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A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioactive Lipids".

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 52331

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Prof. Dr. Mauro Maccarrone

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1. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
2. European Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy
Interests: arachidonate cascade; bioactive lipids; biomarkers; cell membranes; endocannabinoids; resolvins; signal transduction
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Dear Colleagues,

During the last 50 years, the relevance of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive Δ⁹-tetrahydrocannabinol (THC), cannabidiol, 120+ additional cannabinoids and 440+ non-cannabinoid compounds, for human health and disease has become apparent. Approximately 30 years later, the molecular reasons for the biological activity of these plant extracts were made clearer by the discovery of endocannabinoids, which are endogenous lipids able to bind to the same cannabinoid receptors activated by THC. Besides endocannabinoids, which include several N-acylethanolamines and acylesters, a complex array of receptors, metabolic enzymes, transporters (transmembrane, intracellular, and extracellular carriers) were also discovered, and together they form a so-called “endocannabinoid system,” which has been shown to finely tune the manifold biological activities of these lipid signals.

Both plant-derived cannabinoids and endocannabinoids were first discovered by the group of Dr. Raphael Mechoulam, who has just celebrated his 90^th birthday, and clearly stands out as a giant of modern science. The many implications of his seminal work for chemistry, biochemistry, biology, pharmacology, and medicine are described in this Special Issue by the scientists who in the past 20 years have reached the highest recognition in the field of (endo)cannabinoid research, receiving the Mechoulam Award for their major contributions. I thank them for having accepted my invitation to be part of this honorary issue of Molecules, and Raphi for continuing to illuminate our field with his always inspiring investigations and new ideas.

Prof. Dr. Mauro Maccarrone
Guest Editor

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Keywords

Cannabinoids
Drug Discovery
Endocannabinoids
Human Health
Lipid Biochemistry
Metabolism
Signal Tranduction
Therapeutics

Published Papers (12 papers)

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Editorial

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5 pages, 206 KiB

Open AccessEditorial

Tribute to Professor Raphael Mechoulam, The Founder of Cannabinoid and Endocannabinoid Research

by Mauro Maccarrone

Molecules 2022, 27(1), 323; https://doi.org/10.3390/molecules27010323 - 05 Jan 2022

Viewed by 2710

Abstract

During the last 60 years the relevance for human health and disease of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive compound Δ⁹-tetrahydrocannabinol (THC), cannabidiol, 120+ cannabinoids and 440+ non-cannabinoid compounds, has become apparent [...] Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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20 pages, 2647 KiB

Open AccessArticle

Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome

by Mélissa Shen, Claudia Manca, Francesco Suriano, Nayudu Nallabelli, Florent Pechereau, Bénédicte Allam-Ndoul, Fabio Arturo Iannotti, Nicolas Flamand, Alain Veilleux, Patrice D. Cani, Cristoforo Silvestri and Vincenzo Di Marzo

Molecules 2022, 27(1), 1; https://doi.org/10.3390/molecules27010001 - 21 Dec 2021

Cited by 9 | Viewed by 3594

Abstract

The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2/15 epithelial intestinal cells it is elevated by PPARγ activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet—or genetic leptin signaling deficiency—(i.e., ob/ob and db/db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and/or gut mBIome-mediated effects on food intake and energy metabolism. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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24 pages, 15237 KiB

Open AccessArticle

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson’s Disease and Amyotrophic Lateral Sclerosis

by Sonia Burgaz, Concepción García, Claudia Gonzalo-Consuegra, Marta Gómez-Almería, Francisco Ruiz-Pino, Juan Diego Unciti, María Gómez-Cañas, Juan Alcalde, Paula Morales, Nadine Jagerovic, Carmen Rodríguez-Cueto, Eva de Lago, Eduardo Muñoz and Javier Fernández-Ruiz

Molecules 2021, 26(24), 7643; https://doi.org/10.3390/molecules26247643 - 16 Dec 2021

Cited by 11 | Viewed by 3167

Abstract

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB₁) and type-2 (CB₂) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson’s disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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23 pages, 3663 KiB

Open AccessArticle

Subsynaptic Distribution, Lipid Raft Targeting and G Protein-Dependent Signalling of the Type 1 Cannabinoid Receptor in Synaptosomes from the Mouse Hippocampus and Frontal Cortex

by Miquel Saumell-Esnaola, Sergio Barrondo, Gontzal García del Caño, María Aranzazu Goicolea, Joan Sallés, Beat Lutz and Krisztina Monory

Molecules 2021, 26(22), 6897; https://doi.org/10.3390/molecules26226897 - 16 Nov 2021

