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The Endocannabinoid System and its Modulation by Cannabidiol (CBD)

Jamie Corroon, ND, MPH; Jake F. Felice, ND, LMP

 

ABSTRACT

 

The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others. (Altern Ther Health Med. 2019;25(S2):6-14.)

 

 

 

Jamie Corroon, ND, MPH, Medical Director, the Center for Medical Cannabis Education, Del Mar, CA, USA.
Jake F. Felice, ND, LMP, principal, Cannabis Matrix Consulting, Goleta, CA, and professor, Seattle Central College, Seattle, WA, USA

 

 

 

Corresponding author: Jamie Corroon, ND, MPH
E-mail address: jamie@corroon.com

 

 

 

As interest in, and use of, phytocannabinoids from Cannabis Sativa L (Cannabis) has increased with the number of state-regulated Cannabis programs, heightened scientific attention has been directed toward the mechanisms by which delta-9-tetrahydrocannabiniol (delta-9-THC), cannabidiol (CBD), and other phytocannabinoids exert their physiological effects in the body. These exogenous, plant-derived ligands interact with endogenously produced proteins, receptors, enzymes, and endogenous ligands, in one of the most evolutionarily preserved biological systems known to the life sciences, the endogenous cannabinoid signaling system or endocannabinoid system (ECS).

 

The ECS is thought to be 600-million-years-old. Present in every animal species, except insects, it evolved as a stress/harm regulation network that functions to restore homeostasis following cellular stressors.1 The ECS is upregulated and downregulated on a continuous basis as needed. It communicates with all other systems in the body and has been implicated in multiple regulatory functions in both health and disease, including pain, perception, mood, memory, and reward.2,3 This vital physiological system is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids. According to George Kunos, Scientific Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) at the National Institutes of Health (NIH), “Modulating endocannabinoid system activity may have therapeutic potential in almost all diseases affecting humans.”

 

The discovery of the ECS began with the search for the active ingredient in Cannabis.4 CBD was first isolated from a Cannabis extract in 1940.5 Initially, CBD was deemed an inactive constituent because it failed to mimic the effects of Cannabis extracts in animals and humans.6 As a result, it wasn’t characterized structurally until 1963, more than
20 years later.7

 

Delta-9-tetrahydrocannabinol (THC) was isolated and characterized a year later, in 1964.6 Delta-9-THC does mimic the effects of a Cannabis extract, and subsequently, became the focus of phytocannabinoid research going forward.8 In addition to investigating its stereochemistry, pharmacokinetics, and other characteristics, scientists began to explore the pharmacology of delta-9-THC, specifically its mechanisms of action.

 

With the endogenous opioid system as a blueprint, a G-protein-coupled receptor (GPCR), to which delta-9-THC exhibited partial agonism, was identified in 1988.9 The discovery of this receptor, cannabinoid receptor 1 (CB1), paved the way for the detection of endogenous ligands that demonstrated affinity for the receptor.

 

The endocannabinoid anandamide—N-arachidonoylethanolamine, also known as AEA—was subsequently identified in 1992,10 and a second endocannabinoid, 2-Arachidonoylglycerol (2-AG), was discovered in 1995.11 A second, peripheral cannabinoid receptor (CB2) was identified in 1993.12 Investigations into the production and breakdown of endocannabinoids were also being conducted during this time. The enzymes responsible for synthesizing and degrading anandamide and 2-AG were identified in 1994 and 1993, respectively.13,14

 

 

 

ENDOCANNABINOIDS

 

Endocannabinoids are the signaling molecules of the endocannabinoid system. They are fatty-acid neurotransmitters that safeguard body systems by coordinating and fine-tuning intracellular biochemistry and intercellular communication across all physiological systems without exception. A multitude of pathological conditions may involve alterations in endocannabinoid synthesis or degradation, receptor expression, enzyme function, and a variety of other factors.15

 

While anandamide and 2-AG are the most studied endocannabinoids, other endocannabinoid-like mediators that aren’t formally classified as endocannabinoids, such as oleoylethanolamine (OEA) and palmitoylethanolamine (PEA), also exist. Endocannabinoids primarily mediate their effects through interactions with receptors, including
non-cannabinoid receptors, and with other underlying mechanisms. Endocannabinoids share some chemical characteristics with phytocannabinoids, but they are structurally different and generally have a lesser degree of affinity for cannabinoid receptors.16 Also, like their phytochemical counterparts, endocannabinoids are promiscuous ligands, meaning they interact with a broad range of non-cannabinoid receptors.17

 

Unlike conventional neurotransmitter systems, endocannabinoids are lipids, as opposed to peptides like dopamine, gamma-aminobutyric acid (GABA), and acetylcholine. They are synthesized on demand, typically in postganglionic neurons, as opposed to being synthesized a priori and stored in vesicles in preganglionic neurons. Also, unlike conventional neurotransmitter systems, in which neurotransmitters diffuse from preganglionic to postganglionic neurons, endocannabinoids diffuse in a reverse or retrograde direction, exerting their effects through receptors on preganglionic neurons. This review discusses the dynamics of this system in greater detail below.

 

 

 

Anandamide

 

Anandamide is a high-affinity, partial agonist of CB1 and CB2 receptors—Ki: 400 ± 120nM and 1760 ± 360nM, respectively.15,16,18 Research has shown that it can inhibit adenylyl-cyclase activity intracellularly at both receptors.16 In fact, cannabinoids in general appear to act on the adenylate-cyclase, second-messenger pathway in an inhibitory fashion.4

 

Like most other lipid mediators, endocannabinoids have more than just one set of biosynthetic and degrading pathways and enzymes.3 Anandamide is predominantly synthesized by the enzyme N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) and hydrolyzed intracellularly by fatty acid amide hydrolase (FAAH) and secondarily by N-acylethanolamine-hydrolyzing acid amidase (NAAA). In humans, a second enzyme, known as FAAH-2, hydrolyzes anandamide at lower rates than FAAH.

