6. Pharmacology of CBD

Most varieties of the cannabis plant produce an unstable compound called cannabidiolic acid (CBDA), which is non-enzymatically decarboxylated with the aid of heat to produce CBD [49,51]. CBD can exist in more than one form. It consists of a terpenophenolic molecule containing 21 carbon atoms with the formula C21H30O2 [122] and two chiral centers, leading to four stereoisomers [123]. The cannabis plant naturally produces one of these, known as (−)-CBD, while its counterpart, (+)-CBD, is not present in Cannabis sativa. The (+)-CBD exhibits distinct properties, such as high affinity for CB1 receptors [54].

CBDA can be more potent than CBD in certain situations, but its chemical instability complicates its use [51]. Chemical modifications to enhance its stability have been tested in preclinical studies. Other drugs modified from the CBD molecule have also been synthesized, with many showing therapeutic potential in animal models [124].

6.1. Pharmacodynamics

Initially, conducted in vitro studies have identified over 65 potential molecular targets, including enzymes (49%), transporters (20%), receptors (15%), and ion channels (15%), which vary with CBD dosage [125,126,127].

Several mechanisms have been suggested for CBD’s action: activation of TRPV1 receptors, inhibition of anandamide reuptake and metabolism, inhibition of adenosine reuptake, antagonism of GPR55, agonism of PPARγ and 5-HT1A receptors, and increased intracellular Ca++ [128,129,130,131,132,133].

Early research focused on CB1 and CB2 receptors, where Δ9-THC acts as a partial agonist. However, CBD does not bind to the orthostatic binding site of CB1 and CB2 receptors [134,135,136] (see Table 2). Some studies suggest CBD could act as a negative allosteric modulator of CB1 and CB2 receptors [137,138,139]. While this could explain the mitigation of some Δ9-THC effects [140], in vivo results remain debated.

CBD can inhibit the enzyme FAAH (fatty acid amide hydrolase) [141,142,143], which metabolizes anandamide, indirectly increasing this neurotransmitter and interacting with CB receptors, unlike agonists that activate CB1 receptors indiscriminately. Animal models suggest this mechanism may be involved in CBD’s effects on aversive memories, obsessive-compulsive disorder models, and chronic stress consequences [143,144].

Anandamide, a partial agonist of CB1 and CB2 receptors, also activates vanilloid receptors (transient receptor potential cation channel subfamily V member 1 or TRPV1) [145], a subfamily of ion channels involved in inflammation and nociception in the periphery [146] and in glutamate release in the central nervous system [147]. In addition to direct TRPV1 activation, CBD may enhance anandamide’s action on these receptors by inhibiting its metabolism [148]. These effects could be involved in CBD’s inverted U-shaped dose-response curves and antipsychotic effects [149].

Initial in vitro studies suggested CBD could be a 5-HT1A serotonin receptor agonist [150], explaining its broad therapeutic spectrum, given serotonin’s role in various central nervous system pathologies. Subsequent studies showed that some CBD effects, such as the anxiolytic [151], antidepressant [152], anti-stress [153], neuroprotective [154], analgesic [155], and anti-cataleptic [156], are blocked by reversible 5-HT1A antagonists. However, the molecular mechanism by which CBD facilitates 5-HT1A receptor activation remains unclear. Recent research suggests CBD may not act as a direct agonist but likely facilitates 5-HT1A-mediated neurotransmission as a positive allosteric modulator [150,157,158].

Other mechanisms associated with CBD effects include positive allosteric activity on GABA-A receptors [159,160] and GPR55 antagonism [161].

Therefore, the pharmacological complexity of CBD remains a challenge for understanding its effects. While drug development traditionally focuses on creating increasingly selective compounds to enhance therapeutic effects and reduce side effects, CBD’s broad spectrum of potential therapeutic effects likely results from interactions with various molecular targets, exerting fine modulatory actions rather than potent activation or inhibition [162].

6.2. Pharmacokinetics of CBD

The observed effects of CBD are influenced by dose, formulation, and route of administration. Like Δ9-THC, CBD is a highly lipophilic molecule, which significantly determines its pharmacokinetic characteristics [163].

6.2.1. Absorption

CBD is commonly administered orally, topically, inhaled, or vaporized [128]. Inhalation allows CBD to be efficiently absorbed into the lungs from the bloodstream, showing pharmacokinetics similar to intravenous administration [164]. Intravenous administration enables CBD to quickly cross the blood-brain barrier, distributing to the brain, adipose tissue, and other organs, although few studies have investigated this pathway [164]. Due to its lipophilicity, CBD can be slowly released from the adipose tissue [2].

When inhaled, CBD reaches peak plasma concentrations (Cmax) within 5–10 min (Tmax). The bioavailability via this route is up to 31% and depends on factors such as inhalation characteristics, the device used for inhalation, particle size, and deposition site within the respiratory system. However, the need for specialized equipment limits the widespread use of these administration methods [165].

Oral administration results in a variable pharmacokinetic profile, likely due to the poor water solubility of CBD [166]. Maximum plasma concentrations achieved through oral intake are lower than those from inhalation, with an oral bioavailability of 6% in humans, reflecting, among other factors, extensive first-pass metabolism. After oral administration, the plasma concentration of its main metabolite is about 40 times higher than that of CBD, and up to 75% of an oral dose of CBD is eliminated by first-pass hepatic metabolism before reaching systemic circulation [167]. The time to reach peak plasma concentration (Tmax) via this route is about 120 min but can vary depending on the dose and other factors [168].

The oral bioavailability of CBD is significantly influenced by factors such as the vehicle used and food intake [168,169]. For example, a recent study observed that when administered dissolved in corn oil instead of purified powder, CBD (150 mg) reached four times higher Cmax [169]. Additionally, CBD’s oral bioavailability is notably affected by food. Being a highly lipophilic molecule, CBD can dissolve in the fats present in food, increasing its oral availability. Indeed, when administered with fatty foods, its availability increases by approximately 3 to 5 times [170,171,172].

Therefore, there is potential to develop enhanced CBD formulations that offer increased oral bioavailability and are less affected by food interactions [167]. Some promising studies have evaluated the impact of self-emulsifying drug delivery formulation technologies in developing formulations that minimize the impact of CBD’s liposolubility on inter- and intra-subject variability in absorption and distribution [173,174].

Despite some in vitro studies suggesting that CBD can convert to Δ9-THC or Δ8-THC in acidic conditions, raising concerns that this process might occur in the stomach, various in vivo studies have indicated that this does not happen in humans under clinical use conditions [175,176].

Administration via oromucosal routes (e.g., sprays like nabiximols) and sublingual routes offers a more consistent pharmacokinetic profile than oral administration [168]. By avoiding extensive first-pass metabolism, these routes achieve plasma concentrations with less variability than those produced by the same dose orally, making them useful in situations requiring rapid effects, such as pain relief [177].

Cannabinoids can also be administered transdermally, with CBD’s skin permeability being about 10 times greater than that of THC. Factors affecting absorption via this route include local blood flow and skin permeability. Given the extreme lipophilicity of these compounds, transdermal administration requires measures to increase skin permeability [178].

6.2.2. Distribution

The distribution of CBD to various tissues, including the central nervous system, can be affected by body composition, such as the higher relative amount of fat in women and the elderly [168]. CBD has a high volume of distribution (Vd) and, with chronic use, can accumulate in adipose tissue [179].

Some animal studies using CBD administration in knockout rats for the expression of P-glycoproteins (P-gp) and breast cancer resistance protein (Bcrp) have shown that CBD is not a substrate for the action of these transporters, meaning they do not reduce the transport of CBD to the nervous system [180]. These proteins are expressed in the blood-brain barrier and act by pumping drugs such as risperidone out of the central nervous system, which has been hypothesized as a mechanism of intrinsic pharmacological resistance [180]. More recent studies have shown interest in investigating whether CBD could inhibit the action of these transporters on other co-administered drugs, potentially modifying a factor of pharmacoresistance for drugs acting on the central nervous system, such as psychotropic and anticonvulsant drugs [181].

6.2.3. Metabolism

CBD is metabolized in the liver by cytochrome P450 enzymes, including CYP2C19, CYP3A4, CYP1A1, CYP1A2, CYP2C9, and CYP2D6, and is converted into 7-hydroxycannabidiol (7-OH-CBD) [182]. After hydroxylation, CBD undergoes further metabolism in the liver before being excreted primarily through feces and urine [165]. Preclinical and clinical studies suggest that 7-OH-CBD is an active metabolite, also exerting anticonvulsant activity [183,184].

CBD has a half-life of 18–32 h and a clearance rate of 57.6–93.6 L/h [165]. Recent studies propose that CBD undergoes multiphasic elimination, with an initial rapid phase and a slower terminal phase, likely reflecting its slow absorption and distribution to tissues [168].

CBD is well tolerated at therapeutic doses and has a good safety profile [4,185]. However, some studies have indicated that CBD has potent inhibitory effects on CYP2C, CYP2D6, and CYP3A isoforms [186], which can interfere with other drugs metabolized by these isoenzymes (see further discussion on potential drug–drug interactions).

6.3. CBD in Special Populations

Most studies investigating the pharmacokinetic properties of CBD and other cannabinoids have been conducted in adults, predominantly men. The number of pharmacokinetic studies in children and the elderly is limited. Additionally, there is a lack of studies on the prolonged use of oral CBD in patients with renal and hepatic insufficiency [187]. Given the previously mentioned high degree of hepatic clearance experienced by orally administered CBD, this latter population warrants additional attention and caution.

Age-related changes in drug metabolism, such as aging, pregnancy, decreased hepatic and renal function, can alter the pharmacokinetics of CBD [187]. The aged population is at higher risk for drug–drug interactions due to polypharmacy, and the potential for increased sensitivity to CBD’s effects needs further investigation.

A meta-analysis evaluating the efficacy and safety of medical cannabinoids in eight RCTs reinforced the findings that only purified CBD demonstrated accumulated efficacy in the pediatric population for the therapeutic outcome of controlling epileptic seizures in Dravet syndrome [188]. It indicated that all groups of cannabinoids (including purified CBD, nabilone, nabiximols, and standardized Δ9-THC:CBD extract 1:20) were associated with severe adverse effects, including mental adverse events [188]. These safety findings are significant and align with case reports indicating severe neurobehavioral side effects in children with cannabis intoxication, such as ataxia and prolonged coma [189,190,191,192].

Children and adolescents may be affected by cannabinoids differently than adults, considering the differences in neurodevelopment and their pharmacodynamic and pharmacokinetic implications for safety [193]. As long-term exposure to cannabinoids may pose risks to neurodevelopment, the use of CBD and other cannabinoids in the pediatric population requires extreme caution in weighing risks and benefits.

7. Clinical Profile of Pharmaceutical Grade CBD

7.1. Adverse Effects

Recent reviews indicate that the acute, sub-chronic, and chronic administration of CBD in various doses, especially in oral formulations, generally results in mild to moderate side effects, including gastrointestinal symptoms, drowsiness, loss of appetite, and elevated liver enzymes [181,185]. Serious adverse effects are rare, with hypertransaminasemia, marked by serum levels exceeding three times the upper limit, being the most notable. Other reported complications involve seizures, sedation, lethargy, upper respiratory tract infections, and rashes. These adverse events are mainly associated with doses higher than those recommended for human therapy and concurrent use of antiepileptic drugs such as valproate [181,194,195]. The long-term effects of CBD, however, are still unknown [196], demanding caution regarding its use in children, adolescents, and during pregnancy and lactation [31].

7.2. CBD–Drug Interactions

A drug interaction involves a quantifiable modification in the magnitude or duration of effects due to the concurrent or prior administration of other drugs, food, or the patient’s pathophysiologic conditions [197]. These interactions can be additive (1 + 1 = 2), synergistic (1 + 1 > 2), or antagonistic (1 + 1 < 2). Typically, most interactions documented in the literature are attributed to pharmacokinetic mechanisms, involving alterations in the activity of cytochrome P450 (CYP) isoenzymes, P-glycoprotein (P-gp), or other drug transporters [198].

Given that CBD inhibits cytochrome P450 (notably the isoforms 2C19 and 3A4) and UDP-glucuronyltransferase isoforms, it is crucial to assess potential drug–drug interactions carefully [4,167], considering the metabolism of other drugs co-administered with CBD [199]. Also, drug–drug interactions affecting CBD metabolism are likely to have a prominent impact on its systemic exposure after oral administration [200].

Thus, the interaction of CBD with drugs metabolized via the cytochrome P450 pathway can involve bidirectional interference, with CBD and other drugs potentially altering each other’s serum levels. This is particularly relevant for the CYP3A4 isoform, as approximately 60% of clinically used drugs are metabolized by this pathway [167]. These interactions could theoretically result in increased side effects and decreased therapeutic effects over time, underscoring the importance of controlled studies in evaluating the safety of CBD’s pharmacological interactions and their implications for clinical outcomes [167].

Studies on drugs that significantly interfere with the CYP3A4 pathway have shown an increase in CBD plasma concentration in the presence of a CYP3A4 inhibitor (ketoconazole), leading to significant side effects [201,202]. Similarly, the administration of CYP3A4 inducers (rifampicin) reduced CBD serum levels [201,202]. Although in vitro studies suggest that CYP2C19 plays an important role in CBD metabolism, its concentrations did not change in the presence of potent inhibitors of this enzyme.

Additionally, CBD also affects other CYP450 isoenzymes, and interactions may occur in different metabolic pathways, such as 5′-diphospho-glucuronosyltransferase (UGT), as well as interactions at the level of transporters and receptors [181,198].

Among the various potential drug interactions when CBD is used, those with anticonvulsants, benzodiazepines, antidepressants, anticoagulants, and opioids have shown significant implications in clinical practice.

7.2.1. Anticonvulsants

Among anticonvulsants, CBD interacts bidirectionally with clobazam, potentially via the CYP2C19 enzyme [203,204,205]. CBD significantly increases the plasma concentration of clobazam and its active metabolite, N-desmethylclobazam, reducing its clearance by up to five times, while clobazam induces an increase in the 7-hydroxy CBD metabolite [204,205]. Although the antiepileptic action of CBD is independent of this interaction with clobazam, patients using both medications concomitantly may experience better seizure control compared to those using either drug alone. Conversely, there may also be a higher incidence of side effects such as sedation, ataxia, cognitive impairments, cough, difficulty breathing, fever, and behavioral changes. Rigorous monitoring of side effects is recommended during the concomitant use of both medications, including serum clobazam level monitoring if available [198].

