Cannabinoid Receptor Notably, cannabinoid receptor-dependent changes in drug- and food-oriented appetitive behaviors may reflect more general changes in reward-learning processes, including those Receptor CBD Oil Cannabinoid research has greatly expanded Structural biology and computational chemistry jointly provide mechanistic insight Structural data are being generated at an Cannabidiol (CBD), a non-psychoactive component of the marijuana plant, has generated significant interest among scientists and physicians in recent years—but how CBD exerts its therapeutic impact on a molecular level is still being sorted out.
Notably, cannabinoid receptor-dependent changes in drug- and food-oriented appetitive behaviors may reflect more general changes in reward-learning processes, including those whereby the incentive value of the drug or food is assigned to instrumental outcomes or outcome-associated stimuli.
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Analgesic Drugs in Development
Stephen B. McMahon FMedSci, FSB , in Wall & Melzack’s Textbook of Pain , 2013
Cannabinoids and Adenosine Receptor Ligands
Self-medication with cannabis is commonly used to relieve pain and other symptoms in patients with multiple sclerosis ( Clark et al 2004 ), and it now appears that this will lead to a well-validated clinical application. There has been a resurgence in interest of late because of the initiation of a new sequence of clinical trials on pain conditions using standardized preparations of herbal extracts of cannabis containing defined amounts of the active chemical principles ( Notcutt et al 2004 ). Some positive data have been reported ( Notcutt et al 2004 ), but there are also negative studies on experimental pain in volunteers ( Naef et al 2003 ) and on postoperative pain ( Buggy et al 2003 ). It has recently been announced that a phase III trial with a standardized preparation of cannabis (Sativex) has shown a statistically significant reduction in pain, particularly in patients with neuropathic pain or cancer pain, when added to the patients’ existing pain control medication (GW Pharmaceuticals website, accessed October 23, 2010, http://www.gwpharm.com ). Sativex is now licensed for the treatment of spasticity associated with multiple sclerosis in the United Kingdom and is in phase III clinical trials for the treatment of pain ( Buggy et al 2003 ).
Preclinical research on cannabinoid pharmacology is active, and we now know that there are two G protein–coupled receptors (CB1 and CB2) sensitive to cannabis and endogenous cannabinoids ( Sawynok 2003 ). The exclusive peripheral localization of the CB2 receptor raises the possibility of using agonists for this site as analgesics lacking the unwanted central psychotropic effects of cannabis ( Guindon and Hohmann 2008 ). Selective agonists for the CB2 receptor have been claimed in the past, but many of these are partial agonists or have mixed pharmacology. A-796260 does appear to be a selective and efficacious CB2 agonist and is effective in a wide range of animal pain models ( Yao et al 2008 ). There is an interesting overlap in the pharmacology of agents acting at cannabinoid receptors and those acting at VR1/transient receptor potential vanilloid 1 [TRPV1]) (see later). It is noteworthy that selective activation of CB2 receptors was found to suppress the hyperalgesia produced by intradermal capsaicin ( Hohmann et al 2004 ), thus reinforcing the idea that CB2 agonists may have a role as analgesic drugs.
The effect of the endogenous purine adenosine on pain perception in humans is complex, with high intravenous doses evoking pain but low doses providing pain relief ( Sawynok 2003 , Sjolund et al 1999 ). Clinical analgesia has been observed in volunteer studies on cutaneous hyperalgesia following inflammatory pain when adenosine was given intravenously ( Sjolund et al 1999 ) and in patients with neuropathic pain when adenosine was given intrathecally ( Belfrage et al 1999 ). A recent clinical study on postoperative pain patients failed to show analgesia after administration of the selective A1 receptor agonist GR79236X, although the active control diclofenac was effective ( Sneyd et al 2007 ). Recent animal experiments suggest that both A2A and A2B antagonists have potential in the treatment of inflammatory pain ( Bilkei-Gorzo et al 2008 ).
