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This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as...
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... are hypothesised [4], but not yet cloned. Further research has elucidated analgesic mechanisms of cannabinoids, which include effects on numerous neurotransmitter systems and inter- actions with the endogenous opioid system. This paper will focus on the biochemical and clinical effects of two phytocannabinoids, D 9 - tetrahydrocannabinol (THC) (Fig. 1), the main psychoactive component of cannabis, and its non-psychoactive but highly physiologically relevant isomer, cannabidiol (CBD) (Fig. 1). While it was orig- inally thought that CBD was the metabolic parent to THC in the cannabis plant, rather, they are both bio- synthesised as THCA and CBDA from a cannabigerolic acid precursor ...
Context 2
... neurotransmitter systems and inter- actions with the endogenous opioid system. This paper will focus on the biochemical and clinical effects of two phytocannabinoids, D 9 - tetrahydrocannabinol (THC) (Fig. 1), the main psychoactive component of cannabis, and its non-psychoactive but highly physiologically relevant isomer, cannabidiol (CBD) (Fig. 1). While it was orig- inally thought that CBD was the metabolic parent to THC in the cannabis plant, rather, they are both bio- synthesised as THCA and CBDA from a cannabigerolic acid precursor (Fig. 2) according to genetically determined ratios [5], and then decarboxylated by heat or extraction to produce THC and CBD proper. It is ...
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Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray (Sativex®) as add-on therapy to optimized standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity.
Methods: Sativex as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) was a two...
A large proportion of patients with multiple sclerosis (MS) have spasticity, which has a marked impact on their quality of life. Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebo-controlled studies have confirmed the clinical efficacy of cannabinoids for the treatm...
Background
Despite growing interest in the therapeutic use of cannabis to manage chronic pain, only limited data that address these issues are available. In recent years, a number of nations have introduced specific laws to allow patients to use cannabis preparations to treat a variety of medical conditions. In 2015, the Italian government authoriz...
Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if...
The retinal pigment epithelium (RPE) interacts closely with the photoreceptors in fulfilling tasks of visual function. Since an understanding of the RPE function is essential for understanding the patho-mechanisms involved in vision loss, we explored the regulation of the vanilloid receptor subtype transient receptor potential TRPV2 channels that t...
Citations
... Regardless of the mechanism, CBD is not psychoactive. In fact, it attenuates some of the psychoactive effects of THC [25,26]. ...
Background
Psychotic disorders are a leading cause of disability in young adults. Antipsychotics have been the primary intervention for psychosis for over 60 years, and yet, we have made little progress in treating negative symptoms, neurocognition, and functional disability. There is growing evidence that cannabidiol (CBD) is effective in treating positive psychotic symptoms, possibly also negative and neurocognitive symptoms, and moreover is well tolerated compared to other psychotropic medications. Anecdotally, patients participating in the Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment Program at the University of California, San Diego, are self-administering CBD and report subjective improvement in stress, anxiety, and ability to cope with symptoms. The overarching aim of the trial is to explore the effectiveness of CBD augmentation on symptoms and neurocognition in early psychosis while also exploring the mechanism of action of CBD and predictors of response to treatment. The mechanism by which cannabidiol has a therapeutic effect on psychosis is poorly understood. Recent evidence has suggested that CBD may reduce stress and pro-inflammatory biomarker levels. Endocannabinoids also have powerful roles in eating behavior, reward, and mood, indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness and exacerbated by antipsychotic medication. The neurophysiological effects of CBD have been studied in animal models of psychosis that show improvements in information processing in response to CBD, but there are no studies in individuals with early psychosis.
Method
A total of 120 individuals in the early stages of psychosis will be randomized to 1000 mg of CBD versus placebo as an adjunct to existing treatment in a 8-week, double-blind superiority randomized control trial. The primary outcome measures are symptoms and neurocognition.
Discussion
We hypothesized that CBD will improve symptoms and neurocognition as well as secondary outcome measures of neurohormones, inflammation, eating behaviors, and information processing. Importantly, predictors, moderators, and mediators of the CBD effects will be examined. A better understanding of which individuals are likely to respond to CBD can inform treatment planning and personalize treatment.
Trial registration
ClinicalTrials.gov NCT04411225. Registered on June 2, 2020.
... No evidence was found for cognitive impairment when comparing performance under treatment and control conditions; only one study reported impairment, and this was specific to a measure of long-term memory storage [24]. There has been speculation that CBD may attenuate THC effects [25,26], which could explain the lack of cognitive impairment observed in the studies included in the review, but recent evidence suggests that this is unlikely and that coadministration of CBD may even increase blood THC concentrations [17,[27][28][29]. A wide range of cognitive tests were administered across the included studies, as was the case in the previous review [11] and in the study reported here, suggesting the lack of effects of medical cannabis on cognitive function is not specific to particular cognitive domains. ...