 

A group of fatty-acid-binding proteins (FABPs) has been shown to be the intracellular transporter for anandamide and 2-AG from the cell membrane through the cytosol for hydrolysis at the endoplasmic reticulum.19 The role of FABPs is discussed further below.

 

 

 

2-AG

 

This endocannabinoid is very similar to anandamide in chemical structure; however, it’s a moderate-affinity, full agonist at CB1 and CB2—Ki: 472 ± 55nM and 1400 ± 172nM, respectively.15,16,18 It’s synthesized and hydrolyzed by different enzymes, namely diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL), respectively.20 This endocannabinoid is the most abundant one in the central nervous system (CNS) and plays a major role in CNS development and synaptic plasticity.21

 

 

 

Independent Regulation of 2AG and Anandamide

 

Tissue levels of 2AG and anandamide are independently regulated, allowing the two signaling molecules to exert different functions even within the same cell, tissue, or organ system.15 Both pathological and normal physiologic conditions can alter concentrations of only one, or both of these molecules, and opposing changes in the levels of anandamide and 2AG are not uncommon. Endocannabinoids not only interact with cannabinoid receptors, they are involved in cellular tuning and homeostasis through coordinated interactions with more than one target at any one time.2,15

 

 

 

ECS RECEPTORS

 

Cannabinoid receptors are 7-transmembrane-domain GPCRs. CB1 and CB2 receptors differ in their amino-acid sequence, anatomic distribution, mechanisms of signaling, and other characteristics.16 G-protein receptors represent the most common receptor system in vertebrates, and CB1 receptors are the most abundant and densely concentrated receptors in the human CNS.22,23 Some researchers have postulated that cannabinoid receptor may be a misnomer given that THC and THC-V are the only phytocannabinoids that exhibit high affinity for the CB1 and CB2 receptors.15 Practically speaking, however, ligands that exhibit even low affinity are deemed cannabinoids, including CBD, which demonstrates negligible affinity for either CB receptor—CBD: Ki at CB1 = 4350 nM; CB2 = 4200 nM.24

 

 

 

Cannabinoid Receptors

 

CB1 receptors. The CB1 receptor is widely distributed throughout the CNS, particularly in nociceptive areas of the brain and spinal cord but also on certain cells of the immune system, adipose tissue, liver, muscle, reproductive cells, kidney, and lungs.22,25,26

 

These receptors are noticeably absent in the cardiac and respiratory centers of the brainstem,27 which is why cannabis doesn’t depress respiration or stop the heart from beating. Respiratory depression, mediated by opioid receptors in the respiratory center in the brainstem, is the most common cause of opioid-overdose mortality.28 Respiratory depression isn’t a risk with phytocannabinoids.

 

CB2 receptors. In contrast, CB2 receptors are mainly located in the periphery, in lymphoid and immune tissues and on organs like the heart and liver.29 Surprisingly the CB2 receptor has only 44% chemical homology with the CB1 receptor.12

 

The predominance of CB2 receptors in immune tissues underlies the immunomodulatory role of the ECS, with one of its key functional benefits occurring in the presence of inflammation.30,31 Modulation through the CB2 receptor might provide an avenue for the treatment of various inflammatory processes.32

 

Interaction of cannabinoid receptors. Individual cannabinoid receptors interact with one another, and with non-cannabinoid receptors, such as opioid receptors,33,34 forming heteromers that alter the pharmacodynamics of the individual subunits. These heteromers have demonstrated bidirectional cross-antagonism, whereby CB1 antagonists block the effects of CB2 agonists and enable CB2 antagonists to block CB1 agonists.35

 

 

 

Non-cannabinoid Receptors

 

GPR55 receptors. Work by a number of groups of researchers in recent years has provided evidence that the ECS is more complicated and expansive than previously thought. In fact, researchers have hypothesized that the G-protein receptor 55 (GPR-55) may be a third cannabinoid receptor due to its affinity for endo- and phytocannabinoids.3,36,37 GPR55 receptors are also G-GPCRs and are widely distributed in the brain and periphery. They regulate multiple physiological processes that influence motor activity, movement coordination, nociception, energy expenditure, bone metabolism, anxiety modulation, and more.37,38 Activation of this receptor is positively associated with obesity in humans.37 Additionally, the GPR55 receptor is expressed in various cancer types.39

 

TRPV1 receptors. The transient receptor potential, cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, has also received some consideration as a cannabinoid receptor.3 While TRPV1 was first identified as a receptor for capsaicin, a pungent ingredient in hot chili pepper, it’s also activated by vanilla-like compounds as well as compounds in ginger, black pepper, and other botanicals.40,41 Anandamide is a full agonist at the TRPV1 receptor, and 2-AG has also been shown to activate TRPV1, although at concentrations much higher than anandamide.3 CBD has been found to be a weak, full agonist of TRPV1.42

 

TRPV1 expression occurs mainly in sensory nerves. The activation of TRPV1 receptors causes terminals of central and peripheral sensory nerves to release neuropeptides, resulting in smooth-muscle contraction, cough, pain, and neurogenic inflammation.43

 

5-HT/serotonin receptors. The 5-hydroxytryptamine receptors, or 5-HT or serotonin receptors, are a class of GPCRs and ligand-gated ion channels found primarily in the central and peripheral nervous systems. Serotonin, the predominant endogenous ligand, is a biogenic monoamine and is similar in structure to histamine, dopamine, epinephrine, and norepinephrine. In the CNS, serotonin mediates both inhibitory and excitatory neurotransmission via a variety of serotonin receptors, of which 14 types exist.44