In human studies, the concomitant use of CBD and valproic acid is associated with hepatotoxicity, indicated by altered liver enzymes (transaminases and gamma-glutamyl transferase) and thrombocytopenia in pediatric patients [203,206]. These effects tend to be dose-dependent and resolve with the reduction or discontinuation of one of the drugs, although rare cases of severe liver injury leading to jaundice have been reported [203,206]. It is advisable to conduct laboratory evaluations to monitor hepatic profiles and valproic acid levels before introducing CBD into the prescription, with follow-up tests at six weeks.

Moreover, preliminary studies suggest that CBD may interact with other anticonvulsants, potentially increasing the plasma concentration of gabapentin, oxcarbazepine, and topiramate [203]. No interactions have been reported with pregabalin and levetiracetam [203]. Overall, the results are mixed and preliminary, not seeming to bring significant changes in the clinical outcomes of patients, but clinicians should always be vigilant for worsening side effects during the combined use of CBD with these anticonvulsants [198,203].

7.2.2. Benzodiazepines and Antidepressants

In vitro studies suggest that CBD exhibits pharmacokinetic interaction with citalopram and escitalopram through probable CYP3A4 and CYP2C19 interactions, increasing the plasma concentration of these drugs by reducing their metabolism [207]. This interaction does not appear to result in serious side effects. Similarly, preliminary evidence suggests that CBD may interact with sertraline, fluoxetine, and mirtazapine. There is still insufficient evidence regarding the potential interaction of CBD with tricyclic antidepressants, drugs known to increase the QT interval and share the same metabolic pathways as CBD [198].

As mentioned in the case of clobazam, CBD’s action on CYP3A4 and CYP2C19 can interfere with the metabolism of other benzodiazepines such as diazepam and midazolam [198].

7.2.3. Anticoagulants

Case reports suggest that CBD may increase the efficacy of warfarin [208], resulting in gastrointestinal bleeding, which has also been observed during the recreational use of cannabis [209,210,211]. Since other oral anticoagulants, such as rivaroxaban, share the same metabolic pathways, similar interactions are possible, although no human cases have been reported yet. Therefore, it is advisable to be vigilant about these potential interactions, monitoring coagulation tests, and considering dose adjustments of warfarin if necessary [198].

7.2.4. Opioids

Some case reports indicate that CBD may increase the plasma concentration of opioids such as buprenorphine [212] and methadone [213] by inhibiting their metabolism through the CYP3A4 and CYP2C19 isoforms. It remains uncertain whether these effects could be associated with increased analgesic potency of opioids, facilitate their discontinuation in cases of dependence, or result in increased side effects.

It is important to emphasize that, based on available evidence, CBD is generally considered a relatively safe medication, with few clinically significant drug interactions and no absolute contraindications. However, evidence on the pharmacological interactions of cannabis and its derived products remains limited [214]. Many implicated interactions are still theoretical or demonstrated in small studies [198]. Therefore, following the principle of non-maleficence, it is advisable to exercise caution when considering potential pharmacological interactions related to cannabis-derived products such as extracts and whole plants until more robust evidence is available.

7.3. CBD’s Bell-Shaped Curve Dose-Response

Understanding the dose-response profile is an important pharmacological factor in drug studies, allowing correlation with effectiveness data for a specific clinical condition. To date, CBD has shown an established effective dose range only for the treatment of refractory childhood epilepsy in Dravet and Lennox–Gastaut syndromes, for which it has received regulatory approval as a medication [215].

However, preliminary academic studies involving translational research that correlates preclinical models and human studies suggest that some therapeutic effects of CBD, notably its anxiolytic effect, follow an “inverted U” dose-response pattern [3]. While some pioneering studies [93] reported that CBD (10 mg/kg) could reduce conditioned emotional responses in rats, others did not observe any effects of CBD (100 mg/kg) [3]. These apparent contradictions were reviewed by Guimarães [100,216] using an anxiety-sensitive test—the elevated plus maze. Using this model and conducting a comprehensive dose-response analysis, they demonstrated that CBD induces anxiolytic effects at lower doses (2.5–10 mg/kg) in rats, which completely disappear at higher doses [100]. Subsequently, a study involving healthy volunteers subjected to a validated experimental anxiety model (Public Speaking Simulation Test) demonstrated that, among a broad range of single doses studied (150 mg, 300 mg, and 600 mg), CBD exerted the most effective acute anxiolytic effect at the intermediate dose of 300 mg [217]. These results were replicated and expanded in a later study that employed the real public speaking test model in a range of single doses involving 100 mg, 300 mg, and 900 mg, again with the 300 mg dose showing superior acute anxiolytic effect compared to the others [218]. These findings support the idea of an inverted U-shaped dose-response effect for CBD, which presumably involves different dose profiles depending on the therapeutic indication [3].

Indeed, in addition to anxiety models [219], some studies involving animal models for pain [220] and vomiting [157] have also reported inverted U-shaped dose-response effects. However, this hypothesis has not been directly studied in other clinical conditions, highlighting the need to delineate an accurate therapeutic range for each clinical condition [3].

It is also important to note that this relationship has been well-established for the acute anxiolytic effect of single doses of CBD in preliminary social anxiety model studies involving healthy volunteers, not involving the determination of an effective therapeutic range for the treatment of anxiety disorders, which can only be supported by placebo-controlled clinical trials [221,222]. Notably, these studies are still lacking for many clinical conditions for which CBD is recommended [223].

The exception, again, is the indication of CBD in treatment-resistant childhood epilepsies, such as Dravet and Lennox–Gastaut syndromes [215]. In these cases, the recommended starting dose is 5 mg/kg/day with increments every two weeks, reaching up to 25 mg/kg/day if tolerated [18,224,225]. The suggested starting dose for adults is 200 mg/day, increasing to 1.500 mg/day, with the most frequent dose being around 800 mg/day [226].

An important fact is that CBD in pharmacological purity is an expensive product, and titrating to high doses suggested in definitive studies involves a significant investment in treatment, often limiting access for many patients [8]. Due to this fact, some authors have argued for the “entourage effect” and the combination of cannabinoids as a way to overcome the inverted U-shaped dose-response effect of CBD, aiming to use CBD-enriched extracts at lower doses to achieve therapeutic efficacy [63,227,228].

Although preliminary studies involving pain models in animals suggested the need for lower doses of CBD for pain control using extracts with Δ9-THC (a condition for which the combination of both cannabinoids seems to be more effective than either alone) [227], these results should be viewed with caution and should not be generalized to other conditions without properly controlled studies [37]. Furthermore, as discussed later, the combination of cannabinoids may not necessarily result in therapeutic effects for all clinical indications.

8. CBD and Δ9-THC

The pharmacology of Δ9-THC, although well-known, is complex. Δ9-THC interacts with various molecular targets and acts as a partial agonist at CB1 and CB2 receptors, primarily inhibiting presynaptic neurons via CB1 receptors. Chronic administration of Δ9-THC can lead to tolerance of its effects and the action of endocannabinoids [229,230].

In animal models, Δ9-THC and its analogs produce the so-called cannabinoid tetrad (hypolocomotion, catalepsy, analgesia, and hypothermia) [231]. In humans, Δ9-THC is most commonly associated with the psychotomimetic effects of cannabis use, including dysphoria, anxiety, sedation, psychotic symptoms, and psychomotor impairment [232]. More recently, its therapeutic potentials, including analgesic, muscle relaxant, antispasmodic, and anti-inflammatory properties, have been recognized [75].

Clinical emphasis may be placed on the analgesic effect, which, although still under investigation, likely correlates with higher serum levels of Δ9-THC and, consequently, with its potential for intoxication [233,234,235]. In clinical trials assessing the analgesic efficacy of cannabis, Δ9-THC concentrations were close to <10% [234,236,237,238]. In fact, significantly lower concentrations of Δ9-THC (1–3%) were used in some studies and did not result in clinical efficacy [234,238]. Furthermore, adverse effects and treatment discontinuation seemingly tend to increase with higher concentrations used in these studies. This correlation between Δ9-THC concentration and the potential for intoxication and adverse effects has become an increasing concern as the availability of products with high levels of Δ9-THC and cannabis potency rises [239,240].

A more debated issue is whether and how CBD interacts with Δ9-THC when administered together. Many researchers have suggested that CBD may influence the effects of Δ9-THC, enhancing its clinical efficacy and reducing side effects [61,241]. The main evidence for this hypothesis comes from naturalistic studies indicating that cannabis with high CBD content is associated with lower rates of cognitive impairment and verbal memory deficits [242,243,244]. Additionally, pioneering human studies have shown that when co-administered with Δ9-THC, CBD minimizes the occurrence of intense psychoactive effects such as anxiety and psychosis [1].

Evidence from repeated dosing studies is more varied. A parallel group randomized controlled trial (n = 177) in patients with intractable cancer-related pain showed that a combination of Δ9-THC (2.7 mg) and CBD (2.5 mg) in an oromucosal spray produced a significant improvement on a pain rating scale compared to placebo, whereas the Δ9-THC (2.7 mg) group showed no significant change. Twice as many patients (43%) taking Δ9-THC and CBD showed a 30% pain reduction (on a 0–10 Numerical Rating Scale) from baseline compared to placebo (21% of patients) [245]. However, other studies have found Δ9-THC alone to be more clinically effective than the combination of the two in chronic pain, fibromyalgia, and neuropathic pain [235,246,247].

Much uncertainty also exists regarding whether CBD alters the pharmacokinetic profile of Δ9-THC, due to the great heterogeneity of doses and administration routes used in studies evaluating these hypotheses [69].

Among approved medications by regulatory agencies, Sativex is an oromucosal spray formulation containing a 1:1 ratio of CBD and Δ9-THC, shown to be effective as an add-on medication in the treatment of refractory spasticity and pain in multiple sclerosis [248]. It is likely that Δ9-THC:CBD ratios greater than 1:1 tend to exhibit intoxicating pharmacological effects and are associated with increased side effects linked to Δ9-THC, whereas Δ9-THC:CBD ratios less than 1:6 may mitigate these effects [14]; however, this remains an arbitrary categorization. A comprehensive review of the literature that considers the confounding variables involving the ratios of combinations of these cannabinoids, routes of administration, and types of formulations and preparations is necessary. A systematic review is being conducted to assess studies that investigated oral Δ9-THC pharmacokinetics in different cannabinoid formulations (CRD42024569571). Despite this, there are no consistent results on the dose ranges of these cannabinoids in which CBD modulates the therapeutic effects of Δ9-THC to enhance its efficacy and reduce side effects [69].

Although this hypothesis carries positive expectations, caution is required when translating it into clinical practice (considering that Δ9-THC has greater pharmacological potency than CBD), and more controlled studies are needed to evaluate the efficacy and safety of appropriate and standardized combinations for different clinical indications [69].

The literature on the interaction of CBD with other phytocannabinoids and non-cannabinoid compounds is still in its infancy, and little is known beyond theoretical speculation about the extent to which these compounds may positively or negatively influence therapeutic properties. See [36,37] for a more in-depth review.

9. CBD Content in Commercialized Products

With the legalization of hemp for industrial and medicinal purposes, several countries have seen an increase in the availability of hemp-derived products, particularly CBD products. The lack of regulatory oversight in this industry has led to the availability of CBD products with questionable compound quantities and quality [26].

Several studies conducted in different countries, including the United States [9,26,27,249], the United Kingdom [13], Australia [30], the Netherlands [250], Italy [251], and South Africa [15,30], have reported discrepancies between the information on CBD product labels and their actual chemical content. These discrepancies include significant variations in the actual amount of CBD (both higher and lower than stated) [13,27,29], the presence of other controlled phytocannabinoids (such as Δ9-THC, Δ8-THC, and CBN) in amounts exceeding legal limits [13,27], and the presence of residual solvents in quantities unsuitable for human consumption [30].

These reported irregularities can have various negative implications for the health of patients consuming these products. Firstly, unexpected variations in CBD content can result in subtherapeutic or supratherapeutic doses, potentially leading to treatment failures or increased side effects, respectively [26].

Secondly, undisclosed contamination with Δ9-THC in some products can lead to acute side effects and accidental intoxication due to the presence of this phytocannabinoid, a concern increasingly reported in studies involving both adult and pediatric populations [28,252]. Additionally, the long-term effects of inadvertent Δ9-THC exposure, particularly in pediatric populations undergoing neurodevelopment, could lead to an unexpected increase in psychiatric disorders and cognitive impairments [28,232]. This is particularly relevant as Δ9-THC, a partial agonist of CB1 receptors, has greater pharmacological potency than CBD, correlating with its potential adverse effects [187]. For instance, a CBD product labeled as Δ9-THC-free but found to contain approximately 2.071 mg of Δ9-THC per mL, when taken at doses of 1 mL three times a day, would result in a daily intake of about 6.213 mg of Δ9-THC. For comparison, the recommended starting dose for Dronabinol (synthetic oral Δ9-THC) is 2.5 mg [27]. Additionally, the inadvertent Δ9-THC contamination in CBD products raises potential legal issues such as impaired driving, job loss, child custody issues, and positive doping tests in sports, given the possibility of positive results in sensitive toxicology tests for Δ9-THC [27].

Still in this sense, a review of 8534 herbal products available in the cannabis market for both recreational and medicinal use across nine U.S. states revealed that about 58.5% did not indicate any amount of CBD on their labels. Moreover, when categorized based on the potency of these products to cause intoxication or side effects based on the Δ9-THC:CBD ratio, most medicinal products fall into the potentially intoxicating category (Δ9-THC:CBD > 1). The categories identified as less intoxicating (1:>2 < 6 and ≤1:6 THC:CBD) exhibited the lowest number of products [14].

Thirdly, inadvertent exposure to residual solvents, heavy metals, pesticides, and microorganisms can also have long-term negative effects, particularly in populations with clinical conditions that include immunosuppression [27,30].

