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Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 41470

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Special Issue Editors

Prof. Dr. Nicola Simola

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Guest Editor

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
Interests: dopamine; drug abuse; psychostimulants Parkinson’s disease

Prof. Dr. Maria Antonietta De Luca

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Guest Editor

Department of Biomedical Sciences, University of Cagliari, Via Università, 40, 09124 Cagliari CA, Italy
Interests: Liquid Chromatography; Neurobiology; Neurophysiology; Learning and Memory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cannabis sativa has a long history of use for medical purposes despite the addictive properties of its preparations. Cannabis sativa contains about 500 different chemical compounds, of which approximately one hundred are phytocannabinoids. Among these, from a clinical perspective, the most studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, different strains of Cannabis produce different effects resulting in diverse clinical applications. In addition, variable THC:CBD ratios may account for many of the different central and peripheral effects of Cannabis. Therefore, several pre-clinical and clinical studies aimed at investigating the effect of different doses of equal/unequal ratio of THC and CBD on the central nervous system have been performed with a specific focus on the highly promising therapeutic properties of CBD for neurological and psychiatric disorders characterized by altered dopaminergic, GABAergic, and glutamatergic transmission. Nevertheless, other phytocannabinoids, such as cannabigerol (CBG), delta-9-tetrahydrocannabivarin (THCV), and cannabidivarin (CBDV) have shown potential therapeutic effects in preclinical models of central nervous system diseases (e.g., neurodegenerative diseases, epilepsy, affective and feeding behavior disorders) suggesting that phytocannabinoids act on a wide range of pharmacological targets, not solely limited to cannabinoid receptors. This Special Issue will provide an up-to-date overview of the pharmacology and toxicology of phytocannabinoids, with particular reference to molecular mechanisms underlying the desired and adverse effects associated with their putative therapeutical use.

Prof. Dr. Nicola Simola
Prof. Dr. Maria Antonietta De Luca
Guest Editors

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Keywords

phytocannabinoids
addiction
toxicity
cannabidiol

Published Papers (11 papers)

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Research

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13 pages, 2028 KiB

Open AccessArticle

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model

by Sherelle L. Casey, Vanessa A. Mitchell, Eddy E. Sokolaj, Bryony L. Winters and Christopher W. Vaughan

Int. J. Mol. Sci. 2022, 23(15), 8649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158649 - 03 Aug 2022

Cited by 10 | Viewed by 2620

Abstract

(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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11 pages, 962 KiB

Open AccessCommunication

Cannabinerol and NSC-34 Transcriptomic Analysis: Is the Dose Who Makes Neuronal Differentiation?

by Andrea Valeri, Luigi Chiricosta, Agnese Gugliandolo, Federica Pollastro, Stefano Salamone, Valeria Domenica Zingale, Serena Silvestro and Emanuela Mazzon

Int. J. Mol. Sci. 2022, 23(14), 7541; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147541 - 07 Jul 2022

Cited by 2 | Viewed by 1435

Abstract

Cannabis sativa L. proved to be a source of several phytocompounds able to help patients facing different diseases. Moreover, these phytocompounds can help ameliorate general conditions and control certain unpleasant effects of diseases. Some cannabinoids, however, provided more benefits applicable to settings other than palliative care. Using the NSC-34 cell line, we evaluated the barely known phytocompound named cannabinerol (CBNR) at different doses, in order to understand its unique characteristics and the ones shared with other cannabinoids. The transcriptomic analysis suggests a possible ongoing neuronal differentiation, principally due to the activation of cannabinoid receptor 1 (CB1), to which the phosphorylation of serine–threonine protein kinase (Akt) followed, especially between 20 and 7.5 µM. The increase of Neurod1 and Map2 genes at 7.5 µM, accompanied by a decrease of Vim, as well as the increase of Syp at all the other doses, point toward the initiation of differentiation signals. Our preliminary results indicate CBNR as a promising candidate to be added to the list of cannabinoids with neuronal differentiation-enhancer properties. However, further studies are needed to confirm this initial insight. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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17 pages, 3567 KiB

Open AccessArticle

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

by Lara Milián, Irene Monleón-Guinot, María Sancho-Tello, José Marcelo Galbis, Antonio Cremades, María Almenar-Ordaz, Josep Peñaroja-Martinez, Rosa Farras, José Javier Martín de Llano, Carmen Carda and Manuel Mata

Int. J. Mol. Sci. 2022, 23(12), 6766; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126766 - 17 Jun 2022

Cited by 6 | Viewed by 2313

Abstract

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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17 pages, 3470 KiB