 

The 5-HT receptors are present in the GI tract, brain, platelets, lung, kidneys, and other tissues. These receptors are implicated in a wide range of biological activity including pain perception,45 nausea and vomiting,46 anxiety,47 addiction, appetite, and sleep.48 Recent studies have begun to examine interactions between the ECS and serotonergic systems, primarily due to the fact that both play roles in the regulation of stress and other emotional processes, including body temperature, feeding behavior, sleep, and arousal.41

 

Adenosine receptors. Adenosine receptors are a group of GPCRs to which adenosine binds as an endogenous ligand. Caffeine and theophylline are known to serve as exogenous antagonists producing the stimulating effects of coffee, tea, and chocolate.49 In humans, 4 types are known—A1, A2A, A2B and A3, each encoded by different genes. These different receptor types possess distinct areas of localization, different means of regulation, and different signal transduction pathways.50

 

Adenosine receptors provide broad anti-inflammatory effects.51 In the CNS, adenosine provides neuroprotection during hypoxic, ischemic, and oxidative events. Additionally, adenosine modulates synaptic plasticity and neurotransmitter release. Adenosine also plays an important role in the regulation of sleep and the development of various cancers.52

 

PPAR-alpha receptors. The family of transcription factors termed peroxisome proliferator-activated receptors (PPAR) are type II nuclear receptors with 3 isoforms: PPAR-alpha, PPAR-gamma, and PPAR-delta.53 PPARs promote the transcription of specific genes upon activation by small lipophilic ligands. They play an essential role in energy homeostasis and metabolic function, and thus, are localized in most tissues, including liver, skeletal muscle, cardiac, bone, endothelial, and other tissues.54 In addition, PPAR activation has been shown to play a role in neuroprotection, reward pathways, memory and cognition, analgesia, inflammation and immunity, and vasoregulation as well as the regulation of feeding and satiety.55,56

 

PPAR-alpha is activated by endocannabinoids, endocannabinoid?like compounds—oleoylethanolamine (OEA) and palmitoylethanolamine (PEA)), phytocannabinoids, and synthetic cannabinoid ligands.55 Substantial evidence now exists that cannabinoids induce apoptosis in many cancer cell lines via PPARγ receptors.55

 

 

 

NEUROREGULATION AND PROTECTION

 

Among other functions, the ECS is a neuroregulatory system that maintains and restores homeostasis by modulating the release of neurotransmitters, both excitatory and inhibitory. Neuromodulation, or neuroregulation, is an exceptionally important physiological phenomenon, and CB1 activation always reduces neurotransmitter release, regardless of the transmitter involved.57

 

During an action potential, depolarization of a postganglionic neuron results in increased intracellular calcium levels, which triggers the synthesis of endocannabinoids in the postganglionic neuron. These endocannabinoids are then released into the synapse and diffuse in a retrograde direction to bind to CB1 receptors on axon terminals in the preganglionic neuron, a negative feedback process called retrograde inhibition or depolarization-induced suppression of excitation and inhibition.

 

 

 

Seizure Disorders

 

Depolarization-induced suppression of excitation is one of the ways that the ECS protects the nervous system from hyperactivity during seizure events.58 Endocannabinoids are produced during seizures and act on cannabinoid receptors in the hippocampus and neocortex.57 Inhibition of glutamate by endocannabinoids can dampen seizure activity and reduce neuronal death.57 Phytocannabinoids are generally anticonvulsant and have been referred to as circuit breakers because of their ability to reduce seizures and corresponding neurodegeneration.57,59

 

In June 2018, the FDA approved purified CBD as the drug product Epidiolex (Greenwich Biosciences, Carlsbad, CA, USA) to treat 2 severe forms of epilepsy—Lennox–Gastaut syndrome and Dravet syndrome.60-63 The anticonvulsant effects of CBD aren’t confined to these rare forms of epilepsy. Anticonvulsant and neuroprotective effects have been demonstrated in animal models of status epilepticus22 and in humans with generalized epilepsy and treatment-resistant epilepsies.64-66

 

 

 

Traumatic Brain Injury (TBI)

 

Cannabinoids also have the ability to protect neurons from a variety of insults resulting from TBI, such as calcium influx, excitotoxicity, free radical formation, and neuroinflammation.67 In-vivo and in-vitro data suggest that the endocannabinoids anandamide and 2-AG serve as homeostatic regulators to limit brain damage following brain injury.68,69 Furthermore, exogenous cannabinoids given within 4 hours of TBI, have been shown to limit glutamate toxicity and nerve-cell damage in an animal model.68

 

 

 

Ischemic Events

 

As with seizure and TBI, the body’s levels of endocannabinoids spontaneously elevate during stroke, presumably indicating a protective response.70 In experimental models of stroke, cannabinoids significantly reduced infarct size and improved functional outcomes in animals.71 Neuroprotection exerted by exogenous 2-AG suggests that the formation of 2-AG may serve as a molecular regulator of pathophysiological events in the brain.68 CBD appears to provide stronger neuroprotection than delta-9-THC via a CB1-independent mechanism.72 In a study of ischemia produced by carotid artery occlusion, CBD demonstrated a protective effect on neuronal death in mice.73

 

 

 

Autocrine and Paracrine Function

 

A lesser known function of the endocannabinoid system is regulation of homeostasis via autocrine and paracrine signaling. Autocrine regulators are substances produced by a cell that regulate the cell itself. Autocrine regulation is classically modeled in liver regeneration where autocrine signaling triggers the regrowth of liver cells.74 Paracrine regulators are substances produced by a cell that regulate nearby cells. Paracrine regulation is classically modeled in immune activation of T-cells, B-cells, or NK cells. Paracrine signaling is also highly involved in the wound-healing process.75