Some authors argue that these irregularities partly result from the flexibility of the 2018 Agriculture Improvement Act regarding the regulation of industrial and medicinal hemp-based products (cannabis with <0.3% Δ9-THC by dry weight) in the USA. This act specifies control and oversight only for the Δ9-THC limit in the raw plant material, not the final product (up to the individual states), potentially resulting in products with higher than permitted Δ9-THC concentrations that are not adequately supervised [15,27]. Although some cannabis-derived products, such as broad-spectrum extracts (containing CBD, phytocannabinoids, terpenoids but without Δ9-THC) and full-spectrum extracts (including Δ9-THC < 0.3%), claim differences in their Δ9-THC content to varying degrees, the lack of adequate supervision and oversight of these products raises questions about their quality and actual component quantities [27].

In the Brazilian context, for example, these data are relevant following ANVISA’s (local regulatory agency) Collegiate Board Resolution No. 327/2019. Considering the high demand for access to medicinal cannabinoid-derived products, this resolution allows the circulation of imported products in the national market. Furthermore, some companies have received a five-year sanitary authorization for producing and commercializing cannabinoid products, during which they must prove their efficacy and safety [8]. The examples cited from other countries highlight the need for adequate agency oversight regarding product quality, considering the possibility of label discrepancies, and the need for controlled clinical trials to confirm clinical efficacy.

10. Recommendations for Further Research on CBD

Several recent literature reviews on the therapeutic potential of CBD highlight the well-documented lack of placebo-controlled clinical trials needed to provide more robust evidence of its clinical efficacy in different yet nonapproved conditions [7,33,177,223]. These studies become even more essential when evaluating the clinical efficacy of CBD, given the results of recent studies where the placebo effect, associated with the expectation of treatment with CBD for indications such as anxiety and pain [253,254], significantly influenced clinical outcomes [255].

The expectancy effects of treatment can be presumably modulated by various factors, such as the context of access to medication, the regulatory status of the cannabis plant, its therapeutic efficacy in refractory and difficult cases of childhood epilepsy, and media portrayal of it as a natural-derived medication with multiple indications. A recent systematic review indicated that significant attention from social media can elevate expectations and shape the placebo response in future trials. This has the potential to affect clinical trial outcomes, regulatory decisions, clinical practice, and ultimately, patient access to cannabinoids [255].

Although the objective contribution of other factors to the placebo effect has not been rigorously assessed in studies, they may exert significant influence when considering selection and population biases, particularly in open-label and nonrandomized studies [256].

Furthermore, considering the pharmacological profile of CBD, it is crucial to explore the therapeutic dose ranges for specific clinical conditions and potential pharmacological interactions with first-line drugs generally prescribed for these conditions [3]. Given the known interaction between food and the oral administration of CBD, the development of new formulations that minimize these inter- and intrapatient variations is also desirable [167].

Moreover, a significant and challenging confounding factor is the interference of concurrent recreational cannabis use and its influence on the therapeutic response to CBD [7]. This is particularly relevant when considering the potential alteration of the endocannabinoid system tone in patients with acute or chronic cannabis exposure, making the assessment of quantitative phytocannabinoid composition even more complex, even in regulated use scenarios. Added to this complexity is the increasing overlap between sectors of the population reporting both medical and recreational cannabis use [7].

This task is further complicated by the widespread use of varied and often nonspecific terms in the clinical setting, such as “medical cannabis”, and the presence of products on the market that do not meet good manufacturing and labeling standards [13,25,26,35]. Despite these challenges, the use of validated scales that adequately quantify recreational cannabis use and its inclusion in randomized, placebo-controlled studies can help elucidate this issue and reduce the interference of significant confounding factors, aiding complex clinical decision-making [7].

Furthermore, there is a need for more controlled clinical trials that explore the therapeutic potential of standardized cannabis extracts under GAP and GMP and evaluate the impact of different Δ9-THC:CBD ratios on therapeutic outcomes balanced with intoxication effects and other adverse effects associated with Δ9-THC [14].

In this regard, considerations for advancing future research include appropriate regulation linked to dialogue with civil society, patient associations, and related healthcare professionals [8].

11. Conclusions

This narrative review summarized the main factors related to research and clinical practice involving the use of CBD, contextualized within a broader framework of regulation and perspectives on the development of new drug therapies. Conceptual clarification is valuable given the diversity of terms currently found in the literature, which often originate from discussions outside the clinical setting and can significantly influence clinical and research decisions [255]. CBD is neither a “silver bullet” nor a panacea. Its therapeutic efficacy at a pharmacological grade of purity has been demonstrated for a still-limited set of conditions. Current evidence of its pharmacological profile and therapeutic potential highlights the need for more controlled studies that can expand the range of conditions for which it has proven clinical efficacy.

Additionally, it is important to highlight the differences between pharmaceutical grade CBD and CBD-enriched cannabis extracts in terms of their composition, particularly regarding the presence of other cannabinoids in the latter group. This distinction is significant concerning Δ9-THC potential acute and chronic adverse effects associated with, or independent of, intoxication, underscoring the need for more controlled studies using standardized extracts under GAP, GMP, and GLPs. Such research is necessary to explore potential balances between Δ9-THC and CBD doses and ratios that enable therapeutic application considering intoxication and adverse effects. This research is important because, even if some patients may enjoy the psychotomimetic effects or are willing to assume the risks of high doses or chronic Δ9-THC consumption, this is not recommended from a medical standpoint.

Cannabis, even though approved as ‘medicinal marijuana’ by Canada and Uruguay, and several other states in the United States, without sufficient clinical evidence, cannot be considered a therapeutic because neither the US FDA nor any other regulatory body has approved it as medicine. Based on sufficient clinical data from several clinical trials, CBD is approved for treating two rare forms of epilepsy (Lennox–Gastaut and Dravet syndromes) in young children, but not in adults, and another rare form of brain tumor, tuberous sclerosis complex. CBD in a 1:1 combination with THC (nabiximols, Sativex) is available in many countries except the US, for treating MS-related neuropathic pain. Two other cannabinoid-based medications, synthetic THC (Marinol) and a THC analog (Nabilone), are approved for treating chemotherapy-associated nausea and vomiting and appetite stimulation in AIDS-related wasting syndrome.

Just like any other medication in clinical practice, there is off-label use and compassionate use for the cannabinoid-derived medications described above; however, using these medications outside the conditions specified in the package insert exposes patients to uncertain clinical outcomes.

Neither cannabis nor any other cannabinoid isolated or in combination is approved as a therapeutic, even though these are widely promoted as therapeutics. It is also important that clinicians who deal with patients asking for recommendations of cannabis or CBD for self-treatment must educate their patients about the dangers of using recreational cannabis, which is currently highly potent and is associated with serious adverse health consequences, including cannabis use disorder and psychosis, and that CBD is approved only for treating epilepsy and no other indication.

To this end, the steps for its approval as a medication must be followed so that patients can genuinely benefit from its potential clinical efficacy, if appropriately demonstrated. Researchers and clinicians must remain aware of the complexity of the different interfaces of the topic globally while maintaining their focus on their role in developing best practices for prescription and research based on evidence-based medicine.

Author Contributions

J.L.Q.S. were involved in the review’s concept, design, search, writing original draft preparation, review and editing. J.A.S.C. was involved in the review’s concept, design, supervision and writing—review and editing. J.D.R.S. and J.F.P. were involved in writing—review and editing. A.C.C., F.S.G., A.Z. and J.E.C.H. were supervisors of the present review. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

AWZ, FSG, JAC, and JECH are the coinventors of the patent “Fluorinated CBD compounds, compositions, and uses thereof, Pub. No.: WO/2014/108899, International Application No.: PCT/IL2014/050023”, Def. US number Reg. 62193296; 29 July 2015; INPI on 19 August 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). It has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders”. AWZ, FSG, JAC, and JECH are the coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using the same”, INPI on 16 September 2016 (BR 112018005423-2). JAC was a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding and/or receives speaker fees from Janssen-Cilag, Torrent Pharm, Ease Labs Pharm, Prati-Donaduzzi, Mantecorp, ArtMed, PurMed Global, BioBrains, and BSPG Pharm over the past 5 years. JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE)—National Health and Medical Research Council (NHMRC).

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Figure 1. Therapeutic claims of phytocannabinoids and cannabis-derived products in the literature and their respective evidence of efficacy.

Figure 2. Timeline of the advancement in scientific knowledge on CBD, phytocannabinoids, and the endocannabinoid system, and the development and approval of CBD-based medications.

Table 1

Comparison of pharmaceutical grade cannabidiol, non-pharmaceutical grade cannabidiol, and cannabidiol extracts.

Aspect	Pharmaceutical Grade Cannabidiol	Non-Pharmaceutical Grade Cannabidiol	Cannabidiol Extracts
Purity	99.6–99.9% pure	Variable, typically 70–90%, may contain THC	Variable, contains other cannabinoids and terpenes, including THC
Quality Control	Strict regulatory standards (GMP)	Inconsistent, lacks standardized quality	Variable, often lacks rigorous testing
Label	Correct label and actual CBD composition	Frequent discrepancies between label claims and actual cannabinoid compositions	Frequent discrepancies between label claims and actual cannabinoid compositions
Consistency	High batch-to-batch consistency	Variable	Variable
Safety Profile	Well-documented	Less documented	Not documented
Contaminants	No contaminants, heavily tested	Potential presence of contaminants	Potential presence of contaminants
Legal Status	Legal in most countries with prescription	Legal status varies by region	Legal status varies by region
Usage	Medical and clinical use	Often used for supplements and wellness	Often used for supplements and wellness
Efficacy	High efficacy supported by studies	Efficacy varies, less research available	Efficacy varies, less research available
Cost	High due to quality and testing	Lower to moderate cost	Lower cost
Example Products	Epidiolex®, Sativex®	Various over-the-counter products	Full-spectrum CBD oils

Table 2

Comparative pharmacodynamics of CBD and other phytocannabinoids.

Phytocannabinoid	Pharmacological Targets	Properties
[Image omitted. Please see PDF.] Cannabidiol (CBD) C21H30O2	- CB1 negative allosteric modulator - CB2 inverse agonist - 5-HT1A partial agonist - D2 partial agonist - Fatty acid amide hydrolase inhibitor - PPARγ agonist - TRPV1 agonist - GPR55 antagonist	- Non-psychotomimetic - Anxyolitic - Anticonvulsant - Analgesic - Antipsychotic - Anti-inflammatory - Neuroprotective - Antioxidant - Antibacterial
[Image omitted. Please see PDF.] Delta-9- Tetrahydrocannabinol (THC) C21H30O2	- CB1 partial agonist - CB2 partial agonist - GPR55 agonist - PPARγ agonist - TRPV2 agonist - TRPV3 agonist - TRPV4 agonist	- Psychotomimetic - Stimulation of appetite - Analgesic - Anti-inflammatory - Intoxicant - Antiemetic - Antimicrobial
[Image omitted. Please see PDF.] Cannabigerol (CBG) C21H32O2	- CB1 weak agonist - CB2 partial agonist - 5-HT1A antagonist - Alpha2-adrenergic agonist - PPARγ agonist - TRPV1 agonist	- Non-psychotomimetic - Anti-inflammatory - Analgesic - Neuroprotective - Anxyolitic - Antioxidant - Antibacterial - Antitumor
[Image omitted. Please see PDF.] Cannabinol (CBN) C21H26O2	- CB1 partial agonist - CB2 partial agonist - TRPV1 agonist - TRPV2 agonist - TRPV3 agonist - TRPV4 agonist	- Psychotomimetic - (weaker than THC) - Stimulation of appetite - Analgesic - Anti-inflammatory - Intoxicant - Sedative - Sleep improvement - Immunosupressant

References

1. Zuardi, A.W.; Shirakawa, I.; Finkelfarb, E.; Karniol, I.G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology; 1982; 76, pp. 245-250. [DOI: https://dx.doi.org/10.1007/BF00432554] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6285406]

2. Bergamaschi, M.M.; Queiroz, R.H.C.; Zuardi, A.W.; Crippa, J.A.S. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf.; 2011; 6, pp. 237-249. [DOI: https://dx.doi.org/10.2174/157488611798280924] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22129319]

3. Crippa, J.A.; Guimarães, F.S.; Campos, A.C.; Zuardi, A.W. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front. Immunol.; 2018; 9, 2009. [DOI: https://dx.doi.org/10.3389/fimmu.2018.02009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30298064]

4. Huestis, M.A.; Solimini, R.; Pichini, S.; Pacifici, R.; Carlier, J.; Busardò, F.P. Cannabidiol Adverse Effects and Toxicity. Curr. Neuropharmacol.; 2019; 17, pp. 974-989. [DOI: https://dx.doi.org/10.2174/1570159X17666190603171901]

5. Arndt, D.L.; de Wit, H. Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults. Cannabis Cannabinoid Res.; 2017; 2, pp. 105-113. [DOI: https://dx.doi.org/10.1089/can.2017.0014]

6. White, C.M. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J. Clin. Pharmacol.; 2019; 59, pp. 923-934. [DOI: https://dx.doi.org/10.1002/jcph.1387]

7. Haney, M. Cannabis Use and the Endocannabinoid System: A Clinical Perspective. Am. J. Psychiatry; 2022; 179, pp. 21-25. [DOI: https://dx.doi.org/10.1176/appi.ajp.2021.21111138]

8. de Souza, M.R.; Henriques, A.T.; Limberger, R.P. Medical cannabis regulation: An overview of models around the world with emphasis on the Brazilian scenario. J. Cannabis Res.; 2022; 4, 33. [DOI: https://dx.doi.org/10.1186/s42238-022-00142-z]

9. Vandrey, R.; Raber, J.C.; Raber, M.E.; Douglass, B.; Miller, C.; Bonn-Miller, M.O. Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA; 2015; 313, pp. 2491-2493. [DOI: https://dx.doi.org/10.1001/jama.2015.6613]

10. Bonn-Miller, M.O.; Loflin, M.J.E.; Thomas, B.F.; Marcu, J.P.; Hyke, T.; Vandrey, R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA; 2017; 318, pp. 1708-1709. [DOI: https://dx.doi.org/10.1001/jama.2017.11909]

11. Geweda, M.M.; Majumdar, C.G.; Moore, M.N.; Elhendawy, M.A.; Radwan, M.M.; Chandra, S.; ElSohly, M.A. Evaluation of dispensaries’ cannabis flowers for accuracy of labeling of cannabinoids content. J. Cannabis Res.; 2024; 6, 11. [DOI: https://dx.doi.org/10.1186/s42238-024-00220-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38461280]

12. Shea, L.A.; Leeds, M.; Bui, D.; Mujica, M.; Poupard, M.; Rodriguez, R.; Matura, J.; Carnazzo, A.; Spence, A. “Over-the-counter” cannabidiol (CBD) sold in the community pharmacy setting in Colorado. Drugs Ther. Perspect.; 2020; 36, pp. 573-582. [DOI: https://dx.doi.org/10.1007/s40267-020-00781-3]

13. Liebling, J.P.; Clarkson, N.J.; Gibbs, B.W.; Yates, A.S.; O’Sullivan, S.E. An Analysis of Over-the-Counter Cannabidiol Products in the United Kingdom. Cannabis Cannabinoid Res.; 2022; 7, pp. 207-213. [DOI: https://dx.doi.org/10.1089/can.2019.0078] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33998849]

14. Pennypacker, S.D.; Cunnane, K.; Cash, M.C.; Romero-Sandoval, E.A. Potency and Therapeutic THC and CBD Ratios: U.S. Cannabis Markets Overshoot. Front. Pharmacol.; 2022; 13, 921493. [DOI: https://dx.doi.org/10.3389/fphar.2022.921493]

15. Mouton, M.; Gerber, M.; Van der Kooy, F. Cure-All cannabidiol? The cannabidiol content of commercial products. Phytomed Plus; 2024; 4, 100520. [DOI: https://dx.doi.org/10.1016/j.phyplu.2023.100520]

16. European Monitoring Centre for Drugs and Drug Addiction. Medical Use of Cannabis and Cannabinoids: Questions and Answers for Policymaking; Publications Office of the European Union: Luxembourg, 2018.