Medical cannabis use is increasing in Australia and other jurisdictions, yet little is known about the effects of medical cannabis on cognitive function. Findings from studies of non-medical (‘recreational’) cannabis may not be applicable to patients using prescribed medical cannabis to manage a health condition.
In this semi-naturalistic, open-label trial, patients with various health conditions attended a single laboratory session in which they self-administered a standard dose of prescribed medical cannabis as per instructions on the pharmacy label. We assessed cognitive performance using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and Druid application (app) prior to and following (CANTAB: + 3 h; Druid: + 3 and 5.5 h) medical cannabis self-administration. We also assessed subjective drug effects prior to and following (1, 2 and 4 h) medical cannabis self-administration using a range of 0–10 cm visual analogue scales (‘stoned’, ‘sedated’, ‘relaxed’, ‘comfortable’, ‘anxious’ and ‘confident’). Data were analyzed using linear fixed-effect models.
Participants (N = 40; 22 females) were prescribed a range of products including orally administered oils (n = 23) and flower for vaporization (n = 17). Participants had a mean (standard deviation [SD]) age of 41.38 (12.66) years and had been using medical cannabis for a mean (SD) of 10.18 (8.73) months. Chronic non-cancer pain was the most common indication for medical cannabis use (n = 20), followed by sleep disorder (n = 18) and anxiety (n = 11). The mean (SD) delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) dose administered by participants was 9.61 (8.52) mg/9.15 (10.11) mg among those using an oil, and 37.00 (24.53) mg/0.38 (1.58) mg among those who vaporized flower, respectively. Participants’ performance improved over time on the CANTAB Multitasking Test and Rapid Visual Information Processing test (both p-values <0.001). All other changes in cognitive performance measures over time were non-significant (p > 0.05). Vaporization of flower was associated with significantly stronger subjective feelings of ‘stoned’ and ‘sedated’ relative to oils (both p < 0.001).
These findings suggest that prescribed medical cannabis may have minimal acute impact on cognitive function among patients with chronic health conditions, although larger and controlled trials are needed.
... In multiple sclerosis, there is no consensus that white matter lesions are of inflammatory or neurodegenerative origin, considering that in the early stages of the disease inflammation is rarely observed, thus suggesting that there is a direct involvement of lymphocytes in tissue damage or indirect involvement through the activation of microglia [27,28]. CBD and THC formulas, in a 1:1 ratio, have been used to treat neuropathic pain and spasticity in multiple sclerosis considering, according to Russo and Guy [29] that beneficial therapeutic effects are increased when these phytocannabinoids are combined in a single product. In this sense, CBD has been seen as responsible for reducing the adverse effects of THC [16]. ...
Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.
... Some of CBD's mechanisms of action, such as binding to CB1 as an allosteric negative modulator [28], can impact the bioactivity of THC. This has led to the proposal that CBD is an 'entourage compound' [4,5,29]. CBD additionally can impact the pharmacokinetics of THC by, e.g., inhibiting some hepatic CYP enzymes. ...
... Several reviews and perspectives claiming the therapeutic potential of the 'entourage effect' and elucidating it in a primarily optimistic perspective have been published [4,5,29,51]. These papers have in common that they refer to the same few pre-clinical original research papers presented above (e.g., [2,[36][37][38]). ...
... CBD's modulation of the THC response allows for the administration of higher THC doses, potentially enhancing the clinical efficacy and creating a better safety profile. This is of particular importance to patients whose condition requires the presence of THC for therapeutic efficacy [29]. Boggs et al. [31] reviewed the pre-clinical and clinical evidence showing functional interactions between CBD and THC. ...
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
... These findings are complementary to the earlier opinion that the endocannabinoid system is considered an attractive target for regulating the sleep-wake cycle (Huitron-Resendiz et al., 2004;Prospéro-García et al., 2016). Cannabinoids have been used by humans for many years to alleviate insomnia (Russo and Guy, 2006), and obese patients in clinical trials treated with the CB 1 receptor antagonist rimonabant commonly reported insomnia and poor sleep quality (Steinberg and Cannon, 2007). Endocannabinoid receptors have been traditionally considered to act through the effects of lipid endocannabinoids (Bushlin et al., 2010;Han et al., 2014). ...
Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. The previous studies demonstrated that the endocannabinoid system played important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin (α) [(m)VD-HPα], an 11-residue peptide derived from the α1 chain of hemoglobin, was recently presumed as a selective agonist of the CB 1 receptor. The present study was undertaken to investigate the effects of (m)VD-HPα on the sleep–wake cycle and power spectrum of cortical EEG in freely moving rats and the potential neurons in the brain activated by (m)VD-HPα. The results showed that 20.1 nmol of (m)VD-HPα i.c.v. administration increased non-rapid eye movement (NREM) sleep in the first 2 h section accompanied by an increase in EEG delta (0.5–4 Hz) activity. The (m)VD-HPα-induced NREM sleep enhancement was due to extended episode duration instead of the episode number. In addition, the effect of (m)VD-HPα (20.1 nmol) on sleep–wake states was significantly attenuated by an antagonist of the CB 1 receptor, AM251 (20 nmol, i.c.v.) but not by the CB 2 receptor antagonist, AM630 (20 nmol, i.c.v.). In comparison with vehicle, (m)VD-HPα increased Fos-immunoreactive (-ir) neurons in the ventrolateral preoptic nucleus (VLPO), but reduced Fos-ir neurons in the lateral hypothalamus (LH), tuberomammillary nucleus (TMN), and locus coeruleus (LC). These findings suggest that (m)VD-HPα promotes NREM sleep via the CB 1 cannabinoid receptor to probably activate VLPO GABAergic neurons, but inactivates the LH orexinergic, LC noradrenergic, and TMN histaminergic neurons.
... 7 Evidence suggests that plantderived cannabinoid-based medications may present a more extensive therapeutic potential and metabolic profile than synthetic, isolated cannabinoids, however, investigations are still under development. [80][81][82][83][84][85] In this scoping review, RCTs with plant-derived CBD + THC presented some positive potential but were limited to CUD studies only, and results were inconsistent, with two out of three RCTs reporting positive results. 24,26,28 While the clinical evidence supporting the use of plantbased CBD + THC extracts for treating SUD is still limited, recent observational studies indicate that the synergistic effects of cannabinoids and other compounds present in cannabis may improve treatment retention and reduce SUD-related harms, as well as rates of other substance consumption among patients with OUD and CoUD, which suggests the need for more investigations on these fields. ...
Background: The prevalence of Substance Use Disorder (SUD) is increasing along with the need to develop approaches to reduce the harm associated with substance use, including investigating alternatives such as cannabinoids, which show promising results, although the current evidence is limited. This scoping review focuses on the limitations and potentials of cannabinoid-based treatments for SUDs.
Methods: We examined between-subject randomized controlled trials (RCTs) investigating the use of CBD and THC as pharmacological treatment for SUDs in adults, with the procedures attending the expectations of the Preferred Reporting Items for Scoping reviews and Meta-Analyses (PRISMA) for Scoping Reviews guidelines and assessed risk of bias using the Cochrane Risk of Bias Assessment Tool 2.
Results: Ten RCTs were included, with six demonstrating low risk of bias, and positive results were found for treating Cannabis Use Disorder, while contradictory results were found for Opioid Use Disorder, and inconclusive results for treating Cocaine Use Disorder.
Conclusions: CBD and THC demonstrate potential for treating some SUDs, but evidence is limited. Robust RCTs with larger samples and longer follow-up periods are necessary to assess carefully developed outcomes for different SUD patients. New cannabinoid-based medications and scientific-based policies may advance SUD treatment. A comprehensive approach to treatment and careful methodological choices may benefit patients with SUD.
... Short-term use of CBMPs has been associated with higher risks of nonserious adverse events (Wang et al., 2008), and a previous study found high-dose THC to be associated with dissipated incidence of somnolence as treatment period increased (Gorelick et al., 2013). Furthermore, the adverse effects of THC, including anxiety, have been seen to be reversed by other cannabinoids, notably CBD (Andre et al., 2016;Russo & Guy, 2006). This points to a likelihood that these patients may see these events resolve as they continue treatment, after an initial adjustment period or alterations of their preparations. ...
Introduction
: There are limited therapeutic options for individuals with fibromyalgia. The aim of this study is to analyze changes in health‐related quality of life and incidence of adverse events of those prescribed cannabis‐based medicinal products (CBMPs) for fibromyalgia.
Methods
: Patients treated with CBMPs for a minimum of 1 month were identified from the UK Medical Cannabis Registry. Primary outcomes were changes in validated patient‐reported outcome measures (PROMs). A p‐value of <.050 was deemed statistically significant.