 

 

 

Gastrointestinal Function

 

In addition to acting as neurotransmitters do, endocannabinoids also act as autocrine and paracrine regulators. For example, in the presence of inflammatory bowel disease (IBD), immune cells, such as mast cells and macrophages, infiltrate the muscular and mucosal layers of the gastrointestinal (GI) tract and secrete inflammatory mediators, such as cytokines and chemokines like TNF-alpha. The presence of these chemicals stimulates the production of endocannabinoids, which act on cannabinoid and non-cannabinoid receptors, such as TRPV1, on both the immune cells producing the endocannabinoids (autocrine regulation) and the nearby immune cells (paracrine regulation).76 The overall effect is  a decrease in the production of inflammatory chemicals, and ultimately, reduced infiltration of other inflammation-producing white bloods cells.

 

An expanding body of research has demonstrated that cannabinoids also play important roles in normal gastrointestinal physiology. For example, anandamide and delta-9-THC inhibit intestinal motility, delay of gastric emptying, and decrease of gastric secretion, potentially by activating CB1 receptors in cholinergic pathways.77 The
anti-emetic effects of cannabinoids have been shown across a wide variety of experimental models.78 CB1 agonists consistently suppress vomiting, while emesis is achieved through CB1 antagonism. CBD has been shown to exert
anti-nausea/anti-emetic effects by indirect agonism of 5-HT1A receptors.79

 

 

 

Cardiometabolic Function

 

The ECS influences metabolic functions, centrally and peripherally, in tissues of the cardiovascular system, GI tract, musculoskeletal system, and other systems as well as in hepatocytes, adipocytes, and other cells.80 Alterations in endocannabinoid receptors and ligands are found in a number of cardiometabolic diseases, including cardiovascular disease, hypertension, obesity, and diabetes.81 Individuals with obstructive sleep apnea and diabetes, for example, have been shown to have higher circulating levels of endocannabinoids as compared to controls.81 Anandamide has also been positively associated with increased blood pressure,81 while 2-AG has been inversely associated with insulin sensitivity, even after controlling for body fat percentage.82 In addition, 2-AG has been positively associated with body fat and visceral obesity.82 In congestive heart failure, for example, human myocardial cells display upregulated CB2 receptors and downregulated CB1 receptors.83 It’s more likely that these associations and alternations are the result of homeostatic reactions to the stresses of cardiometabolic disease than the primary cause of it.

 

 

 

Food Intake and Reward

 

Cannabinoids can be putatively included in the large family of orexogenic molecules, which are molecules that stimulate appetite.84 Administration of anandamide has been shown to stimulate appetite in mice.84 The ECS modulates food intake both centrally and at the level of the GI tract through multiple mechanisms. CB1 receptors are expressed in key hypothalamic systems.85 Between meals, endocannabinoids gradually increase over time until they reach levels that trigger ECS circuits, thus increasing the motivation to feed.86

 

The dopaminergic system represents one of the most important reward pathways.  Cannabinoid-dopaminergic interactions appear to influence feeding behavior.87,88 Interestingly, the hormone leptin strongly modulates endocannabinoid levels in the hypothalamus.89 Recent studies have indicated that the regulation of food intake may be affected by genetic impairment of the ECS.85

 

 

 

Hypothalamus and HPA Axis

 

Studies of the endocannabinoid system support its importance in modulation of the hypothalamic-pituitary-adrenal (HPA) axis, including regulation of mood and anxiety and extinction of fear learning.90 Cannabinoid action on neuroendocrine functioning, including ACTH levels, is mediated by CB1 signaling in the hypothalamus.91 Alternately, pretreatment with the CB1 antagonist Rimonabant, prior to a stressor, has been shown to blunt HPA function in a mouse model.91

 

 

 

Pain and Inflammation

 

Cannabinoid receptors are present on nociceptors and other sensory neurons in pain processing pathways in the brain and spinal cord,92 often co-localized with opioid receptors.27,33 Activation of CB1 receptors in these areas has been shown to inhibit transmission of pain signals to higher brain regions92 and modulate pain signals in descending pain pathways.33

 

Numerous preclinical studies have demonstrated the beneficial effects of cannabinoids, including CBD, in animal models of acute pain,93,94 chronic pain, and neuropathic pain,95,96 some demonstrating opioid-sparing effects. Human studies investigating CBD-induced analgesia in humans, however, are few.97,98

 

 

 

The Circadian Sleep–wake Cycle

 

The ECS has the capacity to modulate circadian rhythms and is involved in the regulation of circadian sleep–wake cycles.58 Plasma concentrations of anandamide exhibit a circadian rhythm, which can be disrupted by sleep deprivation.99

 

 

 

Reproductive System and Embryogenesis

 

Endocannabinoids are involved in local and central regulation of reproduction and are present in most reproductive fluids and tissues.100 A properly functioning ECS orchestrates nearly all reproductive events from gamete production and fertilization to successful pregnancy, birth, and lactation. These include proper sperm function,101 fertilization,102,103 blastocyst formation,104 oviduct transport,105,106 uterine receptivity (decidualization),107 trophoblast maturation,108 placental development,109 and parturition.110  Interestingly, pharmacologic antagonism of CB1 blocks ECS signaling and leads to failure of pregnancy.111,112 High levels of maternal anandamide appear detrimental to placental and fetal development. The enzymatic degradation of anandamide appears to be an early marker of spontaneous abortion and may even be useful as a diagnostic tool for monitoring of early pregnancy.113