Open AccessArticle

Neuroprotective Effects of Cannabidiol but Not Δ⁹-Tetrahydrocannabinol in Rat Hippocampal Slices Exposed to Oxygen-Glucose Deprivation: Studies with Cannabis Extracts and Selected Cannabinoids

by Elisa Landucci, Costanza Mazzantini, Daniele Lana, Pier Luigi Davolio, Maria Grazia Giovannini and Domenico E. Pellegrini-Giampietro

Int. J. Mol. Sci. 2021, 22(18), 9773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189773 - 09 Sep 2021

Cited by 16 | Viewed by 3712

Abstract

(1) Background: Over the past 10 years, a number of scientific studies have demonstrated the therapeutic potential of cannabinoid compounds present in the Cannabis Sativa and Indica plants. However, their role in mechanisms leading to neurodegeneration following cerebral ischemia is yet unclear. (2) Methods: We investigated the effects of Cannabis extracts (Bedrocan, FM2) or selected cannabinoids (Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabigerol) in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD), an in vitro model of forebrain global ischemia. Cell death in the CA1 subregion of slices was quantified by propidium iodide fluorescence, and morphological analysis and tissue organization were examined by immunohistochemistry and confocal microscopy. (3) Results: Incubation with the Bedrocan extract or THC exacerbated, whereas incubation with the FM2 extract or cannabidiol attenuated CA1 injury induced by OGD. Δ⁹-THC toxicity was prevented by CB1 receptor antagonists, the neuroprotective effect of cannabidiol was blocked by TRPV2, 5-HT1A, and PPARγ antagonists. Confocal microscopy confirmed that CBD, but not THC, had a significant protective effect toward neuronal damage and tissue disorganization caused by OGD in organotypic hippocampal slices. (4) Conclusions: Our results suggest that cannabinoids play different roles in the mechanisms of post-ischemic neuronal death. In particular, appropriate concentrations of CBD or CBD/THC ratios may represent a valid therapeutic intervention in the treatment of post-ischemic neuronal death. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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14 pages, 4678 KiB

Open AccessArticle

Neuroprotective and Symptomatic Effects of Cannabidiol in an Animal Model of Parkinson’s Disease

by Claudio Giuliano, Miriam Francavilla, Gerardo Ongari, Alessandro Petese, Cristina Ghezzi, Nora Rossini, Fabio Blandini and Silvia Cerri

Int. J. Mol. Sci. 2021, 22(16), 8920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168920 - 18 Aug 2021

Cited by 26 | Viewed by 6634

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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17 pages, 1584 KiB

Open AccessArticle

Long-Term Consequences of Adolescent Exposure to THC-Rich/CBD-Poor and CBD-Rich/THC-Poor Combinations: A Comparison with Pure THC Treatment in Female Rats

by Marina Gabaglio, Erica Zamberletti, Cristina Manenti, Daniela Parolaro and Tiziana Rubino

Int. J. Mol. Sci. 2021, 22(16), 8899; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168899 - 18 Aug 2021

Cited by 15 | Viewed by 3932

Abstract

Cannabis is the most-used recreational drug worldwide, with a high prevalence of use among adolescents. In animal models, long-term adverse effects were reported following chronic adolescent exposure to the main psychotomimetic component of the plant, delta-9-tetrahydrocannabinol (THC). However, these studies investigated the effects of pure THC, without taking into account other cannabinoids present in the cannabis plant. Interestingly, cannabidiol (CBD) content seems to mitigate some of the side effects of THC, at least in adult animals. Thus, in female rats, we evaluated the long-term consequences of a co-administration of THC and CBD at a 3:1 ratio, chosen based on the analysis of recently confiscated illegal cannabis samples in Europe. CBD content is able to mitigate some of the long-term behavioral alterations induced by adolescent THC exposure as well as long-term changes in CB1 receptor and microglia activation in the prefrontal cortex (PFC). We also investigated, for the first time, possible long-term effects of chronic administration of a THC/CBD combination reminiscent of “light cannabis” (CBD:THC in a 33:1 ratio; total THC 0.3%). Repeated administration of this CBD:THC combination has long-term adverse effects on cognition and leads to anhedonia. Concomitantly, it boosts Glutamic Acid Decarboxylase-67 (GAD67) levels in the PFC, suggesting a possible lasting effect on GABAergic neurotransmission. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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18 pages, 1786 KiB