Cannabinoid receptors are 7-transmembrane receptors that mediate the central and peripheral actions of extracts from the cannabis plant (Cannabis sativa), known under a variety of pseudonyms from hashish and marijuana to ganja and bhang. Although many endogenous agonists of cannabinoid receptors have been described, a categorical role of these (lipid-derived) molecules as the endogenous ligand for cannabinoid receptors is currently lacking. Cannabinoid receptors have been implicated in diverse physiological and pathophysiological roles in the body, including regulation of mood, appetite, pain sensation, vascular and nonvascular smooth muscle tone, and immune function. The wide distribution of cannabinoid receptors in the central and peripheral nervous systems , as well as non-nervous tissue, supports these putative roles. Currently, there appear to be only two subtypes of cannabinoid receptor, CB1 and CB2 , which appear to be located predominantly on cells of the nervous and immune systems, respectively. Both receptor subtypes couple principally through the Gi/o family of G proteins . Application of cannabis extracts and synthetic cannabinoids elicits a classical “tetrad” of symptoms in experimental animals: catalepsy, hypothermia, antinociception, and hypokinesia.
Stephen B. McMahon FMedSci, FSB , in Wall & Melzack’s Textbook of Pain , 2013
Two cannabinoid receptors (CB 1 and CB2) have been identified to date (for review see Howlett et al 2002 ). Additional receptor subtypes (e.g., the G-protein receptor GPR55) that share little homology with CB1 and CB2 have also been recently postulated to represent novel cannabinoid receptors ( Lauckner et al 2008 ).
In the early days of cannabinoid pharmacology it was hypothesized that lipophilic cannabinoids exerted their effects by perturbing neuronal membranes in a fashion similar to a theory proposed for general anesthetics. However, the demonstration of cannabinoid receptor binding sites (labeled with [ 3 H]CP55,940) in the brain that possessed the characteristics of a G protein–coupled receptor ( Devane et al 1988 ) established the existence of a cannabinoid transmitter system. This discovery was followed by cloning of the CB1 receptor from a rat cDNA library ( Matsuda et al 1990 ). Rat CB1 has, in common with many other G protein–coupled receptors, seven transmembrane-spanning α-helices, a C-terminal that couples to G proteins, an extracellular N-terminal, and three potential glycosylation sites. It is 473 amino acids in length and has a molecular weight of 53 kDa, although variants of 59 and 64 kDa also exist. Cloning of human CB1 (hCB1) (472 amino acids; Gerard et al 1991 ) and mouse (473 amino acids; Chakrabarti et al 1995 ) homologues that share close sequence homology (>97%) with rat CB1 followed. Later, an immune cell human cannabinoid receptor (hCB2) was identified, initially in a human promyelocytic leukemia cell line that has 44% sequence homology (68% in the transmembrane regions) with hCB1 ( Munro et al 1993 ). hCB2 is also a G protein–coupled receptor but is shorter than CB1 (360 amino acids, 40 kDa). Subsequently, the murine and rat homologues of CB2 have been cloned and found to have 82% ( Shire et al 1995 ) and 81% ( Griffin et al 2000 ) sequence homology with hCB2, respectively, and 90% homology between them. The presence of CB2 isoforms with different distributions in different tissues and species has also been documented; in the brain, CB2A has been reported to exist at levels of 0.1 or 1% of those expressed in the spleen ( Liu et al 2009 ). Transgenic mice have been created in which the genes encoding CB1 ( Ledent et al 1999 , Zimmer et al 1999 ) or CB2 ( Buckley et al 2000 ) have been disrupted.
Circumstantial evidence suggests the existence of further, hitherto uncharacterized, cannabinoid receptors predominantly based on residual pharmacological activity in cannabinoid receptor knockout mice or following the administration of receptor antagonists to naïve rodents ( Breivogel et al 2001 ). An obvious strategy for identifying such receptors is to search databases for structural homology to CB1 or CB2. More recently, GPR55 has been identified as a putative third cannabinoid receptor, although it lacks the functional fingerprint of a cannabinoid receptor. GPR55 is highly sensitive to lysophosphatidylinositol (which does not bind cannabinoid receptors) and only some (e.g., tetrahydrocannabinol [THC], methanandamide, JWH015) cannabinoid and endocannabinoid ligands. Activation of GPR55 increases calcium and M currents, which engages signaling mechanisms distinct from CB1 and CB2 ( Lauckner et al 2008 ). Intriguingly, this receptor may play a pro-nociceptive role in the nervous system inasmuch as mechanical hyperalgesia fails to develop in GPR55 −/− mice following treatment with an inflammatory agent, complete Freund’s adjuvant (CFA), or traumatic nerve injury produced by partial sciatic nerve ligation ( Staton et al 2008 ).