 

 

 

THE ENTOURAGE EFFECT

 

In popular culture, the Entourage Effect has become the preferred phrase for describing the purported physiological synergies engendered by various constituents within the Cannabis plant. This effect isn’t exclusive to Cannabis spp., however, nor is it exclusive to phytocannabinoids.114-116

 

In fact, the concept originally described interactions between endocannabinoids, specifically the role of 2 endocannabinoid-like mediators—2-acyl-glycerol esters—in increasing the biological activity of 2-AG at the CB1 receptor.4,117 Additional research has demonstrated that these endocannabinoid-like mediators, with no affinity for the CB1 receptor, also inhibit anandamide metabolism, thus potentially leading to increased levels and greater anandamide signaling.118

 

These examples underscore the important notion that the Entourage Effect can exist in the absence of phytocannabinoids. Therefore, perhaps a more accurate characterization of this phenomenon might describe the sum-total of the pharmacokinetic and pharmacodynamic interactions within and between endocannabinoids and biologically active constituents within Cannabis, including terpenes and terpenoids.

 

 

 

Allosteric Modulation

 

Phytocannabinoids are also involved in pharmacodynamic interactions at the CB1 receptor. For example, CBD has been shown to antagonize delta-9-THC at CB1, presumably through negative allosteric modulation.119,120 In contrast to ligands that bind to an active site on a receptor—the orthosteric site, allosteric modulators bind to a nonactive site—the allosteric site.

 

Allosteric modulators can prime receptors for potentiation or antagonism in subtle, yet powerful ways by changing the conformation of a receptor and influencing agonist signaling. Thus, CB1 signaling by delta-9-THC is altered by the presence of CBD. This is one of the ways in which CBD may attenuate some of the undesirable effects of delta-9-THC, such as anxiety, tachycardia, and short-term memory loss.121 This pharmacodynamic interaction involves 2 phytocannabinoids, just as the aforementioned interaction involved 2, or more, endocannabinoids. CBD may also act as a negative allosteric modulator of 2-AG.119

 

 

 

CBD and Non-Cannabinoid Receptors

 

Allosteric modulators, like CBD, don’t activate receptors directly. Thus CBD’s widespread biological effects are largely attributable to other mechanisms, including interactions with non-cannabinoid receptors.3,42,122 CBD is pleiotropic in that it interacts with opioid, serotonin, adenosine, and GABA receptors as well as non-GPCRs-like nuclear receptors, such as PPARγ, and ligand-gated ion channels, such as TRPV1.123 For example, one of the ways that CBD is thought to modulate inflammation and temperature and pain perception is through activation of TRPV1.42 Anti-anxiety and
anti-emetic effects have been associated with direct and indirect agonism of the 5-HT1A receptor, respectively.79,124 Anti-proliferative effects, inducing tumor regression, have been associated with PPARs. Please note: This list isn’t intended to be comprehensive.55

 

Other indirect mechanisms involving receptors are postulated. For example, CBD may also affect intracellular signal transduction by disturbing neuronal membrane fluidity,4,125,126 or by remodeling G-proteins associated with GPCRs.127

 

 

 

Inhibition of FAAH

 

Receptor-independent mechanisms have also been demonstrated. Interactions between phytocannabinoids and intracellular enzymes may lead to inhibition of the enzymatic hydrolysis of endocannabinoids, thus increasing their signaling.117,128 CBD, in particular, has been shown to moderately inhibit anandamide hydrolysis by FAAH in both mice and humans.3,129-131 Other research suggests that CBD doesn’t inhibit human FAAH.19 Nonsteroidal anti-inflammatory drugs (NSAIDs) are also demonstrated FAAH inhibitors.95

 

 

 

Inhibition of FABPs

 

Other intracellular proteins are also involved in Entourage interactions. For example, a family of intracellular transport proteins, FABPs, effectively solubilizes cannabinoids and shuttles them from the cell membrane to the endoplasmic reticulum where they are degraded by FAAH and MAGL in the case of anandamide and 2-AG, respectively. Studies have demonstrated that delta-9-THC and CBD compete with anandamide for binding sites on FABPs, inhibiting the cellular uptake and catabolism of anandamide.19 In addition to FAAH inhibition, this competition may explain the increased circulating levels of anandamide reported after ingestion of CBD.132 This mechanism may also explain in part the action of CBD in modulating endocannabinoid tone and its effectiveness in treating epilepsy and other neurological disorders.133

 

 

 

CBD, Pain, and Inflammation

 

The mechanisms underlying CBD-induced analgesia aren’t well understood. Inhibition of FAAH and MAGL has been associated with increased endocannabinoid levels, analgesia, and opioid-sparing effects in preclinical models of pain.134 Broadly speaking, cannabinoids are powerful modulators of inflammatory mediators.30,31,135 For example, inhibition of tumor necrosis factor-alpha (TNF-α) and other inflammatory mediators by CBD has been demonstrated in a rodent model of acute pain136 and in another of rheumatoid arthritis.137 Enhancement of adenosine signaling by CBD through inhibition of adenosine uptake has been associated with decreased inflammation in preclinical models.138 Additionally, activation of TRPV1 has been shown to inhibit hyperalgesia in an animal model of acute pain.42 These mechanisms aren’t intended to represent an exhaustive list. Cannabinoid-induced analgesia is likely achieved through a complex interplay of mechanisms.