Open AccessArticle

Changes in Phospholipid/Ceramide Profiles and Eicosanoid Levels in the Plasma of Rats Irradiated with UV Rays and Treated Topically with Cannabidiol

by Wojciech Łuczaj, Anna Jastrząb, Maria do Rosário Domingues, Pedro Domingues and Elżbieta Skrzydlewska

Int. J. Mol. Sci. 2021, 22(16), 8700; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168700 - 13 Aug 2021

Cited by 6 | Viewed by 1954

Abstract

Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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14 pages, 1546 KiB

Open AccessArticle

Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)

by Marta Marszalek-Grabska, Irena Smaga, Paulina Surowka, Pawel Grochecki, Tymoteusz Slowik, Malgorzata Filip and Jolanta H. Kotlinska

Int. J. Mol. Sci. 2021, 22(15), 7940; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157940 - 26 Jul 2021

Cited by 2 | Viewed by 2065

Abstract

The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a priming dose of WIN 55,212-2 to cross-reinstate ethanol-induced conditioned place preference (CPP). To test this hypothesis, ethanol-induced (1.0 g/kg, 10% w/v, i.p.) CPP (unbiased method) was established using male adult Wistar rats. After CPP extinction, one group of animals received WIN 55,212-2 (1.0 and 2.0 mg/kg, i.p.), the cannabinoid receptor 1 (CB1) agonist, or ethanol, and the other group received memantine (3.0 or 10 mg/kg, i.p.), the NMDA antagonist and WIN 55,212-2 on the reinstatement day. Our results showed that a priming injection of WIN 55,212-2 (2.0 mg/kg, i.p.) reinstated (cross-reinstated) ethanol-induced CPP with similar efficacy to ethanol. Memantine (3.0 or 10 mg/kg, i.p.) pretreatment blocked this WIN 55,212-2 effect. Furthermore, our experiments indicated that ethanol withdrawal (7 days withdrawal after 10 days ethanol administration) down-regulated the CNR1 (encoding CB1), GRIN1/2A (encoding GluN1 and GluN2A subunit of the NMDA receptor) genes expression in the prefrontal cortex and dorsal striatum, but up-regulated these in the hippocampus, confirming the involvement of these receptors in ethanol rewarding effects. Thus, our results show that the endocannabinoid system is involved in the motivational properties of ethanol, and glutamate may control cannabinoid induced relapse into ethanol seeking behavior. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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Review

Jump to: Research

36 pages, 2448 KiB

Open AccessReview

THC and CBD: Villain versus Hero? Insights into Adolescent Exposure

by Nicholas Pintori, Francesca Caria, Maria Antonietta De Luca and Cristina Miliano

Int. J. Mol. Sci. 2023, 24(6), 5251; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065251 - 09 Mar 2023

Cited by 8 | Viewed by 4259

Abstract

Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered “safe”. An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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22 pages, 2124 KiB

Open AccessReview

The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System

by Annia A. Martínez-Peña, Genevieve A. Perono, Sarah Alexis Gritis, Reeti Sharma, Shamini Selvakumar, O’Llenecia S. Walker, Harmeet Gurm, Alison C. Holloway and Sandeep Raha

Int. J. Mol. Sci. 2021, 22(16), 8576; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168576 - 09 Aug 2021

Cited by 12 | Viewed by 5635

Abstract

Cannabis use during pregnancy has continued to rise, particularly in developed countries, as a result of the trend towards legalization and lack of consistent, evidence-based knowledge on the matter. While there is conflicting data regarding whether cannabis use during pregnancy leads to adverse outcomes such as stillbirth, preterm birth, low birthweight, or increased admission to neonatal intensive care units, investigations into long-term effects on the offspring’s health are limited. Historically, studies have focused on the neurobehavioral effects of prenatal cannabis exposure on the offspring. The effects of cannabis on other physiological aspects of the developing fetus have received less attention. Importantly, our knowledge about cannabinoid signaling in the placenta is also limited. The endocannabinoid system (ECS) is present at early stages of development and represents a potential target for exogenous cannabinoids in utero. The ECS is expressed in a broad range of tissues and influences a spectrum of cellular functions. The aim of this review is to explore the current evidence surrounding the effects of prenatal exposure to cannabinoids and the role of the ECS in the placenta and the developing fetus. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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16 pages, 723 KiB

Open AccessReview

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement

by Marta De Felice and Steven R. Laviolette

Int. J. Mol. Sci. 2021, 22(15), 7861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157861 - 23 Jul 2021

Cited by 6 | Viewed by 5297

Abstract

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes. Full article

(This article belongs to the Special Issue Exposure to Phytocannabinoids: Exploring Central Effects and Toxicity)

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