Cited by 10 | Viewed by 3014

Abstract

Numerous studies have investigated the roles of the type 1 cannabinoid receptor (CB1) in glutamatergic and GABAergic neurons. Here, we used the cell-type-specific CB1 rescue model in mice to gain insight into the organizational principles of plasma membrane targeting and Gαi/o protein signalling of the CB1 receptor at excitatory and inhibitory terminals of the frontal cortex and hippocampus. By applying biochemical fractionation techniques and Western blot analyses to synaptosomal membranes, we explored the subsynaptic distribution (pre-, post-, and extra-synaptic) and CB1 receptor compartmentalization into lipid and non-lipid raft plasma membrane microdomains and the signalling properties. These data infer that the plasma membrane partitioning of the CB1 receptor and its functional coupling to Gαi/o proteins are not biased towards the cell type of CB1 receptor rescue. The extent of the canonical Gαi/o protein-dependent CB1 receptor signalling correlated with the abundance of CB1 receptor in the respective cell type (glutamatergic versus GABAergic neurons) both in frontal cortical and hippocampal synaptosomes. In summary, our results provide an updated view of the functional coupling of the CB1 receptor to Gαi/o proteins at excitatory and inhibitory terminals and substantiate the utility of the CB1 rescue model in studying endocannabinoid physiology at the subcellular level. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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19 pages, 1255 KiB

Open AccessArticle

Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner

by Joanna Agnieszka Komorowska-Müller, Tanushka Rana, Bolanle Fatimat Olabiyi, Andreas Zimmer and Anne-Caroline Schmöle

Molecules 2021, 26(19), 5984; https://doi.org/10.3390/molecules26195984 - 02 Oct 2021

Cited by 12 | Viewed by 2719

Abstract

Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB₂R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB₂R in physiological brain aging. We used CB₂R^−/− mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB₂R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB₂R^−/− mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB₂R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB₂R^−/− microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB₂R^−/− microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB₂Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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17 pages, 16049 KiB

Open AccessArticle

Novel CBG Derivatives Can Reduce Inflammation, Pain and Obesity

by Natalya M. Kogan, Yarden Lavi, Louise M. Topping, Richard. O. Williams, Fiona E. McCann, Zhanna Yekhtin, Marc Feldmann, Ruth Gallily and Raphael Mechoulam

Molecules 2021, 26(18), 5601; https://doi.org/10.3390/molecules26185601 - 15 Sep 2021

Cited by 10 | Viewed by 10587

Abstract

Interest in CBG (cannabigerol) has been growing in the past few years, due to its anti-inflammatory properties and other therapeutic benefits. Here we report the synthesis of three new CBG derivatives (HUM-223, HUM-233 and HUM-234) and show them to possess anti-inflammatory and analgesic properties. In addition, unlike CBG, HUM-234 also prevents obesity in mice fed a high-fat diet (HFD). The metabolic state of the treated mice on HFD is significantly better than that of vehicle-treated mice, and their liver slices show significantly less steatosis than untreated HFD or CBG-treated ones from HFD mice. We believe that HUM-223, HUM-233 and HUM-234 have the potential for development as novel drug candidates for the treatment of inflammatory conditions, and in the case of HUM-234, potentially for obesity where there is a huge unmet need. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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13 pages, 1216 KiB

Open AccessArticle

Contribution of the Adenosine 2A Receptor to Behavioral Effects of Tetrahydrocannabinol, Cannabidiol and PECS-101

by Todd M. Stollenwerk, Samantha Pollock and Cecilia J. Hillard

Molecules 2021, 26(17), 5354; https://doi.org/10.3390/molecules26175354 - 02 Sep 2021

Cited by 6 | Viewed by 3229

Abstract

The cannabis-derived molecules, ∆⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. In addition to their other pharmacological targets, both THC and CBD are competitive inhibitors of the equilibrative nucleoside transporter-1 (ENT-1), a primary inactivation mechanism for adenosine, and thereby increase adenosine signaling. The goal of this study was to examine the role of adenosine A2A receptor activation in the effects of intraperitoneally administered THC alone and in combination with CBD or PECS-101, a 4′-fluorinated derivative of CBD, in the cannabinoid tetrad, elevated plus maze (EPM) and marble bury assays. Comparisons between wild-type (WT) and A2AR knock out (A2AR-KO) mice were made. The cataleptic effects of THC were diminished in A2AR-KO; no other THC behaviors were affected by A2AR deletion. CBD (5 mg/kg) potentiated the cataleptic response to THC (5 mg/kg) in WT but not A2AR-KO. Neither CBD nor THC alone affected EPM behavior; their combination produced a significant increase in open/closed arm time in WT but not A2AR-KO. Both THC and CBD reduced the number of marbles buried in A2AR-KO but not WT mice. Like CBD, PECS-101 potentiated the cataleptic response to THC in WT but not A2AR-KO mice. PECS-101 also reduced exploratory behavior in the EPM in both genotypes. These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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17 pages, 3417 KiB