 

 

 

Clinical Endocannabinoid Deficiency (CECD)

 

In 2004, CECD was coined by neurologist Ethan Russo to describe the potential pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions that seemed to be alleviated by Cannabis.139 Russo hypothesized that a wide variety of medical conditions with previously uncharacterized clinical, biochemical, and pathophysiological features may, in fact, be due to deficiencies, or alterations, in the endocannabinoid system. In 2016, Russo expanded the list of conditions thought to be associated with CECD to include autoimmune disorders, epilepsy, cardiovascular disease, anxiety, depression, failure to thrive, schizophrenia, multiple sclerosis, Parkinson’s disease, and others.140

 

 

 

Tolerability and Safety of CBD

 

Comprehensive reviews of the safety and adverse effects of CBD conducted in 2011 and 2017 showed that even chronic use at very high doses—up to 1,500 mg/day of isolated CBD—are safe and well tolerated without significant adverse effects.141,142 CBD doesn’t appear to induce catalepsy nor alter psychomotor and cognitive functions. In addition, the World Health Organization’s Expert Committee on Drug Dependence recommended that CBD shouldn’t be controlled by Schedule I of the 1961 UN Single Convention on Narcotic Drugs.143 Their comprehensive report is expected in 2019.

 

CBD isn’t without adverse effects, however. The most commonly reported adverse effects are fatigue, diarrhea, dry mouth, and changes of appetite and weight.142,144

 

When used to treat medical conditions, CBD has a better adverse-effect profile than many FDA-approved drugs.142 This low-adverse-effect profile can improve patients’ adherence to treatment.

 

It’s important to note that the pharmacokinetics and pharmacodynamics of phytocannabinoids may be different across different methods of administration and when administered as components of a botanical extract as opposed to isolated compounds. For example, recent studies show a linear dose-response curve for CBD administered in a broad-spectrum extract and a bell-shaped dose-response curve for CBD administered as an isolated compound.136 Not only do these differing characteristics influence the dose-response curve, they also influence the adverse-effect profile. The higher efficiency of a plant extract might be explained by additive or synergistic interactions between CBD and other phytocannabinoids or non-cannabinoids present in extracts, the Entourage Effect.

 

 

 

CONCLUSIONS

 

The endocannabinoid system (ECS) is an extensive endogenous signaling system, and its very concept may be changing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like CBD and others. Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.

 

 

 

AUTHORS' DISCLOSURE STATEMENT

 

Jamie Corroon is the Medical Director at the Center for Medical Cannabis Education, a for-profit, clinical practice and research and consulting entity. Jake F. Felice is a principal of Cannabis Matrix Consulting, a for-profit consulting entity.

 

 

 

REFERENCES

 