The Protein–Protein Interactions of Cannabinoid Receptor Interacting Protein 1a (CRIP1a) and Cannabinoid 1 Receptor: The Molecular Mechanism Study Through an Integrated Molecular Modeling Approach
CRIP1a secondary structure predication
James M. Ritter DPhil FRCP HonFBPhS FMedSci , in Rang & Dale’s Pharmacology , 2020
Cannabinoids, being highly lipid-soluble, were originally thought to act in a similar way to general anaesthetics. However, in 1988, saturable high-affinity binding of a tritiated cannabinoid was demonstrated in membranes prepared from homogenised rat brain. This led to the identification of specific cannabinoid receptors in brain. These are now termed CB 1 receptors to distinguish them from the CB2 receptors subsequently identified in peripheral tissues. Cannabinoid receptors are typical members of the family of G protein–coupled receptors ( Ch. 3 ). CB1 receptors are linked via Gi/o to inhibition of adenylyl cyclase and of voltage-operated calcium channels, and to activation of G protein-sensitive inwardly rectifying potassium (GIRK) channels, causing membrane hyperpolarisation ( Fig. 20.2 ). These effects are similar to those mediated by opioid receptors ( Ch. 43 ). CB1 receptors are located in the plasma membrane of nerve endings and inhibit transmitter release from presynaptic terminals, which is caused by depolarisation and Ca 2+ entry ( Ch. 4 ). CB receptors also influence gene expression, both directly by activating mitogen-activated protein kinase, and indirectly by reducing the activity of protein kinase A as a result of reduced adenylyl cyclase activity (see Ch. 3 ).
CB1 receptors are abundant in the brain, with similar numbers to receptors for glutamate and GABA – the main central excitatory and inhibitory neurotransmitters ( Ch. 39 ). They are not homogeneously distributed, being concentrated in the hippocampus (relevant to effects of cannabinoids on memory), cerebellum (relevant to loss of coordination), hypothalamus (important in control of appetite and body temperature; see Ch. 33 and further in this chapter), substantia nigra, mesolimbic dopamine pathways that have been implicated in psychological ‘reward’ (Ch.50), and in association areas of the cerebral cortex. There is a relative paucity of CB1 receptors in the brain stem, consistent with the lack of serious depression of respiratory or cardiovascular function by cannabinoids. At a cellular level, CB1 receptors are mainly localised presynaptically, and inhibit transmitter release as depicted in Fig. 20.2 . Like opioids, they can, however, increase the activity of some neuronal pathways by inhibiting inhibitory connections, including GABA-ergic interneurons in the hippocampus and amygdala.
In addition to their well-recognised location in the CNS, CB1 receptors are also expressed in peripheral tissues, for example on endothelial cells, adipocytes and peripheral nerves. Cannabinoids promote lipogenesis through activation of CB1 receptors, an action that could contribute to their effect on body weight (see DiPatrizio & Piomele, 2012 ).
The CB2 receptor has only approximately 45% amino acid homology with CB1 and is located mainly in lymphoid tissue (spleen, tonsils and thymus as well as circulating lymphocytes, monocytes and tissue mast cells). CB2 receptors are also present on microglia – immune cells in the CNS which, when activated, contribute to chronic pain ( Ch. 38 ). The localisation of CB2 receptors on cells of the immune system was unexpected, but may account for inhibitory effects of cannabis on immune function. CB2 receptors differ from CB1 receptors in their responsiveness to cannabinoid ligands (see Table 20.1 ). They are linked via Gi/o to adenylyl cyclase, GIRK channels and mitogen-activated protein kinase similarly to CB1, but not to voltage-operated calcium channels (which are not expressed in immune cells). So far, rather little is known about their function. They are present in atherosclerotic lesions (see Ch. 24 ), and CB2 agonists have potentially anti-atherosclerotic effects on macrophages and foam cells ( Chiurchiu et al., 2014 ).