Open AccessArticle

An Evaluation of Understudied Phytocannabinoids and Their Effects in Two Neuronal Models

by Alex Straiker, Sierra Wilson, Wesley Corey, Michaela Dvorakova, Taryn Bosquez, Joye Tracey, Caroline Wilkowski, Kathleen Ho, Jim Wager-Miller and Ken Mackie

Molecules 2021, 26(17), 5352; https://doi.org/10.3390/molecules26175352 - 02 Sep 2021

Cited by 9 | Viewed by 3221

Abstract

Cannabis contains more than 100 phytocannabinoids. Most of these remain poorly characterized, particularly in neurons. We tested a panel of five phytocannabinoids—cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), and Δ⁹-tetrahydrocannabivarin (THCV) in two neuronal models, autaptic hippocampal neurons and dorsal root ganglion (DRG) neurons. Autaptic neurons expressed a form of CB1-dependent retrograde plasticity while DRGs expressed a variety of transient receptor potential (TRP) channels. CBC, CBDA, and CBDVA had little or no effect on neuronal cannabinoid signaling. CBDV and THCV differentially inhibited cannabinoid signaling. THCV inhibited CB1 receptors presynaptically while CBDV acted post-synaptically, perhaps by inhibiting 2-AG production. None of the compounds elicited a consistent DRG response. In summary, we find that two of five ‘minor’ phytocannabinoids tested antagonized CB1-based signaling in a neuronal model, but with very different mechanisms. Our findings highlight the diversity of potential actions of phytocannabinoids and the importance of fully evaluating these compounds in neuronal models. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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14 pages, 4941 KiB

Open AccessArticle

Involvement of the γ Isoform of cPLA₂ in the Biosynthesis of Bioactive N-Acylethanolamines

by Yiman Guo, Toru Uyama, S. M. Khaledur Rahman, Mohammad Mamun Sikder, Zahir Hussain, Kazuhito Tsuboi, Minoru Miyake and Natsuo Ueda

Molecules 2021, 26(17), 5213; https://doi.org/10.3390/molecules26175213 - 27 Aug 2021

Cited by 10 | Viewed by 2000

Abstract

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A₂ (cPLA₂) functions as an N-acyltransferase to form NAPE. Since the cPLA₂ family consists of six isoforms (α, β, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA₂ isoforms were labeled with [¹⁴C]ethanolamine, the increase in the production of [¹⁴C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [¹⁴C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [¹⁴C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA₂γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA₂γ is involved in the biosynthesis of NAE by its phospholipase A₁/A₂ and lysophospholipase activities. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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15 pages, 1482 KiB

Open AccessArticle

Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia

by Luis Santos-Molina, Alexa Herrerias, Charles N. Zawatsky, Ozge Gunduz-Cinar, Resat Cinar, Malliga R. Iyer, Casey M. Wood, Yuhong Lin, Bin Gao, George Kunos and Grzegorz Godlewski

Molecules 2021, 26(16), 5089; https://doi.org/10.3390/molecules26165089 - 22 Aug 2021

Cited by 5 | Viewed by 2436

Abstract

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a “two-bottle” as well as a “drinking in the dark” paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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Review

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Open AccessReview

The Spicy Story of Cannabimimetic Indoles

by Allyn C. Howlett, Brian F. Thomas and John W. Huffman

Molecules 2021, 26(20), 6190; https://doi.org/10.3390/molecules26206190 - 14 Oct 2021

Cited by 12 | Viewed by 3447

Abstract

The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB₁ cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB₁ helix-3 lysine. The Huffman laboratory identified strategies to establish CB₂ receptor selectivity among cannabimimetic indoles to avoid their CB₁-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB₁ receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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23 pages, 3459 KiB

Open AccessReview

CB1 Cannabinoid Receptor Signaling and Biased Signaling

by Luciana M. Leo and Mary E. Abood

Molecules 2021, 26(17), 5413; https://doi.org/10.3390/molecules26175413 - 06 Sep 2021

Cited by 46 | Viewed by 9587

Abstract

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling. Full article

(This article belongs to the Special Issue A Themed Issue in Honor of Professor Raphael Mechoulam: The Father of Cannabinoid and Endocannabinoid Research)

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