  1. McPartland JM, Matias I, Di Marzo V, Glass M. Evolutionary origins of the endocannabinoid system. 2006; 370:64-74.
  2. Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998; 21(12):521-528.
  3. Di Marzo V, Piscitelli F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics: The journal of the American Society for Experimental NeuroTherapeutics. 2015; 12(4):692-698.
  4. Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: the ongoing story of cannabis. Natural product reports. 1999; 16(2):131-143.
  5. Adams R, Hunt M, Clark JH. Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. I. 2002.
  6. Gaoni Y, Mechoulam R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. 2002.
  7. Mechoulam R, Shvo Y. Hashish. I. The structure of cannabidiol. 1963; 19(12):2073-2078.
  8. Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of hashish activity. 1970; 169(3945):611-612.
  9. Howlett AC, Johnson MR, Melvin LS, Milne GM. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol. 1988; 33(3):297-302.
  10. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. 1992; 258(5090):1946-1949.
  11. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50(1):83-90.
  12. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. 1993; 365(6441):61-65.
  13. Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. 1994; 372(6507):686-691.
  14. Deutsch DG, Chin SA. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol. 1993; 46(5):791-796.
  15. Di Marzo V, De Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607):3216-3228.
  16. Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995; 48(3):443-450.
  17. Alexander SP, Kendall DA. The complications of promiscuity: endocannabinoid action and metabolism. Br J Pharmacol. 2007; 152(5):602-623.
  18. Hillard CJ. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins & other lipid mediators. 2000; 61(1-2):3-18.
  19. Elmes MW, Kaczocha M, Berger WT, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem. 2015; 290(14):8711-8721.
  20. Bisogno T, Howell F, Williams G, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003; 163(3):463-468.
  21. Murataeva N, Straiker A, Mackie K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014; 171(6):1379-1391.
  22. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proceedings of the National Academy of Sciences of the United States of America. 1990; 87(5):1932-1936.
  23. Devane WA, Dysarz FA, 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988; 34(5):605-613.
  24. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007; 150(5):613-623.
  25. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocrine reviews. 2006; 27(1):73-100.
  26. Hohmann AG, Briley EM, Herkenham M. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res. 1999; 822(1-2):17-25.
  27. Pickel VM, Chan J, Kash TL, Rodriguez JJ, MacKie K. Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens. 2004; 127(1):101-112.
  28. Fox LM, Hoffman RS, Vlahov D, Manini AF. Risk factors for severe respiratory depression from prescription opioid overdose. Addiction (Abingdon, England). 2018; 113(1):59-66.
  29. Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. European journal of biochemistry. 1995; 232(1):54-61.
  30. Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003; 74(4):486-496.
  31. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005; 5(5):400-411.
  32. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016; 73(23):4449-4470.
  33. Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol. 2010; 10(1):80.
  34. Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74(11):1317-1324.
  35. Callen L, Moreno E, Barroso-Chinea P, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. 2012; 287(25):20851-20865.
  36. Ryberg E, Larsson N, Sjogren S, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007; 152(7):1092-1101.
  37. Tuduri E, Imbernon M, Hernandez-Bautista RJ, et al. GPR55: a new promising target for metabolism? J Mol Endocrinol. 2017; 58(3):R191-r202.
  38. Idris AI. Cannabinoid Receptors as Target for Treatment of Osteoporosis: A Tale of Two Therapies. Curr Neuropharmacol. 2010; 8(3):243-253.
  39. Hu G, Ren G, Shi Y. The putative cannabinoid receptor GPR55 promotes cancer cell proliferation. 2011; 30(2):139-141.
  40. Russo EB. Beyond Cannabis: Plants and the Endocannabinoid System. Trends Pharmacol Sci. 2016; 37(7):594-605.
  41. Haj-Dahmane S, Shen RY. Modulation of the Serotonin System by Endocannabinoid Signaling. 2011; 61(3):414-420.
  42. Costa B, Giagnoni G, Franke C, Trovato AE, 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(2):247-250.
  43. Jia Y, McLeod RL, Hey JA. TRPV1 receptor: a target for the treatment of pain, cough, airway disease and urinary incontinence. Drug News Perspect. 2005; 18(3):165-171.
  44. Frazer A, Hensler JG. Serotonin Receptors. Lippincott-Raven; 1999.
  45. Sommer C. Serotonin in pain and analgesia: actions in the periphery. Mol Neurobiol. 2004; 30(2):117-125.
  46. Gan TJ. Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005; 19(3):225-238.
  47. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. 1998; 392(6673):245-252.
  48. Frazer A, Hensler JG. Serotonin Involvement in Physiological Function and Behavior. Lippincott-Raven; 1999.
  49. Fredholm BB, AP IJ, Jacobson KA, Linden J, Muller CE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev. 2011; 63(1):1-34.
  50. Linden JM. Purinergic Receptors. Lippincott-Raven; 1999.
  51. Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med. 2011; 51(5):1054-1061.
  52. Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine Receptors: Expression, Function and Regulation. Int J Mol Sci. 2014; 15(2):2024-2052.
  53. Alexander SP, Cidlowski JA, Kelly E, et al. The Concise Guide to Pharmacology 2015/16: Nuclear hormone receptors. Br J Pharmacol. 2015; 172(24):5956-5978.
  54. Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. In: J Adv Pharm Technol Res. Vol 2.2011:236-240.
  55. O’Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016; 173(12):1899-1910.
  56. Clark RB. The role of PPARs in inflammation and immunity. J Leukoc Biol. 2002;71(3):388-400.
  57. Alger BE. Seizing an Opportunity for the Endocannabinoid System. Epilepsy Curr. 2014; 14(5):272-276.
  58. Sanford AE, Castillo E, Gannon RL. Cannabinoids and hamster circadian activity rhythms. Brain Res. 2008; 1222:141-148.
  59. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008; 14(9):923-930.
  60. Press Announcements - FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Office of the Commissioner2018.
  61. Greenwich Biosciences I. Epidiolex - Highlights of Prescribing Information. 2018; Epidiolex Drug Monograph. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed 02-25-2019.
  62. Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, et al. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. 2019; 60(3):419-428.
  63. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med.
  64. Devinsky O, Verducci C, Thiele EA, et al. Open-label use of highly purified CBD (Epidiolex(R)) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy & behavior : E&B. 2018; 86:131-137.
  65. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. 2014; 55(6):791-802.
  66. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. 1980; 21(3):175-185.
  67. Biegon A. Cannabinoids as Neuroprotective Agents in Traumatic Brain Injury. 2004.
  68. Mechoulam R, Shohami E. Endocannabinoids and traumatic brain injury. Mol Neurobiol. 2007; 36(1):68-74.
  69. Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002; 8(2):58-61.
  70. Nagayama T, Sinor AD, Simon RP, et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999; 19(8):2987-2995.
  71. England TJ, Hind WH, Rasid NA, O’Sullivan SE. Cannabinoids in experimental stroke: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2015; 35(3):348-358.