Constitutive Activity in Receptors and Other Proteins, Part B
Tung M. Fong , in Methods in Enzymology , 2010
The cannabinoid receptors are G protein-coupled receptors that are activated by endocannabinoids or exogenous agonists such as tetrahydrocannabinol. Upon agonist binding, cannabinoid receptors will activate Gi which in turn inhibits adenylyl cyclase. Recently, inverse agonists for the cannabinoid receptors have been identified, demonstrating constitutive activity of the cannabinoid receptors. Several methods have been used to measure inverse agonist activity of ligands for the cannabinoid receptors, including Gi-cAMP second messenger assay, GTPγS binding assay, and electrophysiological assays. Each assay has its advantages and limitations, and the Gi-cAMP second messenger assay appears to provide the best overall measurement of inverse agonism in a cellular environment.
Cannabinoids and the Cannabinoid Receptors: An Overview
Cannabinoid receptors are the G-protein-coupled receptors that mediate the biological effects of phytocannabinoids, endocannabinoids, and synthetic cannabimimetic compounds.
Cannabinoids are a group of biologically active compounds isolated from the plant cannabis, and are often referred to as phytocannabinoids, some of which are responsible for the psychoactive effects of cannabis.
Endocannabinoids are the molecules produced by human and animals which exhibit similar biological activities as phytocannabinoids.
G-protein-coupled receptors (GPCRs) are membrane-bound signal transduction proteins that associate with guanosine nucleotide-binding proteins (G-proteins) on their intracellular side. Upon binding to certain type of chemical compounds, the GPCRs change shapes, and cause the disassembly of the associated G-proteins into subunits, which further transduce the signal to the downstream proteins and eventually lead to cellular responses.
Chemical compounds synthesized in laboratories that exhibit similar biological activities as phytocannabinoids.
Cannabis, Endocannabinoid CB1 Receptors, and the Neuropathology of Vision
Cannabinoid (CB) receptors are widely distributed through the central nervous system, where they play a relevant role in various cognitive processes such as learning, memory, or attention. However, despite the distortion in sensory perception caused by cannabis, it has not been until recently that the effect of CB activation on visual physiology and pathophysiology has been studied in detail. These studies reflect a critical role for CB in visual perception, modulating not only the processing of visual information by the retina, but also further processing and computation of visual signals by the thalamus and cortex. Interestingly, activation of cannabinoid receptors in therapies can result in some cases in an improvement of visual function.
Molecular Pharmacology of CB1 and CB2 Cannabinoid Receptors
The cannabinoid receptors are highly expressed in nearly all mammalian tissues.
The various classes of cannabinoid receptors share a significant amount of sequence homology.
The CB1 and CB2 receptors have distinct expression profiles; CB1 is localized in neuronal tissue, while CB2 is found on cells of immune origin.
There exist at least five distinct classes of cannabinoid ligands.
Genomics studies have revealed strong associations between substance abuse and cannabinoid receptor polymorphisms.
Developing modern therapeutic cannabinergic agents will depend on how well the ECS is understood.
Cannabinoid receptor mutational analysis has provided insight into how these receptors can influence drug addiction-related disorders and disease progression.
Cannabinoids and Their Receptors
Morag R. Hunter , . Michelle Glass , in Methods in Enzymology , 2017
Cannabinoid receptors , like other GPCRs, signal via a spectrum of related signaling pathways. Recently, monitoring GPCR-mediated cAMP signaling has become significantly easier with the development of genetically encoded, transfectable cAMP biosensors. Cell lines transfected with these biosensors can be monitored continuously, allowing the analysis of receptor-mediated signaling in unprecedented detail. Here, we describe a protocol for transfectable biosensors which report cellular cAMP concentrations by bioluminescence resonance energy transfer (BRET). This assay system has been utilized to elucidate the temporal nature of agonists and allosteric modulators of the cannabinoid receptor CB1. In particular, the CB1 allosteric modulator ORG27569 has been shown to modify receptor agonism in a time-dependent fashion; a characteristic which would not have been observed via traditional endpoint methods of detecting cAMP signaling. BRET cAMP biosensors are suitable for miniaturization and automation, and as such are valuable and cost-effective tools for moderate- to high-throughput experimental protocols.