17. Hill, K.P. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA; 2015; 313, pp. 2474-2483. [DOI: https://dx.doi.org/10.1001/jama.2015.6199]

18. Devinsky, O.; Cross, J.H.; Laux, L.; Marsh, E.; Miller, I.; Nabbout, R.; Scheffer, I.; Thiele, E.; Wright, S. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N. Engl. J. Med.; 2017; 376, pp. 2011-2020. [DOI: https://dx.doi.org/10.1056/NEJMoa1611618]

19. Berkovic, S.F. Cannabinoids for Epilepsy—Real Data, at Last. N. Engl. J. Med.; 2017; 376, pp. 2075-2076. [DOI: https://dx.doi.org/10.1056/NEJMe1702205]

20. Stockings, E.; Zagic, D.; Campbell, G.; Weier, M.; Hall, W.D.; Nielsen, S.; Herkes, G.; Farrell, M.; Degenhardt, L. Evidence for cannabis and cannabinoids for epilepsy: A systematic review of controlled and observational evidence. J. Neurol. Neurosurg. Psychiatry; 2018; 89, pp. 741-753. [DOI: https://dx.doi.org/10.1136/jnnp-2017-317168]

21. Whiting, P.F.; Wolff, R.F.; Deshpande, S.; Di Nisio, M.; Duffy, S.; Hernandez, A.V.; Keurentjes, J.C.; Lang, S.; Misso, K.; Ryder, S. et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA; 2015; 313, pp. 2456-2473. [DOI: https://dx.doi.org/10.1001/jama.2015.6358]

22. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research; National Academies Press: Washington, DC, USA, 2017.

23. Chow, R.; Valdez, C.; Chow, N.; Zhang, D.; Im, J.; Sodhi, E.; Lock, M. Oral cannabinoid for the prophylaxis of chemotherapy-induced nausea and vomiting-a systematic review and meta-analysis. Support Care Cancer; 2020; 28, pp. 2095-2103. [DOI: https://dx.doi.org/10.1007/s00520-019-05280-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31916006]

24. Glinn, M.A.; Michaud, G.P. Potency levels of regulated cannabis products in Michigan 2021–2022. J. Forensic Sci.; 2023; 68, pp. 1894-1905. [DOI: https://dx.doi.org/10.1111/1556-4029.15345] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37501559]

25. Evans, D.G. Medical Fraud, Mislabeling, Contamination: All Common in CBD Products. Mo. Med.; 2020; 117, pp. 394-399. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33311737]

26. Johnson, E.; Kilgore, M.; Babalonis, S. Label accuracy of unregulated cannabidiol (CBD) products: Measured concentration vs. label claim. J. Cannabis Res.; 2022; 4, 28. [DOI: https://dx.doi.org/10.1186/s42238-022-00140-1] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35658956]

27. Johnson, E.; Kilgore, M.; Babalonis, S. Cannabidiol (CBD) product contamination: Quantitative analysis of Δ-tetrahydrocannabinol (Δ-THC) concentrations found in commercially available CBD products. Drug Alcohol. Depend.; 2022; 237, 109522. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2022.109522]

28. Crippa, J.A.S.; Crippa, A.C.S.; Hallak, J.E.C.; Martín-Santos, R.; Zuardi, A.W. Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol. Front. Pharmacol.; 2016; 7, 359. [DOI: https://dx.doi.org/10.3389/fphar.2016.00359]

29. Ray, C.L.; Bylo, M.P.; Pescaglia, J.; Gawenis, J.A.; Greenlief, C.M. Delta-8 Tetrahydrocannabinol Product Impurities. Molecules; 2022; 27, 6924. [DOI: https://dx.doi.org/10.3390/molecules27206924]

30. Suraev, A.; Benson, M.J.; Martin, L.; Lintzeris, N.; McGregor, I.S. Determination of contaminants in artisanal cannabis products used for childhood epilepsy in the Australian community: A sub-analysis of the “PELICAN” study. Epilepsy Behav.; 2022; 127, 108496. [DOI: https://dx.doi.org/10.1016/j.yebeh.2021.108496] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34954507]

31. Kachru, R.; Perry-Lunardo, C.; Thompson, L.A. CBD Use in Children-Miracle, Myth, or Mystery?. JAMA Pediatr.; 2021; 175, 652. [DOI: https://dx.doi.org/10.1001/jamapediatrics.2021.0367]

32. Volkow, N.D.; Baler, R.D.; Compton, W.M.; Weiss, S.R.B. Adverse health effects of marijuana use. N. Engl. J. Med.; 2014; 370, pp. 2219-2227. [DOI: https://dx.doi.org/10.1056/NEJMra1402309]

33. Solmi, M.; De Toffol, M.; Kim, J.Y.; Choi, M.J.; Stubbs, B.; Thompson, T.; Firth, J.; Miola, A.; Croatto, G.; Baggio, F. et al. Balancing risks and benefits of cannabis use: Umbrella review of meta-analyses of randomised controlled trials and observational studies. BMJ; 2023; 382, e072348. [DOI: https://dx.doi.org/10.1136/bmj-2022-072348] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37648266]

34. Russo, E.B. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol.; 2011; 163, pp. 1344-1364. [DOI: https://dx.doi.org/10.1111/j.1476-5381.2011.01238.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21749363]

35. Cogan, P.S. The “entourage effect” or “hodge-podge hashish”: The questionable rebranding, marketing, and expectations of cannabis polypharmacy. Expert. Rev. Clin. Pharmacol.; 2020; 13, pp. 835-845. [DOI: https://dx.doi.org/10.1080/17512433.2020.1721281] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32116073]

36. Christensen, C.; Rose, M.; Cornett, C.; Allesø, M. Decoding the Postulated Entourage Effect of Medicinal: What It Is and What It Isn’t. Biomedicines; 2023; 11, 2323. [DOI: https://dx.doi.org/10.3390/biomedicines11082323]

37. Simei, J.L.Q.; Souza, J.D.R.; Lisboa, J.R.; Campos, A.C.; Guimarães, F.S.; Zuardi, A.; Crippa, J.A.S. Does the “Entourage Effect” in Cannabinoids Exist? A Narrative Scoping Review. Cannabis Cannabinoid Res.; 2023; 9, pp. 1202-1216. [DOI: https://dx.doi.org/10.1089/can.2023.0052]

38. Bonini, S.A.; Premoli, M.; Tambaro, S.; Kumar, A.; Maccarinelli, G.; Memo, M.; Mastinu, A. Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. J. Ethnopharmacol.; 2018; 227, pp. 300-315. [DOI: https://dx.doi.org/10.1016/j.jep.2018.09.004]

39. Pisanti, S.; Bifulco, M. Modern History of Medical Cannabis: From Widespread Use to Prohibitionism and Back. Trends Pharmacol. Sci.; 2017; 38, pp. 195-198. [DOI: https://dx.doi.org/10.1016/j.tips.2016.12.002]

40. Russo, E.B. History of cannabis and its preparations in saga, science, and sobriquet. Chem. Biodivers.; 2007; 4, pp. 1614-1648. [DOI: https://dx.doi.org/10.1002/cbdv.200790144]

41. Zuardi, A.W. History of cannabis as a medicine: A review. Braz. J. Psychiatry; 2006; 28, pp. 153-157. [DOI: https://dx.doi.org/10.1590/S1516-44462006000200015]

42. United Nations. Secretary-General. Commentary on the Single Convention on Narcotic Drugs, 1961; United Nations: New York, NY, USA, 1973.

43. Adams, R.; Hunt, M.; Clark, J.H. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I. J. Am. Chem. Soc.; 1940; 62, pp. 196-200. [DOI: https://dx.doi.org/10.1021/ja01858a058]

44. Mechoulam, R.; Shvo, Y. Hashish. I. The structure of cannabidiol. Tetrahedron; 1963; 19, pp. 2073-2078. [DOI: https://dx.doi.org/10.1016/0040-4020(63)85022-X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/5879214]

45. Mechoulam, R.; Gaoni, Y. The absolute configuration of delta-1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lett.; 1967; 12, pp. 1109-1111. [DOI: https://dx.doi.org/10.1016/S0040-4039(00)90646-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6039537]

46. World Health Organization. WHO Expert Committee on Drug Dependence: Forty-First Report; World Health Organization: Geneva, Switzerland, 2019.

47. United Nations Office on Drugs and Crime. World Drug Report; United Nations: New York, NY, USA, 2022.

48. Radwan, M.M.; Wanas, A.S.; Chandra, S.; ElSohly, M.A. Natural cannabinoids of cannabis and methods of analysis. Cannabis sativa L.—Botany and Biotechnology; Springer International Publishing: Cham, Switzerland, 2017; pp. 161-182.

49. Jin, D.; Dai, K.; Xie, Z.; Chen, J. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Sci. Rep.; 2020; 10, 3309. [DOI: https://dx.doi.org/10.1038/s41598-020-60172-6]

50. Welling, M.T.; Deseo, M.A.; Bacic, A.; Doblin, M.S. Biosynthetic origins of unusual cannabimimetic phytocannabinoids in Cannabis sativa L: A review. Phytochemistry; 2022; 201, 113282. [DOI: https://dx.doi.org/10.1016/j.phytochem.2022.113282]

51. Maccarrone, M.; Di Marzo, V.; Gertsch, J.; Grether, U.; Howlett, A.C.; Hua, T.; Makriyannis, A.; Piomelli, D.; Ueda, N.; Stelt, M.V.D. Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years. Pharmacol. Rev.; 2023; 75, pp. 885-958. [DOI: https://dx.doi.org/10.1124/pharmrev.122.000600]

52. Turner, C.E.; Elsohly, M.A.; Boeren, E.G. Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J. Nat. Prod.; 1980; 43, pp. 169-234. [DOI: https://dx.doi.org/10.1055/s-0028-1097331]

53. Lewis, M.M.; Yang, Y.; Wasilewski, E.; Clarke, H.A.; Kotra, L.P. Chemical Profiling of Medical Cannabis Extracts. ACS Omega; 2017; 2, pp. 6091-6103. [DOI: https://dx.doi.org/10.1021/acsomega.7b00996] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30023762]

54. Bosquez-Berger, T.; Wilson, S.; Iliopoulos-Tsoutsouvas, C.; Jiang, S.; Wager-Miller, J.; Nikas, S.P.; Mackie, K.P.; Makriyannis, A.; Straiker, A. Differential Enantiomer-Specific Signaling of Cannabidiol at CB Receptors. Mol. Pharmacol.; 2022; 102, pp. 259-268. [DOI: https://dx.doi.org/10.1124/molpharm.121.000305]

55. Wang, X.; Zhang, H.; Liu, Y.; Xu, Y.; Yang, B.; Li, H.; Chen, L. An overview on synthetic and biological activities of cannabidiol (CBD) and its derivatives. Bioorg Chem.; 2023; 140, 106810. [DOI: https://dx.doi.org/10.1016/j.bioorg.2023.106810]

56. Elzinga, S.; Fischedick, J.; Podkolinski, R.; Raber, J.C. Cannabinoids and Terpenes as Chemotaxonomic Markers in Cannabis. Nat. Prod. Chem. Res.; 2015; pp. 1-9. [DOI: https://dx.doi.org/10.4172/2329-6836.1000181]

57. Sommano, S.R.; Chittasupho, C.; Ruksiriwanich, W.; Jantrawut, P. The Cannabis Terpenes. Molecules; 2020; 25, 5792. [DOI: https://dx.doi.org/10.3390/molecules25245792] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33302574]

58. Kasper, S.; Gastpar, M.; Müller, W.E.; Volz, H.-P.; Möller, H.-J.; Schläfke, S.; Dienel, A. Lavender oil preparation Silexan is effective in generalized anxiety disorder--a randomized, double-blind comparison to placebo and paroxetine. Int. J. Neuropsychopharmacol.; 2014; 17, pp. 859-869. [DOI: https://dx.doi.org/10.1017/S1461145714000017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24456909]

59. Ferber, S.G.; Namdar, D.; Hen-Shoval, D.; Eger, G.; Koltai, H.; Shoval, G.; Shbiro, L.; Weller, A. The “Entourage Effect”: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders. Curr. Neuropharmacol.; 2020; 18, pp. 87-96. [DOI: https://dx.doi.org/10.2174/1570159X17666190903103923]

60. Pollastro, F.; Minassi, A.; Fresu, L.G. Cannabis Phenolics and their Bioactivities. Curr. Med. Chem.; 2018; 25, pp. 1160-1185. [DOI: https://dx.doi.org/10.2174/0929867324666170810164636] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28799497]

61. Bonn-Miller, M.O.; ElSohly, M.A.; Loflin, M.J.E.; Chandra, S.; Vandrey, R. Cannabis and cannabinoid drug development: Evaluating botanical versus single molecule approaches. Int. Rev. Psychiatry; 2018; 30, pp. 277-284. [DOI: https://dx.doi.org/10.1080/09540261.2018.1474730]

62. Koltai, H.; Poulin, P.; Namdar, D. Promoting cannabis products to pharmaceutical drugs. Eur. J. Pharm. Sci.; 2019; 132, pp. 118-120. [DOI: https://dx.doi.org/10.1016/j.ejps.2019.02.027] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30851400]

63. Russo, E.B. The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain”, No Gain. Front. Plant Sci.; 2018; 9, 1969. [DOI: https://dx.doi.org/10.3389/fpls.2018.01969]

64. McPartland, J.M. Systematics at the Levels of Family, Genus, and Species. Cannabis Cannabinoid Res.; 2018; 3, pp. 203-212. [DOI: https://dx.doi.org/10.1089/can.2018.0039]

65. Ben-Shabat, S.; Fride, E.; Sheskin, T.; Tamiri, T.; Rhee, M.H.; Vogel, Z.; Bisogno, T.; De Petrocellis, L.; Di Marzo, V.; Mechoulam, R. An entourage effect: Inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol.; 1998; 353, pp. 23-31. [DOI: https://dx.doi.org/10.1016/S0014-2999(98)00392-6]

66. John MMcPartland, D.O.M.S.; Russo, E.B. Cannabis and Cannabis Extracts. J. Cannabis Ther.; 2001; 1, pp. 103-132. [DOI: https://dx.doi.org/10.1300/J175v01n03_08]

67. McPartland, J.M.; Russo, E.B. Non-Phytocannabinoid Constituents of Cannabis and Herbal Synergy; Oxford University Press: Oxford, UK, 2014.