Results
: In total, 306 patients with fibromyalgia were included for analysis. There were improvements in global health‐related quality of life at 1, 3, 6, and 12 months (p < .0001). The most frequent adverse events were fatigue (n = 75; 24.51%), dry mouth (n = 69; 22.55%), concentration impairment (n = 66; 21.57%), and lethargy (n = 65; 21.24%).
Conclusion
: CBMP treatment was associated with improvements in fibromyalgia‐specific symptoms, in addition to sleep, anxiety, and health‐related quality of life. Those who reported prior cannabis use appeared to have a greater response. CBMPs were generally well‐tolerated. These results must be interpreted within the limitations of study design.
... Studies in experimental models and humans have suggested anti-inflammatory, neuroprotective, anxiolytic, and antipsychotic properties of chemicals extracted from cannabis [4]. Cannabis contains more than 100 cannabinoids, where CBD and THC are the subjects of most studies [5,6]. THC is the main psychoactive constituent and can produce neuroprotective, analgesic, antiemetic, and antiglaucoma effects [7,8]. ...
Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.
... Currently, Cannabis-derived products are used as the common ingredients in skin care products such as body oils, moisturizers, lotions, and lip balms, but scientific research on the topical safety and usefulness of the formulations are scarce (Anwar et al., 2006;Stella et al., 2019). Recently, the endocannabinoid system was found, which comprises receptors, ligands, and enzymes that are broadly expressed in the brain and the periphery, where they operate to achieve stability in many homeostatic processes (Russo & Guy, 2006;Russo, 2017;Vaidya et al., 2022). ...
Cannabis sativa L. is a flowering plant in the family Cannabaceae, and has been cultivated since ancient times for its fibres, oils, resins, dried inflorescences, and leaves. It can be used for a variety of industrial purposes. Over the years, the therapeutic and pharmacological efficacy of its phytoconstituents is shown in a variety of human diseases and health. The use and exploitation of the plant have sparked controversy; however, there are recent legalizations of its use for medical and other purposes in many countries within the corresponding legislative framework. In addition to this legalization, C. sativa is encouraging the very rapid growth of the cannabis oriented pharmaceutical industry. This chapter summarized recent developments in the science of C. sativa and its products about their industrial application, while also addressing gaps in the existing knowledge and future research directions for this high-value multi-use, and potential industrial plant with universal benefits.
... While the active ingredient of Epidiolex is purified CBD [122], Sativex is a roughly 1:1 combination of a high THC and high CBD whole plant extracts, which includes minor cannabinoids [123]. The benefits of combining CBD with THC have been acknowledged in the case of Sativex, combining evidence from numerous studies in animals and humans from throughout the twentieth century, as comprehensively reviewed by Russo and Guy [124] and McPartland and colliagues [43]. Briefly, higher doses of THC are tolerated when administered with CBD, and CBD reduced adverse effects of THC, such as tachycardia, intoxication, and sedation, without reducing the beneficial effect of reduced muscle spasticity [29,124,125]. ...
... The benefits of combining CBD with THC have been acknowledged in the case of Sativex, combining evidence from numerous studies in animals and humans from throughout the twentieth century, as comprehensively reviewed by Russo and Guy [124] and McPartland and colliagues [43]. Briefly, higher doses of THC are tolerated when administered with CBD, and CBD reduced adverse effects of THC, such as tachycardia, intoxication, and sedation, without reducing the beneficial effect of reduced muscle spasticity [29,124,125]. In addition, THC alone had a moderate and long-lasting analgesic effect that was potentiated when CBC was coadministered in an electroshock seizure model, although this synergistic effect did not extend to neurobehavioral effects (motility), anti-seizure effects, or conditioned avoidance responses [126]. ...
Traumatic brain injury is common, and often results in debilitating consequences. Even mild traumatic brain injury leaves approximately 20% of patients with symptoms that persist for months. Despite great clinical need there are currently no approved pharmaceutical interventions that improve outcomes after traumatic brain injury. Increased understanding of the endocannabinoid system in health and disease has accompanied growing evidence for therapeutic benefits of Cannabis sativa. This has driven research of Cannabis’ active chemical constituents (phytocannabinoids), alongside endogenous and synthetic counterparts, collectively known as cannabinoids. Also of therapeutic interest are other Cannabis constituents, such as terpenes. Cannabinoids interact with neurons, microglia, and astrocytes, and exert anti-inflammatory and neuroprotective effects which are highly desirable for the management of traumatic brain injury. In this review, we comprehensively appraised the relevant scientific literature, where major and minor phytocannabinoids, terpenes, synthetic cannabinoids, and endogenous cannabinoids were assessed in TBI, or other neurological conditions with pathology and symptomology relevant to TBI, as well as recent studies in preclinical TBI models and clinical TBI populations.