Receptor CBD Oil
Cannabinoid research has greatly expanded
Structural biology and computational chemistry jointly provide mechanistic insight
Structural data are being generated at an exponentially increasing rate
Phytocannabinoid targeting of other GPCR receptors deserves investigation
Like most modern molecular biology and natural product chemistry, understanding cannabinoid pharmacology centers around molecular interactions, in this case, between the cannabinoids and their putative targets, the G-protein coupled receptors (GPCRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Understanding the complex structure and interplay between the partners in this molecular dance is required to understand the mechanism of action of synthetic, endogenous, and phytochemical cannabinoids. This review, with 91 references, surveys our understanding of the structural biology of the cannabinoids and their target receptors including both a critical comparison of the extant crystal structures and the computationally derived homology models, as well as an in-depth discussion about the binding modes of the major cannabinoids. The aim is to assist in situating structural biochemists, synthetic chemists, and molecular biologists who are new to the field of cannabis research.
How CBD Works
Cannabidiol ( CBD ), a non-intoxicating component of the cannabis plant, has generated significant interest among scientists and physicians in recent years—but how CBD exerts its therapeutic impact on a molecular level is still being sorted out. Cannabidiol is a pleiotropic drug in that it produces many effects through multiple molecular pathways. The scientific literature has identified more than 65 molecular targets of CBD .
Although CBD has little binding affinity for either of the two cannabinoid receptors ( CB1 and CB2 ), cannabidiol modulates several non-cannabinoid receptors and ion channels. CBD also acts through various receptor-independent pathways—for example, by delaying the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and by enhancing or inhibiting the binding action of certain G-protein coupled receptors.
Here are some of the ways that CBD confers its manifold therapeutic effects.
Jose Alexandre Crippa and his colleagues at the University of San Paulo in Brazil and King’s College in London have conducted pioneering research into CBD and the neural correlates of anxiety. At high concentrations, CBD directly activates the 5- HT1A (hydroxytryptamine) serotonin receptor, thereby conferring an anti-anxiety effect. This G-coupled protein receptor is implicated in a range of biological and neurological processes, including (but not limited to) anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting.
5- HT1A is a member of the family of 5- HT receptors, which are activated by the neurotransmitter serotonin. Found in both the central and peripheral nervous systems, 5- HT receptors trigger various intracellular cascades of chemical messages to produce either an excitatory or inhibitory response, depending on the chemical context of the message.
CBDA [Cannabidiolic acid], the raw, unheated version of CBD that is present in the cannabis plant, also has a strong affinity for the 5- HT1A receptor (even more so than CBD ). Preclinical studies indicate that CBDA is a potent anti-emetic, stronger than either CBD or THC , which also have anti-nausea properties.
CBD directly interacts with various ion channels to confer a therapeutic effect. CBD , for example, binds to TRPV1 receptors, which also function as ion channels. TRPV1 is known to mediate pain perception, inflammation and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” TRPV1 is one of several dozen TRP (pronounced “trip”) receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs.
Scientists also refer to TRPV1 as a “vanilloid receptor,” named after the flavorful vanilla bean. Vanilla contains eugenol, an essential oil that has antiseptic and analgesic properties; it also helps to unclog blood vessels. Historically, the vanilla bean has been used as a folk cure for headaches.
CBD binds to TRPV1 , which can influence pain perception.
Capsaicin—the pungent compound in hot chili peppers—activates the TRPV1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV1 agonist.
GPR55 —orphan receptors
Whereas cannabidiol directly activates the 5- HT1A serotonin receptor and several TRPV ion channels, some studies indicate that CBD functions as an antagonist that blocks, or deactivates, another G protein-coupled receptor known as GPR55 .
GPR55 has been dubbed an “orphan receptor” because scientists are still not sure if it belongs to a larger family of receptors. GPR55 is widely expressed in the brain, especially in the cerebellum. It is involved in modulating blood pressure and bone density, among other physiological processes.
GPR55 promotes osteoclast cell function, which facilitates bone reabsorption. Overactive GPR55 receptor signaling is associated with osteoporosis.
GPR55 , when activated, also promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai. This receptor is expressed in various types of cancer.