68. Piomelli, D. Waiting for the Entourage. Cannabis Cannabinoid Res.; 2019; 4, pp. 137-138. [DOI: https://dx.doi.org/10.1089/can.2019.29014.dpi] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31579831]

69. Freeman, A.M.; Petrilli, K.; Lees, R.; Hindocha, C.; Mokrysz, C.; Curran, H.V.; Saunders, R.; Freeman, T.P. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neurosci. Biobehav. Rev.; 2019; 107, pp. 696-712. [DOI: https://dx.doi.org/10.1016/j.neubiorev.2019.09.036]

70. Santiago, M.; Sachdev, S.; Arnold, J.C.; McGregor, I.S.; Connor, M. Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors. bioRxiv; 2019; [DOI: https://dx.doi.org/10.1101/569079]

71. Blasco-Benito, S.; Seijo-Vila, M.; Caro-Villalobos, M.; Tundidor, I.; Andradas, C.; García-Taboada, E.; Wade, J.; Smith, S.; Gusmán, M.; Pérez-Gómez, E. et al. Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem. Pharmacol.; 2018; 157, pp. 285-293. [DOI: https://dx.doi.org/10.1016/j.bcp.2018.06.025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29940172]

72. Raz, N.; Eyal, A.M.; Zeitouni, D.B.; Hen-Shoval, D.; Davidson, E.M.; Danieli, A.; Tauber, M.; Ben-Chaim, Y. Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation. Biochem. Pharmacol.; 2023; 212, 115548. [DOI: https://dx.doi.org/10.1016/j.bcp.2023.115548] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37084981]

73. Aran, A.; Harel, M.; Cassuto, H.; Polyansky, L.; Schnapp, A.; Wattad, N.; Shmueli, D.; Golan, D.; Castellanos, F.X. Cannabinoid treatment for autism: A proof-of-concept randomized trial. Mol. Autism.; 2021; 12, 6. [DOI: https://dx.doi.org/10.1186/s13229-021-00420-2]

74. Hazekamp, A.; Ware, M.A.; Muller-Vahl, K.R.; Abrams, D.; Grotenhermen, F. The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms. J. Psychoact. Drugs; 2013; 45, pp. 199-210. [DOI: https://dx.doi.org/10.1080/02791072.2013.805976] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24175484]

75. Legare, C.A.; Raup-Konsavage, W.M.; Vrana, K.E. Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals. Pharmacology; 2022; 107, pp. 131-149. [DOI: https://dx.doi.org/10.1159/000521683]

76. Gobbi, G.; Atkin, T.; Zytynski, T.; Wang, S.; Askari, S.; Boruff, J.; Ware, M.; Marmorstein, N.; Cipriani, A.; Dendukuri, N. et al. Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood: A Systematic Review and Meta-analysis. JAMA Psychiatry; 2019; 76, pp. 426-434. [DOI: https://dx.doi.org/10.1001/jamapsychiatry.2018.4500]

77. Marconi, A.; Di Forti, M.; Lewis, C.M.; Murray, R.M.; Vassos, E. Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Schizophr. Bull.; 2016; 42, pp. 1262-1269. [DOI: https://dx.doi.org/10.1093/schbul/sbw003]

78. McCartney, D.; Arkell, T.R.; Irwin, C.; McGregor, I.S. Determining the magnitude and duration of acute Δ-tetrahydrocannabinol (Δ-THC)-induced driving and cognitive impairment: A systematic and meta-analytic review. Neurosci. Biobehav. Rev.; 2021; 126, pp. 175-193. [DOI: https://dx.doi.org/10.1016/j.neubiorev.2021.01.003] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33497784]

79. Wang, G.S.; Roosevelt, G.; Heard, K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr.; 2013; 167, pp. 630-633. [DOI: https://dx.doi.org/10.1001/jamapediatrics.2013.140] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23712626]

80. Trangenstein, P.J.; Whitehill, J.M.; Jenkins, M.C.; Jernigan, D.H.; Moreno, M.A. Cannabis Marketing and Problematic Cannabis Use Among Adolescents. J. Stud. Alcohol. Drugs; 2021; 82, pp. 288-296. [DOI: https://dx.doi.org/10.15288/jsad.2021.82.288] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33823976]

81. Monte, A.A.; Zane, R.D.; Heard, K.J. The implications of marijuana legalization in Colorado. JAMA; 2015; 313, pp. 241-242. [DOI: https://dx.doi.org/10.1001/jama.2014.17057]

82. Shah, S.; Narouze, S. Cannabis as a Therapeutic or Snake Oil? A Desperate Call for Critical Appraisal of the Literature. Anesth. Analg.; 2024; 138, pp. 2-4. [DOI: https://dx.doi.org/10.1213/ANE.0000000000006592] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38100796]

83. Sousa, I.M.C.d.; Hortale, V.A.; Bodstein, R.C.d.A. Traditional Complementary and Integrative Medicine: Challenges in constructing an evaluation model of care. Cien Saude Colet.; 2018; 23, pp. 3403-3412. [DOI: https://dx.doi.org/10.1590/1413-812320182310.23792016]

84. Mechoulam, R.; Shani, A.; Edery, H.; Grunfeld, Y. Chemical basis of hashish activity. Science; 1970; 169, pp. 611-612. [DOI: https://dx.doi.org/10.1126/science.169.3945.611]

85. Carlini, E.A.; Santos, M.; Claussen, U.; Bieniek, D.; Korte, F. Structure activity relationship of four tetrahydrocannabinols and the pharmacological activity of five semi-purified extracts of Cannabis sativa. Psychopharmacologia; 1970; 18, pp. 82-93. [DOI: https://dx.doi.org/10.1007/BF00402387]

86. Karniol, I.G.; Carlini, E.A. The content of (-) 9-trans-tetrahydrocannabinol (9-thc) does not explain all biological activity of some Brazilian marihuana samples. J. Pharm. Pharmacol.; 1972; 24, pp. 833-834. [DOI: https://dx.doi.org/10.1111/j.2042-7158.1972.tb08897.x]

87. Bitencourt, R.M.; Takahashi, R.N.; Carlini, E.A. From an Alternative Medicine to a New Treatment for Refractory Epilepsies: Can Cannabidiol Follow the Same Path to Treat Neuropsychiatric Disorders?. Front. Psychiatry; 2021; 12, 638032. [DOI: https://dx.doi.org/10.3389/fpsyt.2021.638032]

88. Carlini, E.A.; Leite, J.R.; Tannhauser, M.; Berardi, A.C. Letter: Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J. Pharm. Pharmacol.; 1973; 25, pp. 664-665. [DOI: https://dx.doi.org/10.1111/j.2042-7158.1973.tb10660.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/4148442]

89. Carlini, E.A.; Mechoulam, R.; Lander, N. Anticonvulsant activity of four oxygenated cannabidiol derivatives. Res. Commun. Chem. Pathol. Pharmacol.; 1975; 12, pp. 1-15. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1188178]

90. Mechoulam, R.; Carlini, E.A. Toward drugs derived from cannabis. Naturwissenschaften; 1978; 65, pp. 174-179. [DOI: https://dx.doi.org/10.1007/BF00450585] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/351429]

91. Cunha, J.M.; Carlini, E.A.; Pereira, A.E.; Ramos, O.L.; Pimentel, C.; Gagliardi, R.; Sanvito, W.L.; Lander, N.; Mechoulam, R. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology; 1980; 21, pp. 175-185. [DOI: https://dx.doi.org/10.1159/000137430]

92. Zuardi, A.W.; Teixeira, N.A.; Karniol, I.C. Pharmacological interaction of the effects of delta 9-trans-tetrahydrocannabinol and cannabidiol on serum corticosterone levels in rats. Arch. Int. Pharmacodyn. Ther.; 1984; 269, pp. 12-19.

93. Zuardi, A.W.; Karniol, I.G. Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination. Braz. J. Med. Biol. Res.; 1983; 16, pp. 141-146.

94. Zuardi, A.W. Cannabidiol: From an inactive cannabinoid to a drug with wide spectrum of action. Braz. J. Psychiatry; 2008; 30, pp. 271-280. [DOI: https://dx.doi.org/10.1590/S1516-44462008000300015]

95. Campos, A.C.; Fogaça, M.V.; Sonego, A.B.; Guimarães, F.S. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol. Res.; 2016; 112, pp. 119-127. [DOI: https://dx.doi.org/10.1016/j.phrs.2016.01.033] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26845349]

96. Carlini, E.A.; Cunha, J.M. Hypnotic and antiepileptic effects of cannabidiol. J. Clin. Pharmacol.; 1981; 21, pp. 417S-427S. [DOI: https://dx.doi.org/10.1002/j.1552-4604.1981.tb02622.x]

97. Consroe, P.; Benedito, M.A.; Leite, J.R.; Carlini, E.A.; Mechoulam, R. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur. J. Pharmacol.; 1982; 83, pp. 293-298. [DOI: https://dx.doi.org/10.1016/0014-2999(82)90264-3]

98. Leite, J.R.; Carlini, E.A.; Lander, N.; Mechoulam, R. Anticonvulsant effects of the (−) and (+)isomers of cannabidiol and their dimethylheptyl homologs. Pharmacology; 1982; 24, pp. 141-146. [DOI: https://dx.doi.org/10.1159/000137588] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/7071126]

99. Zuardi, A.W.; Finkelfarb, E.; Bueno, O.F.; Musty, R.E.; Karniol, I.G. Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol. Arch. Int. Pharmacodyn. Ther.; 1981; 249, pp. 137-146.

100. Guimarães, F.S.; Chiaretti, T.M.; Graeff, F.G.; Zuardi, A.W. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology; 1990; 100, pp. 558-559. [DOI: https://dx.doi.org/10.1007/BF02244012]

101. Zuardi, A.W.; Cosme, R.A.; Graeff, F.G.; Guimarães, F.S. Effects of ipsapirone and cannabidiol on human experimental anxiety. J. Psychopharmacol.; 1993; 7, pp. 82-88. [DOI: https://dx.doi.org/10.1177/026988119300700112]

102. Zuardi, A.W.; Rodrigues, J.A.; Cunha, J.M. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology; 1991; 104, pp. 260-264. [DOI: https://dx.doi.org/10.1007/BF02244189] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/1678894]

103. Zuardi, A.W.; Morais, S.L.; Guimarães, F.S.; Mechoulam, R. Antipsychotic effect of cannabidiol. J. Clin. Psychiatry; 1995; 56, pp. 485-486.