  72. Hayakawa K, Mishima K, Nozako M, et al. Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. 2007; 52(4):1079-1087.
  73. Schiavon AP, Soares LM, Bonato JM, Milani H, Guimaraes FS, Weffort de Oliveira RM. Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice. Neurotox Res. 2014; 26(4):307-316.
  74. Zheng ZY, Weng SY, Yu Y. Signal molecule-mediated hepatic cell communication during liver regeneration. World J Gastroenterol. 2009; 15(46):5776-5783.
  75. Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007; 127(5):998-1008.
  76. Kunos G, Pacher P. Cannabinoids cool the intestine. Nat Med. 2004; 10(7):678-679.
  77. Massa F, Storr M, Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med (Berl). 2005; 83(12):944-954.
  78. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol. 2011; 163(7):1411-1422.
  79. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005; 30(8):1037-1043.
  80. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance. 2006.
  81. Engeli S, Bluher M, Jumpertz R, et al. Circulating anandamide and blood pressure in patients with obstructive sleep apnea. J Hypertens. 2012; 30(12):2345-2351.
  82. Bluher M, Engeli S, Kloting N, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. 2006; 55(11):3053-3060.
  83. Weis F, Beiras-Fernandez A, Sodian R, et al. Substantially altered expression pattern of cannabinoid receptor 2 and activated endocannabinoid system in patients with severe heart failure. J Mol Cell Cardiol. 2010; 48(6):1187-1193.
  84. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001; 134(6):1151-1154.
  85. Cota D, Marsicano G, Tschöp M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. The Journal of clinical investigation. 2003; 112:423-431.
  86. Williams CM, Kirkham TC. Observational analysis of feeding induced by Delta9-THC and anandamide. Physiology & behavior. 2002; 76:241-250.
  87. Verty ANA, McGregor IS, Mallet PE. The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Delta9-tetrahydrocannabinol. Brain research. 2004; 1020:188-195.
  88. Gardner EL, Vorel SR. Cannabinoid transmission and reward-related events. Neurobiology of disease. 1998; 5:502-533.
  89. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. 2001; 410:822-825.
  90. Korem N, Zer-Aviv TM, Ganon-Elazar E, Abush H, Akirav I. Targeting the endocannabinoid system to treat anxiety-related disorders. J Basic Clin Physiol Pharmacol. 2016; 27(3):193-202.
  91. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. 2004; 145:5431-5438.
  92. Palazzo E, Luongo L, de Novellis V, Rossi F, Maione S. The Role of Cannabinoid Receptors in the Descending Modulation of Pain. Pharmaceuticals (Basel). 2010; 3(8):2661-2673.
  93. Costa B, Colleoni M, Conti S, et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn-Schmiedeberg’s archives of pharmacology. 2004; 369(3):294-299.
  94. Smith FL, Fujimori K, Lowe J, Welch SP. Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav. 1998; 60(1):183-191.
  95. Guindon J, Beaulieu P. Antihyperalgesic effects of local injections of anandamide, ibuprofen, rofecoxib and their combinations in a model of neuropathic pain. 2006; 50(7):814-823.
  96. Fox A, Kesingland A, Gentry C, et al. The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. 2001; 92(1-2):91-100.
  97. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. 2004; 59(5):440-452.
  98. van de Donk T, Niesters M, Kowal MA, 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. 2019; 160(4):860-869.
  99. Vaughn LK, Denning G, Stuhr KL, de Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm? Br J Pharmacol. 2010; 160(3):530-543.
  100. Schuel H, Burkman LJ, Lippes J, et al. Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Molecular Reproduction and Development. 2002; 63:376-387.
  101. Schuel H, Burkman LJ, Lippes J, et al. N-Acylethanolamines in human reproductive fluids. Paper presented at: Chemistry and Physics of Lipids 2002.
  102. Francavilla F, Battista N, Barbonetti A, et al. Characterization of the Endocannabinoid System in Human Spermatozoa and Involvement of Transient Receptor Potential Vanilloid 1 Receptor in Their Fertilizing Ability. 2009;150:4692-4700.
  103. Gervasi MG, Rapanelli M, Ribeiro ML, et al. The endocannabinoid system in bull sperm and bovine oviductal epithelium: role of anandamide in sperm–oviduct interaction. 2009; 137:403-414.
  104. Wang H, Matsumoto H, Guo Y, Paria BC, Roberts RL, Dey SK. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proceedings of the National Academy of Sciences. 2003; 100:14914-14919.
  105. Gervasi MG, Marczylo TH, Lam PM, et al. Anandamide levels fluctuate in the bovine oviduct during the oestrous cycle. PloS one. 2013; 8:e72521.
  106. Schmid PC, Paria BC, Krebsbach RJ, Schmid HH, Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proceedings of the National Academy of Sciences of the United States of America. 1997; 94:4188-4192.
  107. Paria BC, Song H, Wang X, et al. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. The Journal of biological chemistry. 2001; 276:20523-20528.
  108. Sun X, Xie H, Yang J, Wang H, Bradshaw HB, Dey SK. Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation. Proceedings of the National Academy of Sciences. 2010; 107:16887-16892.
  109. Sun X, Xie H, Yang J, Wang H, Bradshaw HB, Dey SK. Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107:16887-16892.
  110. Wang H, Xie H, Dey SK. Loss of Cannabinoid Receptor CB1 Induces Preterm Birth. PLoS ONE. 2008; 3:e3320.
  111. Maccarrone M, Cecconi S, Rossi G, Battista N, Pauselli R, Finazzi-Agrò A. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. 2003; 144:20-28.
  112. Maccarrone M, Finazzi-Agrò A. Anandamide hydrolase: a guardian angel of human reproduction? Trends in pharmacological sciences. 2004; 25:353-357.
  113. Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet (London, England). 2000; 355:1326-1329.
  114. Spelman K. “Silver Bullet” Drugs vs. Traditional Herbal Remedies: Perspectives on Malaria. 2009; 84(84):44-55.
  115. Rath K, Taxis K, Walz G, Gleiter CH, Li SM, Heide L. Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood). The American journal of tropical medicine and hygiene. 2004; 70(2):128-132.
  116. Butterweck V, Lieflander-Wulf U, Winterhoff H, Nahrstedt A. Plasma levels of hypericin in presence of procyanidin B2 and hyperoside: a pharmacokinetic study in rats. Planta medica. 2003; 69(3):189-192.
  117. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998; 353(1):23-31.
  118. Mechoulam R, Fride E, Hanus L, et al. Anandamide may mediate sleep induction. 1997; 389(6646):25-26.
  119. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015; 172(20):4790-4805.
  120. Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol.
  121. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical hypotheses. 2006; 66(2):234-246.
  122. Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002; 42(S1):11s-19s.
  123. Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids-A Complex Picture. Progress in the chemistry of organic natural products. 2017; 103:103-131.
  124. de Mello Schier AR, de Oliveira Ribeiro NP, Coutinho DS, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa. CNS & neurological disorders drug targets. 2014; 13(6):953-960.
  125. Krylatov AV, Uzhachenko RV, Maslov LN, et al. Endogenous cannabinoids improve myocardial resistance to arrhythmogenic effects of coronary occlusion and reperfusion: a possible mechanism. Bulletin of experimental biology and medicine. 2002; 133(2):122-124.
  126. Frontiers | Cannabis sativa: The Plant of the Thousand and One Molecules | Plant Science. 2018.
  127. John M. McPartland D, MS, Ethan B. Russo M. Cannabis and Cannabis Extracts. https://doiorg/101300/J175v01n03_08.
  128. Bisogno T, Hanu
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