CBD is a GPR55 antagonist, as University of Aberdeen scientist Ruth Ross disclosed at the 2010 conference of the International Cannabinoid Research Society in Lund, Sweden. By blocking GPR55 signaling, CBD may act to decrease both bone reabsorption and cancer cell proliferation.
PPAR s – nuclear receptors
CBD also exerts an anti-cancer effect by activating PPAR s [peroxisome proliferator activated receptors] that are situated on the surface of the cell’s nucleus. Activation of the receptor known as PPAR -gamma has an anti-proliferative effect as well as an ability to induce tumor regression in human lung cancer cell lines. PPAR -gamma activation degrades amyloid-beta plaque, a key molecule linked to the development of Alzheimer’s disease. This is one of the reasons why cannabidiol, a PPAR -gamma agonist, may be a useful remedy for Alzheimer’s patients.
PPAR receptors also regulate genes that are involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions. Diabetics, accordingly, may benefit from a CBD -rich treatment regimen.
CBD as a reuptake inhibitor
How does CBD , an exogenous plant compound, get inside a human cell to bind to a nuclear receptor? First it has to pass through the cell membrane by hitching a ride with a fatty acid binding protein ( FABP ), which chaperones various lipid molecules into the cell’s interior. These intracellular transport molecules also escort tetrahydrocannabinol ( THC ) and the brain’s own marijuana-like molecules, the endocannabinoids anandamide and 2AG , across the membrane to several targets within the cell. CBD and THC both modulate receptors on the surface of the nucleus, which regulate gene expression and mitochondrial activity.
CBD also exerts an anti-cancer effect by activating PPAR s on the surface of the cell’s nucleus.
Cannabidiol, it turns out, has a strong affinity for three kinds of FABP s, and CBD competes with our endocannabinoids, which are fatty acids, for the same transport molecules. Once it is inside the cell, anandamide is broken down by FAAH [fatty acid amide hydrolase], a metabolic enzyme, as part of its natural molecular life cycle. But CBD interferes with this process by reducing anandamide’s access to FABP transport molecules and delaying endocannabinoid passage into the cell’s interior.
According to a team of Stony Brook University scientists, CBD functions as an anandamide reuptake and breakdown inhibitor, thereby raising endocannabinoid levels in the brain’s synapses. Enhancing endocannabinod tone via reuptake inhibition may be a key mechanism whereby CBD confers neuroprotective effects against seizures, as well as many other health benefits.
CBD ’s anti-inflammatory and anti-anxiety effects are in part attributable to its inhibition of adenosine reuptake. By delaying the reuptake of this neurotransmitter, CBD boosts adenosine levels in the brain, which regulates adenosine receptor activity. A1A and A2A adenosine receptors play significant roles in cardiovascular function, regulating myocardial oxygen consumption and coronary blood flow. These receptors have broad anti-inflammatory effects throughout the body.
CBD as an allosteric modulator
CBD also functions as an allosteric receptor modulator, which means that it can either enhance or inhibit how a receptor transmits a signal by changing the shape of the receptor.
Australian scientists report that CBD acts as a “positive allosteric modulator” of the GABA -A receptor. In other words, CBD interacts with the GABA -A receptor in a way that enhances the receptor’s binding affinity for its principal endogenous agonist, gamma-Aminobutyric acid ( GABA ), which is the main inhibitory neurotransmitter in the mammalian central nervous system. The sedating effects of Valium and other Benzos are mediated by GABA receptor transmission. CBD reduces anxiety by changing the shape of the GABA -A receptor in a way that amplifies the natural calming effect of GABA .
Canadian scientists have identified CBD as a “negative allosteric modulator” of the cannabinoid CB1 receptor, which is concentrated in the brain and central nervous system. While cannabidiol doesn’t bind to the CB1 receptor directly like THC does, CBD interacts allosterically with CB1 and changes the shape of the receptor in a way that weakens CB1 ’s ability to bind with THC .
As a negative allosteric modulator of the CB1 receptor, CBD lowers the ceiling on THC ’s psychoactivity—which is why people don’t feel as “high” when using CBD -rich cannabis compared to when they consume THC -dominant medicine. A CBD -rich product with little THC can convey therapeutic benefits without having a euphoric or dysphoric effect.