104. Devane, W.A.; Dysarz, F.A., 3rd; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol.; 1988; 34, pp. 605-613. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2848184]

105. Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA; 1990; 87, pp. 1932-1936. [DOI: https://dx.doi.org/10.1073/pnas.87.5.1932]

106. Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science; 1992; 258, pp. 1946-1949. [DOI: https://dx.doi.org/10.1126/science.1470919]

107. Mechoulam, R.; Ben-Shabat, S.; Hanus, L.; Ligumsky, M.; Kaminski, N.E.; Schatz, A.R.; Gopher, A.; Almong, S.; Martin, B.R.; Compton, D.R. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol.; 1995; 50, pp. 83-90. [DOI: https://dx.doi.org/10.1016/0006-2952(95)00109-D]

108. Fride, E.; Mechoulam, R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur. J. Pharmacol.; 1993; 231, pp. 313-314. [DOI: https://dx.doi.org/10.1016/0014-2999(93)90468-W] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8384116]

109. Kano, M.; Ohno-Shosaku, T.; Maejima, T. Retrograde signaling at central synapses via endogenous cannabinoids. Mol. Psychiatry; 2002; 7, pp. 234-235. [DOI: https://dx.doi.org/10.1038/sj.mp.4000999] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11920149]

110. Freund, T.F.; Katona, I.; Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev.; 2003; 83, pp. 1017-1066. [DOI: https://dx.doi.org/10.1152/physrev.00004.2003]

111. Di Marzo, V.; Fontana, A.; Cadas, H.; Schinelli, S.; Cimino, G.; Schwartz, J.C.; Piomelli, D. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature; 1994; 372, pp. 686-691. [DOI: https://dx.doi.org/10.1038/372686a0]

112. Beltramo, M.; Stella, N.; Calignano, A.; Lin, S.Y.; Makriyannis, A.; Piomelli, D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science; 1997; 277, pp. 1094-1097. [DOI: https://dx.doi.org/10.1126/science.277.5329.1094] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9262477]

113. Cravatt, B.F.; Giang, D.K.; Mayfield, S.P.; Boger, D.L.; Lerner, R.A.; Gilula, N.B. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature; 1996; 384, pp. 83-87. [DOI: https://dx.doi.org/10.1038/384083a0]

114. Cassano, T.; Villani, R.; Pace, L.; Carbone, A.; Bukke, V.N.; Orkisz, S.; Avolio, C.; Serviddio, G. From to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases. Front. Pharmacol.; 2020; 11, 124. [DOI: https://dx.doi.org/10.3389/fphar.2020.00124]

115. Di Marzo, V.; Bifulco, M.; De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov.; 2004; 3, pp. 771-784. [DOI: https://dx.doi.org/10.1038/nrd1495] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15340387]

116. Kathuria, S.; Gaetani, S.; Fegley, D.; Valiño, F.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; La Rana, G.; Calignano, A. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med.; 2003; 9, pp. 76-81. [DOI: https://dx.doi.org/10.1038/nm803]

117. Marsicano, G.; Wotjak, C.T.; Azad, S.C.; Bisogno, T.; Rammes, G.; Cascio, M.G.; Hermann, H.; Tang, J.; Hofmann, C.; Zieglgänsberger, W. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature; 2002; 418, pp. 530-534. [DOI: https://dx.doi.org/10.1038/nature00839]

118. van der Stelt, M.; Di Marzo, V. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: Implications for neurological and psychiatric disorders. Eur. J. Pharmacol.; 2003; 480, pp. 133-150. [DOI: https://dx.doi.org/10.1016/j.ejphar.2003.08.101] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14623357]

119. Dlugos, A.; Childs, E.; Stuhr, K.L.; Hillard, C.J.; de Wit, H. Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans. Neuropsychopharmacology; 2012; 37, pp. 2416-2427. [DOI: https://dx.doi.org/10.1038/npp.2012.100] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22763622]

120. Hill, M.N.; Miller, G.E.; Ho, W.-S.V.; Gorzalka, B.B.; Hillard, C.J. Serum endocannabinoid content is altered in females with depressive disorders: A preliminary report. Pharmacopsychiatry; 2008; 41, pp. 48-53. [DOI: https://dx.doi.org/10.1055/s-2007-993211]

121. Kogan, N.M.; Mechoulam, R. The chemistry of endocannabinoids. J. Endocrinol. Investig.; 2006; 29, pp. 3-14.

122. Jones, P.G.; Falvello, L.; Kennard, O.; Sheldrick, G.M.; Mechoulam, R. Cannabidiol. Acta Crystallogr. B; 1977; 33, pp. 3211-3214. [DOI: https://dx.doi.org/10.1107/S0567740877010577]

123. Lago-Fernandez, A.; Redondo, V.; Hernandez-Folgado, L.; Figuerola-Asencio, L.; Jagerovic, N. New Methods for the Synthesis of Cannabidiol Derivatives. Methods Enzymol.; 2017; 593, pp. 237-257.

124. Breuer, A.; Haj, C.G.; Fogaça, M.V.; Gomes, F.V.; Silva, N.R.; Pedrazzi, J.F.; Del Bel, E.A.; Hallak, J.C.; Crippa, J.A.; Zuardi, A.W. et al. Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects. PLoS ONE; 2016; 11, e0158779.

125. Campos, A.C.; Fogaça, M.V.; Scarante, F.F.; Joca, S.R.L.; Sales, A.J.; Gomes, F.V.; Sonego, A.B.; Rodrigues, N.S.; Galve-Roperh, I.; Guimarães, F.S. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. Front. Pharmacol.; 2017; 8, 269. [DOI: https://dx.doi.org/10.3389/fphar.2017.00269]

126. Vitale, R.M.; Iannotti, F.A.; Amodeo, P. The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets. Int. J. Mol. Sci.; 2021; 22, 4876. [DOI: https://dx.doi.org/10.3390/ijms22094876]

127. Silvestro, S.; Schepici, G.; Bramanti, P.; Mazzon, E. Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease. Molecules; 2020; 25, 5186. [DOI: https://dx.doi.org/10.3390/molecules25215186]

128. Mechoulam, R.; Parker, L.A.; Gallily, R. Cannabidiol: An overview of some pharmacological aspects. J. Clin. Pharmacol.; 2002; 42, pp. 11S-19S. [DOI: https://dx.doi.org/10.1002/j.1552-4604.2002.tb05998.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12412831]

129. Mechoulam, R.; Peters, M.; Murillo-Rodriguez, E.; Hanus, L.O. Cannabidiol—Recent advances. Chem. Biodivers.; 2007; 4, pp. 1678-1692. [DOI: https://dx.doi.org/10.1002/cbdv.200790147] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17712814]

130. Zhornitsky, S.; Potvin, S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals; 2012; 5, pp. 529-552. [DOI: https://dx.doi.org/10.3390/ph5050529] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24281562]

131. Campos, A.C.; Moreira, F.A.; Gomes, F.V.; Del Bel, E.A.; Guimarães, F.S. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos. Trans. R. Soc. Lond. B Biol. Sci.; 2012; 367, pp. 3364-3378. [DOI: https://dx.doi.org/10.1098/rstb.2011.0389]

132. Fernández-Ruiz, J.; Sagredo, O.; Pazos, M.R.; García, C.; Pertwee, R.; Mechoulam, R.; Martinez- Orgado, F. Cannabidiol for neurodegenerative disorders: Important new clinical applications for this phytocannabinoid?. Br. J. Clin. Pharmacol.; 2013; 75, pp. 323-333. [DOI: https://dx.doi.org/10.1111/j.1365-2125.2012.04341.x]

133. Peng, J.; Fan, M.; An, C.; Ni, F.; Huang, W.; Luo, J. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic. Clin. Pharmacol. Toxicol.; 2022; 130, pp. 439-456. [DOI: https://dx.doi.org/10.1111/bcpt.13710]

134. McPartland, J.M.; Glass, M.; Pertwee, R.G. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: Interspecies differences. Br. J. Pharmacol.; 2007; 152, pp. 583-593. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707399]

135. Thomas, A.; Baillie, G.L.; Phillips, A.M.; Razdan, R.K.; Ross, R.A.; Pertwee, R.G. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol.; 2007; 150, pp. 613-623. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707133]

136. Tham, M.; Yilmaz, O.; Alaverdashvili, M.; Kelly, M.E.M.; Denovan-Wright, E.M.; Laprairie, R.B. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol.; 2019; 176, pp. 1455-1469. [DOI: https://dx.doi.org/10.1111/bph.14440]

137. Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol.; 2015; 172, pp. 4790-4805. [DOI: https://dx.doi.org/10.1111/bph.13250]

138. Morales, P.; Goya, P.; Jagerovic, N.; Hernandez-Folgado, L. Allosteric Modulators of the CB Cannabinoid Receptor: A Structural Update Review. Cannabis Cannabinoid Res.; 2016; 1, pp. 22-30. [DOI: https://dx.doi.org/10.1089/can.2015.0005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28861476]

139. Martínez-Pinilla, E.; Varani, K.; Reyes-Resina, I.; Angelats, E.; Vincenzi, F.; Ferreiro-Vera, C.; Oyarzabal, J.; Canela, E.I.; Lanciego, J.L.; Nadal, X. et al. Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB Receptors. Front. Pharmacol.; 2017; 8, 744. [DOI: https://dx.doi.org/10.3389/fphar.2017.00744] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29109685]

140. Elmes, M.W.; Kaczocha, M.; Berger, W.T.; Leung, K.; Ralph, B.P.; Wang, L.; Sweeney, J.M.; Miyauchi, J.T.; Tsirka, S.E.; Ótima, O. et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J. Biol. Chem.; 2015; 290, pp. 8711-8721. [DOI: https://dx.doi.org/10.1074/jbc.M114.618447] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25666611]

141. Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D.E.; Brandi, I.; Moriello, A.S.; Davis, J.B.; Mechoulam, R.; Di Marzo, V. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol.; 2001; 134, pp. 845-852. [DOI: https://dx.doi.org/10.1038/sj.bjp.0704327]

142. Leweke, F.M.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.W.; Hoyer, C.; Klosterkotter, J.; Hellmitch, M.; Koethe, D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry; 2012; 2, e94. [DOI: https://dx.doi.org/10.1038/tp.2012.15]

143. Campos, A.C.; Ortega, Z.; Palazuelos, J.; Fogaça, M.V.; Aguiar, D.C.; Díaz-Alonso, J.; Ortega-Guierrez, S.; Vasquez-Villa, H.; Moreira, F.A.; Guzman, M. et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: Involvement of the endocannabinoid system. Int. J. Neuropsychopharmacol.; 2013; 16, pp. 1407-1419. [DOI: https://dx.doi.org/10.1017/S1461145712001502]

144. Casarotto, P.C.; Gomes, F.V.; Resstel, L.B.M.; Guimarães, F.S. Cannabidiol inhibitory effect on marble-burying behaviour: Involvement of CB1 receptors. Behav. Pharmacol.; 2010; 21, pp. 353-358. [DOI: https://dx.doi.org/10.1097/FBP.0b013e32833b33c5]

145. Pertwee, R.G.; Thomas, A.; Stevenson, L.A.; Maor, Y.; Mechoulam, R. Evidence that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol activates a non-CB(1), non-CB(2), non-TRPV1 target in the mouse vas deferens. Neuropharmacology; 2005; 48, pp. 1139-1146. [DOI: https://dx.doi.org/10.1016/j.neuropharm.2005.01.010]

146. Costa, B.; Giagnoni, G.; Franke, C.; Trovato, A.E.; Colleoni, M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br. J. Pharmacol.; 2004; 143, pp. 247-250. [DOI: https://dx.doi.org/10.1038/sj.bjp.0705920]

147. Lu, C.W.; Lin, T.Y.; Hsie, T.Y.; Huang, S.K.; Wang, S.J. Capsaicin presynaptically inhibits glutamate release through the activation of TRPV1 and calcineurin in the hippocampus of rats. Food Funct.; 2017; 8, pp. 1859-1868. [DOI: https://dx.doi.org/10.1039/C7FO00011A]

148. Iannotti, F.A.; Hill, C.L.; Leo, A.; Alhusaini, A.; Soubrane, C.; Mazzarella, E.; Russo, E.; Whalley, B.J.; Di Marzo, V.; Stephens, G.J. et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: Potential for the treatment of neuronal hyperexcitability. ACS Chem. Neurosci.; 2014; 5, pp. 1131-1141. [DOI: https://dx.doi.org/10.1021/cn5000524] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25029033]

149. Campos, A.C.; Guimarães, F.S. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog. Neuropsychopharmacol. Biol. Psychiatry; 2009; 33, pp. 1517-1521. [DOI: https://dx.doi.org/10.1016/j.pnpbp.2009.08.017] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19735690]

150. Russo, E.B.; Burnett, A.; Hall, B.; Parker, K.K. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem. Res.; 2005; 30, pp. 1037-1043. [DOI: https://dx.doi.org/10.1007/s11064-005-6978-1]

151. Campos, A.C.; Guimarães, F.S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology; 2008; 199, pp. 223-230. [DOI: https://dx.doi.org/10.1007/s00213-008-1168-x]

152. Sales, A.J.; Crestani, C.C.; Guimarães, F.S.; Joca, S.R.L. Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels. Prog. Neuropsychopharmacol. Biol. Psychiatry; 2018; 86, pp. 255-261. [DOI: https://dx.doi.org/10.1016/j.pnpbp.2018.06.002]

153. Campos, A.C.; Ferreira, F.R.; Guimarães, F.S. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: Possible involvement of 5HT1A receptors. J. Psychiatr. Res.; 2012; 46, pp. 1501-1510. [DOI: https://dx.doi.org/10.1016/j.jpsychires.2012.08.012]

154. Avraham, Y.; Grigoriadis, N.; Poutahidis, T.; Vorobiev, L.; Magen, I.; Ilan, Y.; Mechoulam, E.; Berry, E.M. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br. J. Pharmacol.; 2011; 162, pp. 1650-1658. [DOI: https://dx.doi.org/10.1111/j.1476-5381.2010.01179.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21182490]

155. De Gregorio, D.; McLaughlin, R.J.; Posa, L.; Ochoa-Sanchez, R.; Enns, J.; Lopez-Canul, M.; Aboud, M.; Maione, S.; Comai, S.; Gobbi, G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain; 2019; 160, pp. 136-150. [DOI: https://dx.doi.org/10.1097/j.pain.0000000000001386] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30157131]

156. Gomes, F.V.; Del Bel, E.A.; Guimarães, F.S. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry; 2013; 46, pp. 43-47. [DOI: https://dx.doi.org/10.1016/j.pnpbp.2013.06.005]

157. Rock, E.M.; Bolognini, D.; Limebeer, C.L.; Cascio, M.G.; Anavi-Goffer, S.; Fletcher, P.J.; Mechoulam, R.; Pertwee, R.G.; Parker, L.A. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br. J. Pharmacol.; 2012; 165, pp. 2620-2634. [DOI: https://dx.doi.org/10.1111/j.1476-5381.2011.01621.x]

158. Martínez-Aguirre, C.; Carmona-Cruz, F.; Velasco, A.L.; Velasco, F.; Aguado-Carrillo, G.; Cuéllar-Herrera, M.; Rocha, L. Cannabidiol Acts at 5-HT Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy. Front. Behav. Neurosci.; 2020; 14, 611278. [DOI: https://dx.doi.org/10.3389/fnbeh.2020.611278] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33384591]

159. Anderson, L.L.; Absalom, N.L.; Abelev, S.V.; Low, I.K.; Doohan, P.T.; Martin, L.J.; Chebib, M.; Mcgregor, I.S.; Arnold, J.C. Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia; 2019; 60, pp. 2224-2234. [DOI: https://dx.doi.org/10.1111/epi.16355] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31625159]

160. Bakas, T.; van Nieuwenhuijzen, P.S.; Devenish, S.O.; McGregor, I.S.; Arnold, J.C.; Chebib, M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA receptors. Pharmacol. Res.; 2017; 119, pp. 358-370. [DOI: https://dx.doi.org/10.1016/j.phrs.2017.02.022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28249817]

161. Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol.; 2007; 152, pp. 1092-1101. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707460]

162. Hurd, Y.L. Leading the Next CBD Wave-Safety and Efficacy. JAMA Psychiatry; 2020; 77, pp. 341-342. [DOI: https://dx.doi.org/10.1001/jamapsychiatry.2019.4157]

163. Newmeyer, M.N.; Swortwood, M.J.; Barnes, A.J.; Abulseoud, O.A.; Scheidweiler, K.B.; Huestis, M.A. Free and Glucuronide Whole Blood Cannabinoids’ Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake. Clin. Chem.; 2016; 62, pp. 1579-1592. [DOI: https://dx.doi.org/10.1373/clinchem.2016.263475]

164. Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet.; 2003; 42, pp. 327-360. [DOI: https://dx.doi.org/10.2165/00003088-200342040-00003]

165. Fasinu, P.S.; Phillips, S.; ElSohly, M.A.; Walker, L.A. Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents. Pharmacotherapy; 2016; 36, pp. 781-796. [DOI: https://dx.doi.org/10.1002/phar.1780] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27285147]

166. Huestis, M.A. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol. Handb. Exp. Pharmacol.; 2005; pp. 657-690.

167. Perucca, E.; Bialer, M. Critical Aspects Affecting Cannabidiol Oral Bioavailability and Metabolic Elimination, and Related Clinical Implications. CNS Drugs; 2020; 34, pp. 795-800. [DOI: https://dx.doi.org/10.1007/s40263-020-00741-5]

168. Moazen-Zadeh, E.; Chisholm, A.; Bachi, K.; Hurd, Y.L. Pharmacokinetics of Cannabidiol: A Systematic Review and Meta-Regression Analysis. Cannabis Cannabinoid Res.; 2023; 9, pp. 939-966. [DOI: https://dx.doi.org/10.1089/can.2023.0025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37643301]

169. Crippa, J.A.; Pereira Junior, L.C.; Pereira, L.C.; Zimmermann, P.M.; Brum Junior, L.; Rechia, L.M.; Dias, I.; Hallak, J.E.; Campos, A.C.; Guimarães, F.S. et al. Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: Pharmaceutical vehicle matters. Braz. J. Psychiatry; 2022; 44, pp. 15-20. [DOI: https://dx.doi.org/10.1590/1516-4446-2020-1684] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34076067]

170. Birnbaum, A.K.; Karanam, A.; Marino, S.E.; Barkley, C.M.; Remmel, R.P.; Roslawski, M.; Gramling-Aden, M.; Lepikk, I.E. Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia; 2019; 60, pp. 1586-1592. [DOI: https://dx.doi.org/10.1111/epi.16093]

171. Taylor, L.; Gidal, B.; Blakey, G.; Tayo, B.; Morrison, G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs; 2018; 32, pp. 1053-1067. [DOI: https://dx.doi.org/10.1007/s40263-018-0578-5]

172. Crockett, J.; Critchley, D.; Tayo, B.; Berwaerts, J.; Morrison, G. A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia; 2020; 61, pp. 267-277. [DOI: https://dx.doi.org/10.1111/epi.16419] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32012251]

173. Knaub, K.; Sartorius, T.; Dharsono, T.; Wacker, R.; Wilhelm, M.; Schön, C. A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects. Molecules; 2019; 24, 2967. [DOI: https://dx.doi.org/10.3390/molecules24162967]

174. Brocks, D.R.; Davies, N.M. Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development. J. Pharm. Pharm. Sci.; 2018; 21, pp. 254s-270s. [DOI: https://dx.doi.org/10.18433/jpps30217]

175. Crippa, J.A.S.; Zuardi, A.W.; Hallak, J.E.C.; Miyazawa, B.; Bernardo, S.A.; Donaduzzi, C.M.; Guzzi, S.; Favreto, W.A.J.; Campos, A.C.; Queiroz, M.E.C. et al. Oral Cannabidiol Does Not Convert to Δ-THC or Δ-THC in Humans: A Pharmacokinetic Study in Healthy Subjects. Cannabis Cannabinoid Res.; 2020; 5, pp. 89-98. [DOI: https://dx.doi.org/10.1089/can.2019.0024]

176. Franz, S.; Herzog, J.; Skopp, G.; Musshoff, F. Will tetrahydrocannabinol be formed from cannabidiol in gastric fluid? An in vivo experiment. Int. J. Legal Med.; 2023; 137, pp. 79-87. [DOI: https://dx.doi.org/10.1007/s00414-022-02896-w]

177. Bilbao, A.; Spanagel, R. Medical cannabinoids: A pharmacology-based systematic review and meta-analysis for all relevant medical indications. BMC Med.; 2022; 20, 259. [DOI: https://dx.doi.org/10.1186/s12916-022-02459-1]

178. Scholfield, C.N.; Waranuch, N.; Kongkaew, C. Systematic Review on Transdermal/Topical Cannabidiol Trials: A Reconsidered Way Forward. Cannabis Cannabinoid Res.; 2023; 8, pp. 589-602. [DOI: https://dx.doi.org/10.1089/can.2021.0154] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35605018]

179. Martini, S.; Gemma, A.; Ferrari, M.; Cosentino, M.; Marino, F. Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance. Int. J. Mol. Sci.; 2023; 24, 3125. [DOI: https://dx.doi.org/10.3390/ijms24043125] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36834537]

180. Brzozowska, N.; Li, K.M.; Wang, X.S.; Booth, J.; Stuart, J.; McGregor, I.S.; Arnold, J.C. ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ; 2016; 4, e2081. [DOI: https://dx.doi.org/10.7717/peerj.2081] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27257556]

181. Iffland, K.; Grotenhermen, F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res.; 2017; 2, pp. 139-154. [DOI: https://dx.doi.org/10.1089/can.2016.0034] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28861514]

182. Zendulka, O.; Dovrtělová, G.; Nosková, K.; Turjap, M.; Šulcová, A.; Hanuš, L.; Jurica, J. Cannabinoids and Cytochrome P450 Interactions. Curr. Drug Metab.; 2016; 17, pp. 206-226. [DOI: https://dx.doi.org/10.2174/1389200217666151210142051]

183. Rana, R.R.; Rajasekaran, K.; Knappertz, V.; Gray, R.A. Pharmacodynamic synergism contributes to the antiseizure action of cannabidiol and clobazam. Exp. Neurol.; 2023; 360, 114286. [DOI: https://dx.doi.org/10.1016/j.expneurol.2022.114286]

184. Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin. Pharmacol. Drug Dev.; 2019; 8, pp. 1009-1031. [DOI: https://dx.doi.org/10.1002/cpdd.665]

185. Souza, J.D.R.; Pacheco, J.C.; Rossi, G.N.; de-Paulo, B.O.; Zuardi, A.W.; Guimarães, F.S.; Hallak, J.E.C.; Crippa, J.A.S.; Dos Santos, R.G. Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020–2022). Pharmaceutics.; 2022; 14, 2598. [DOI: https://dx.doi.org/10.3390/pharmaceutics14122598]

186. Jiang, R.; Yamaori, S.; Okamoto, Y.; Yamamoto, I.; Watanabe, K. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab. Pharmacokinet.; 2013; 28, pp. 332-338. [DOI: https://dx.doi.org/10.2133/dmpk.DMPK-12-RG-129]

187. Lucas, C.J.; Galettis, P.; Schneider, J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br. J. Clin. Pharmacol.; 2018; 84, pp. 2477-2482. [DOI: https://dx.doi.org/10.1111/bcp.13710]

188. Treves, N.; Mor, N.; Allegaert, K.; Bassalov, H.; Berkovitch, M.; Stolar, O.E.; Matok, I. Efficacy and safety of medical cannabinoids in children: A systematic review and meta-analysis. Sci. Rep.; 2021; 11, 23462. [DOI: https://dx.doi.org/10.1038/s41598-021-02770-6] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34873203]

189. Appelboam, A.; Oades, P.J. Coma due to cannabis toxicity in an infant. Eur. J. Emerg. Med.; 2006; 13, pp. 177-179. [DOI: https://dx.doi.org/10.1097/01.mej.0000194405.38206.f2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16679885]

190. Carstairs, S.D.; Fujinaka, M.K.; Keeney, G.E.; Ly, B.T. Prolonged coma in a child due to hashish ingestion with quantitation of THC metabolites in urine. J. Emerg. Med.; 2011; 41, pp. e69-e71. [DOI: https://dx.doi.org/10.1016/j.jemermed.2010.05.032] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20634020]

191. Bonkowsky, J.L.; Sarco, D.; Pomeroy, S.L. Ataxia and shaking in a 2-year-old girl: Acute marijuana intoxication presenting as seizure. Pediatr. Emerg. Care.; 2005; 21, pp. 527-528. [DOI: https://dx.doi.org/10.1097/01.pec.0000173349.38024.33]

192. Richards, J.R.; Smith, N.E.; Moulin, A.K. Unintentional Cannabis Ingestion in Children: A Systematic Review. J. Pediatr.; 2017; 190, pp. 142-152. [DOI: https://dx.doi.org/10.1016/j.jpeds.2017.07.005]

193. Netzahualcoyotzi, C.; Rodríguez-Serrano, L.M.; Chávez-Hernández, M.E.; Buenrostro-Jáuregui, M.H. Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior. Int. J. Mol. Sci.; 2021; 22, 7450. [DOI: https://dx.doi.org/10.3390/ijms22147450]

194. Dos Santos, R.G.; Guimarães, F.S.; Crippa, J.A.S.; Hallak, J.E.C.; Rossi, G.N.; Rocha, J.M.; Zuardi, A.W. Serious adverse effects of cannabidiol (CBD): A review of randomized controlled trials. Expert. Opin. Drug Metab. Toxicol.; 2020; 16, pp. 517-526. [DOI: https://dx.doi.org/10.1080/17425255.2020.1754793]

195. Liu, S.; He, Z.; Li, J. Long-term efficacy and adverse effects of cannabidiol in adjuvant treatment of drug-resistant epilepsy: A systematic review and meta-analysis. Ther. Adv. Neurol. Disord.; 2023; 16, 17562864231207755. [DOI: https://dx.doi.org/10.1177/17562864231207755] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37915501]

196. Laux, L.C.; Bebin, E.M.; Checketts, D.; Chez, M.; Flamini, R.; Marsh, E.D.; Miller, I.; Nichol, K.E.; Park, Y.; Segal, E. et al. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res.; 2019; 154, pp. 13-20. [DOI: https://dx.doi.org/10.1016/j.eplepsyres.2019.03.015]

197. Amariles, P.; Giraldo, N.A.; Faus, M.J. Clinical relevance of drug interactions. Med. Clin.; 2007; 129, pp. 27-35. [DOI: https://dx.doi.org/10.1157/13106681]

198. Lopera, V.; Rodríguez, A.; Amariles, P. Clinical Relevance of Drug Interactions with Cannabis: A Systematic Review. J. Clin. Med. Res.; 2022; 11, 1154. [DOI: https://dx.doi.org/10.3390/jcm11051154] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35268245]

199. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) Turck, D.; Bohn, T.; Castenmiller, J.; De Henauw, S.; Hirsch-Ernst, K.I.; Ildico, K.; Maciuk, A.; Mangelsdorf, I.; Mcardle, H.J. et al. Statement on safety of cannabidiol as a novel food: Data gaps and uncertainties. EFSA J.; 2022; 20, e07322.

200. Wilkinson, G.R.; Shand, D.G. Commentary: A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther.; 1975; 18, pp. 377-390. [DOI: https://dx.doi.org/10.1002/cpt1975184377]

201. Stott, C.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus; 2013; 2, 236. [DOI: https://dx.doi.org/10.1186/2193-1801-2-236]

202. Stout, S.M.; Cimino, N.M. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: A systematic review. Drug Metab. Rev.; 2014; 46, pp. 86-95. [DOI: https://dx.doi.org/10.3109/03602532.2013.849268]

203. Gaston, T.E.; Bebin, E.M.; Cutter, G.R.; Liu, Y.; Szaflarski, J.P. UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia; 2017; 58, pp. 1586-1592. [DOI: https://dx.doi.org/10.1111/epi.13852] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28782097]

204. Geffrey, A.L.; Pollack, S.F.; Bruno, P.L.; Thiele, E.A. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia; 2015; 56, pp. 1246-1251. [DOI: https://dx.doi.org/10.1111/epi.13060]

205. Wheless, J.W.; Dlugos, D.; Miller, I.; Oh, D.A.; Parikh, N.; Phillips, S.; Renfroe, J.B.; Roberts, C.M.; Saeed, I.; Sparagana, S.P. et al. Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy. CNS Drugs; 2019; 33, pp. 593-604. [DOI: https://dx.doi.org/10.1007/s40263-019-00624-4] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31049885]

206. McNamara, N.A.; Dang, L.T.; Sturza, J.; Ziobro, J.M.; Fedak Romanowski, E.M.; Smith, G.C.; Joshi, S.M.; Leber, S.; Carlson, M.; Robertson, P. et al. Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid. Epilepsia; 2020; 61, pp. e85-e89. [DOI: https://dx.doi.org/10.1111/epi.16596]

207. Anderson, L.L.; Doohan, P.T.; Oldfield, L.; Kevin, R.C.; Arnold, J.C.; Berger, M.; Amminger, G.P.; Mcgregor, I.S. Citalopram and Cannabidiol: In Vitro and In Vivo Evidence of Pharmacokinetic Interactions Relevant to the Treatment of Anxiety Disorders in Young People. J. Clin. Psychopharmacol.; 2021; 41, pp. 525-533. [DOI: https://dx.doi.org/10.1097/JCP.0000000000001427]

208. Grayson, L.; Vines, B.; Nichol, K.; Szaflarski, J.P. UAB CBD Program. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav. Case Rep.; 2018; 9, pp. 10-11. [DOI: https://dx.doi.org/10.1016/j.ebcr.2017.10.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29387536]

209. Damkier, P.; Lassen, D.; Christensen, M.M.H.; Madsen, K.G.; Hellfritzsch, M.; Pottegård, A. Interaction between warfarin and cannabis. Basic. Clin. Pharmacol. Toxicol.; 2019; 124, pp. 28-31. [DOI: https://dx.doi.org/10.1111/bcpt.13152] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30326170]

210. Hsu, A.; Painter, N.A. Probable Interaction Between Warfarin and Inhaled and Oral Administration of Cannabis. J. Pharm. Pract.; 2020; 33, pp. 915-918. [DOI: https://dx.doi.org/10.1177/0897190019854958]

211. Yamreudeewong, W.; Wong, H.K.; Brausch, L.M.; Pulley, K.R. Probable interaction between warfarin and marijuana smoking. Ann. Pharmacother.; 2009; 43, pp. 1347-1353. [DOI: https://dx.doi.org/10.1345/aph.1M064] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19531696]

212. Vierke, C.; Marxen, B.; Boettcher, M.; Hiemke, C.; Havemann-Reinecke, U. Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy. Eur. Arch. Psychiatry Clin. Neurosci.; 2021; 271, pp. 847-856. [DOI: https://dx.doi.org/10.1007/s00406-019-01091-0]

213. Madden, K.; Tanco, K.; Bruera, E. Clinically Significant Drug-Drug Interaction Between Methadone and Cannabidiol. Pediatrics; 2020; 145, e20193256. [DOI: https://dx.doi.org/10.1542/peds.2019-3256]

214. Alsherbiny, M.A.; Li, C.G. Medicinal cannabis-potential drug interactions. Medicines; 2018; 6, 3. [DOI: https://dx.doi.org/10.3390/medicines6010003]

215. Website. Epidiolex. Available online: https://www.gwpharm.com/healthcare-professionals (accessed on 16 June 2024).

216. Guimarães, F.S.; de Aguiar, J.C.; Mechoulam, R.; Breuer, A. Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. Gen. Pharmacol.; 1994; 25, pp. 161-164. [DOI: https://dx.doi.org/10.1016/0306-3623(94)90027-2]

217. Linares, I.M.; Zuardi, A.W.; Pereira, L.C.; Queiroz, R.H.; Mechoulam, R.; Guimarães, F.S.; Crippa, J.A.S. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz. J. Psychiatry; 2019; 41, pp. 9-14. [DOI: https://dx.doi.org/10.1590/1516-4446-2017-0015]

218. Zuardi, A.W.; Rodrigues, N.P.; Silva, A.L.; Bernardo, S.A.; Hallak, J.E.C.; Guimarães, F.S.; Crippa, J.A.S. Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Front. Pharmacol.; 2017; 8, 259. [DOI: https://dx.doi.org/10.3389/fphar.2017.00259]

219. Nazario, L.R.; Antonioli, R., Jr.; Capiotti, K.M.; Hallak, J.E.C.; Zuardi, A.W.; Crippa, J.A.S.; Bonan, C.; da Silva, R.S. Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio). Pharmacol. Biochem. Behav.; 2015; 135, pp. 210-216. [DOI: https://dx.doi.org/10.1016/j.pbb.2015.06.008] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26099242]

220. Malfait, A.M.; Gallily, R.; Sumariwalla, P.F.; Malik, A.S.; Andreakos, E.; Mechoulam, R.; Feldmann, M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA; 2000; 97, pp. 9561-9566. [DOI: https://dx.doi.org/10.1073/pnas.160105897] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10920191]

221. Fliegel, D.K.; Lichenstein, S.D. Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety. Psychiatry Res. Commun.; 2022; 2, 100074. [DOI: https://dx.doi.org/10.1016/j.psycom.2022.100074]

222. Narayan, A.J.; Downey, L.A.; Manning, B.; Hayley, A.C. Cannabinoid treatments for anxiety: A systematic review and consideration of the impact of sleep disturbance. Neurosci. Biobehav. Rev.; 2022; 143, 104941. [DOI: https://dx.doi.org/10.1016/j.neubiorev.2022.104941] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36370842]

223. Black, N.; Stockings, E.; Campbell, G.; Tran, L.T.; Zagic, D.; Hall, W.D.; Farrell, M.; Degenhardt, L. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis. Lancet Psychiatry; 2019; 6, pp. 995-1010. [DOI: https://dx.doi.org/10.1016/S2215-0366(19)30401-8]

224. Thiele, E.A.; Marsh, E.D.; French, J.A.; Mazurkiewicz-Beldzinska, M.; Benbadis, S.R.; Joshi, C.; Devinsky, O.; Checketts, D.; Roberts, C. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet; 2018; 391, pp. 1085-1096. [DOI: https://dx.doi.org/10.1016/S0140-6736(18)30136-3]

225. Devinsky, O.; Patel, A.D.; Cross, J.H.; Villanueva, V.; Wirrell, E.C.; Privitera, M.; Greenwood, S.M.; Roberts, C.; Checketts, D.; VanLandingham, K.E. et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N. Engl. J. Med.; 2018; 378, pp. 1888-1897. [DOI: https://dx.doi.org/10.1056/NEJMoa1714631]

226. Szaflarski, J.P.; Bebin, E.M.; Comi, A.M.; Patel, A.D.; Joshi, C.; Checketts, D.; Beal, J.; Laux, L.C.; De Bôer, L.M.; Wong, M.H. et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia; 2018; 59, pp. 1540-1548. [DOI: https://dx.doi.org/10.1111/epi.14477]

227. Gallily, R.; Yekhtin, Z.; Hanuš, L.O. Overcoming the bell-shaped dose-response of cannabidiol by using cannabis extract enriched in cannabidiol. Pharmacol. Pharm.; 2015; 06, pp. 75-85. [DOI: https://dx.doi.org/10.4236/pp.2015.62010]

228. Pamplona, F.A.; da Silva, L.R.; Coan, A.C. Potential Clinical Benefits of CBD-Rich Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front. Neurol.; 2018; 9, 759. [DOI: https://dx.doi.org/10.3389/fneur.2018.00759]

229. Pertwee, R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol.; 2008; 153, pp. 199-215. [DOI: https://dx.doi.org/10.1038/sj.bjp.0707442] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17828291]

230. Colizzi, M.; Bhattacharyya, S. Cannabis use and the development of tolerance: A systematic review of human evidence. Neurosci. Biobehav. Rev.; 2018; 93, pp. 1-25. [DOI: https://dx.doi.org/10.1016/j.neubiorev.2018.07.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30056176]

231. Metna-Laurent, M.; Mondésir, M.; Grel, A.; Vallée, M.; Piazza, P.-V. Cannabinoid-induced tetrad in mice. Curr. Protoc. Neurosci.; 2017; 80, pp. 9.59.1-9.59.10. [DOI: https://dx.doi.org/10.1002/cpns.31]

232. Volkow, N.D.; Swanson, J.M.; Evins, A.E.; De Lisi, L.E.; Meier, M.H.; Gonzalez, R.; Bloomfield, M.A.P.; Curran, H.V.; Baler, R. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: A review. JAMA Psychiatry; 2016; 73, pp. 292-297. [DOI: https://dx.doi.org/10.1001/jamapsychiatry.2015.3278]

233. Andreae, M.H.; Carter, G.M.; Shaparin, N.; Suslov, K.; Ellis, R.J.; Ware, M.A.; Abrams, D.I.; Prasad, H.; Wilsey, B.; Indyk, B. et al. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J. Pain.; 2015; 16, pp. 1221-1232. [DOI: https://dx.doi.org/10.1016/j.jpain.2015.07.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26362106]

234. Wallace, M.S.; Marcotte, T.D.; Umlauf, A.; Gouaux, B.; Atkinson, J.H. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J. Pain.; 2015; 16, pp. 616-627. [DOI: https://dx.doi.org/10.1016/j.jpain.2015.03.008]

235. van de Donk, T.; Niesters, M.; Kowal, M.A.; Olofsen, E.; Dahan, A.; van Velzen, M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain; 2019; 160, pp. 860-869. [DOI: https://dx.doi.org/10.1097/j.pain.0000000000001464]

236. Abrams, D.I.; Jay, C.A.; Shade, S.B.; Vizoso, H.; Reda, H.; Press, S.; Kelly, M.E.; Rowbotham, M.C.; Petersen, K.L. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. Neurology; 2007; 68, pp. 515-521. [DOI: https://dx.doi.org/10.1212/01.wnl.0000253187.66183.9c]

237. Ellis, R.J.; Toperoff, W.; Vaida, F.; van den Brande, G.; Gonzales, J.; Gouaux, B.; Bentley, H.; Atkinson, J.H. Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology; 2009; 34, pp. 672-680. [DOI: https://dx.doi.org/10.1038/npp.2008.120]

238. Wilsey, B.; Marcotte, T.D.; Deutsch, R.; Zhao, H.; Prasad, H.; Phan, A. An exploratory human laboratory experiment evaluating vaporized cannabis in the treatment of neuropathic pain from spinal cord injury and disease. J. Pain; 2016; 17, pp. 982-1000. [DOI: https://dx.doi.org/10.1016/j.jpain.2016.05.010]

239. ElSohly, M.A.; Mehmedic, Z.; Foster, S.; Gon, C.; Chandra, S.; Church, J.C. Changes in cannabis potency over the last 2 decades (1995-2014): Analysis of current data in the United States. Biol. Psychiatry; 2016; 79, pp. 613-619. [DOI: https://dx.doi.org/10.1016/j.biopsych.2016.01.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26903403]

240. Chandra, S.; Radwan, M.M.; Majumdar, C.G.; Church, J.C.; Freeman, T.P.; ElSohly, M.A. New trends in cannabis potency in USA and Europe during the last decade (2008–2017). Eur. Arch. Psychiatry Clin. Neurosci.; 2019; 269, pp. 5-15. [DOI: https://dx.doi.org/10.1007/s00406-019-00983-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30671616]

241. Russo, E.B.; McPartland, J.M. Cannabis is more than simply delta(9)-tetrahydrocannabinol. Psychopharmacology; 2003; 165, pp. 431-432. author reply 433–434 [DOI: https://dx.doi.org/10.1007/s00213-002-1348-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12491031]

242. Demirakca, T.; Sartorius, A.; Ende, G.; Meyer, N.; Welzel, H.; Skopp, G.; Mann, K.; Hermann, D. Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol. Drug Alcohol. Depend.; 2011; 114, pp. 242-245. [DOI: https://dx.doi.org/10.1016/j.drugalcdep.2010.09.020]

243. Morgan, C.J.A.; Curran, H.V. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br. J. Psychiatry; 2008; 192, pp. 306-307. [DOI: https://dx.doi.org/10.1192/bjp.bp.107.046649]

244. Morgan, C.J.A.; Gardener, C.; Schafer, G.; Swan, S.; Demarchi, C.; Freeman, T.P.; Warrington, P.; Rupasinghe, I.; Ramoutar, A.; Tan, N. et al. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol Med.; 2012; 42, pp. 391-400. [DOI: https://dx.doi.org/10.1017/S0033291711001322]

245. Johnson, J.R.; Burnell-Nugent, M.; Lossignol, D.; Ganae-Motan, E.D.; Potts, R.; Fallon, M.T. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J. Pain. Symptom Manag.; 2010; 39, pp. 167-179. [DOI: https://dx.doi.org/10.1016/j.jpainsymman.2009.06.008]

246. Notcutt, W.; Price, M.; Miller, R.; Newport, S.; Phillips, C.; Simmons, S.; Sansom, C. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 “N of 1” studies. Anaesthesia; 2004; 59, pp. 440-452. [DOI: https://dx.doi.org/10.1111/j.1365-2044.2004.03674.x]

247. Wade, D.T.; Robson, P.; House, H.; Makela, P.; Aram, J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin. Rehabil.; 2003; 17, pp. 21-29. [DOI: https://dx.doi.org/10.1191/0269215503cr581oa]

248. Giacoppo, S.; Bramanti, P.; Mazzon, E. Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation. Mult. Scler. Relat. Disord.; 2017; 17, pp. 22-31. [DOI: https://dx.doi.org/10.1016/j.msard.2017.06.015]

249. Gurley, B.J.; Murphy, T.P.; Gul, W.; Walker, L.A.; ElSohly, M. Content versus Label Claims in Cannabidiol (CBD)-Containing Products Obtained from Commercial Outlets in the State of Mississippi. J. Diet. Suppl.; 2020; 17, pp. 599-607. [DOI: https://dx.doi.org/10.1080/19390211.2020.1766634] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32431186]

250. Hazekamp, A. The Trouble with CBD Oil. Med. Cannabis Cannabinoids; 2018; 1, pp. 65-72. [DOI: https://dx.doi.org/10.1159/000489287] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34676324]

251. Pavlovic, R.; Nenna, G.; Calvi, L.; Panseri, S.; Borgonovo, G.; Giupponi, L.; Cannazza, G.; Giorgi, A. Quality Traits of “Cannabidiol Oils”: Cannabinoids Content, Terpene Fingerprint and Oxidation Stability of European Commercially Available Preparations. Molecules; 2018; 23, 1230. [DOI: https://dx.doi.org/10.3390/molecules23051230] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29783790]

252. Herbst, J.; Musgrave, G. Respiratory depression following an accidental overdose of a CBD-labeled product: A pediatric case report. J Am Pharm Assoc.; 2020; 60, pp. 248-252. [DOI: https://dx.doi.org/10.1016/j.japh.2019.09.023]

253. Zhekova, R.M.; Perry, R.N.; Spinella, T.C.; Dockrill, K.; Stewart, S.H.; Barrett, S.P. The impact of cannabidiol placebo on responses to an acute stressor: A replication and proof of concept study. J. Psychopharmacol.; 2024; 38, pp. 116-124. [DOI: https://dx.doi.org/10.1177/02698811231219060]

254. De Vita, M.J.; Maisto, S.A.; Gilmour, C.E.; McGuire, L.; Tarvin, E.; Moskal, D. The effects of cannabidiol and analgesic expectancies on experimental pain reactivity in healthy adults: A balanced placebo design trial. Exp. Clin. Psychopharmacol.; 2022; 30, pp. 536-546. [DOI: https://dx.doi.org/10.1037/pha0000465] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34251840]

255. Gedin, F.; Blomé, S.; Pontén, M.; Lalouni, M.; Fust, J.; Raquette, A.; Lundquist, V.V.; Thompson, W.H.; Jensen, K. Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis. JAMA Netw. Open; 2022; 5, e2243848. [DOI: https://dx.doi.org/10.1001/jamanetworkopen.2022.43848]

256. Požgain, I.; Požgain, Z.; Degmečić, D. Placebo and nocebo effect: A mini-review. Psychiatr. Danub.; 2014; 26, pp. 100-107.