Search Results (33)

Numerous studies on specific cannabis compounds (cannabinoids and phenolic acids) have demonstrated their therapeutic potential, with their administration methods remaining a key research focus. Transdermal drug delivery (TDD) systems are gaining attention due to their advantages, such as painless administration, controlled release, direct absorption into the bloodstream, and its ability to bypass hepatic metabolism. The thin films obtained via pulsed laser deposition consist of micro- and nanoparticles capable of migrating through skin pores upon contact. This study investigates the interaction of phenolic compounds in hemp seeds with pulsed laser beams. The main goal is to achieve the ablation and deposition of these compounds as thin films suitable for TDD applications. The other key objective is optimizing laser energy to enhance the industrial feasibility of this method. Thin layers were deposited on glass and hemp fabric using dual pulsed laser (DPL) ablation on a compressed hemp seed target held in a stainless steel ring. The target was irradiated for 30 min with two synchronized pulsed laser beams, each with parameters of 30 mJ, 532 nm, pulse width of 10 ns, and a repetition rate of 10 Hz. Each beam had an angle of incidence with the target surface of 45°, and the angle between the two beams was also 45°. To improve laser absorption, two approaches were used: (1) HS-DPL/glass and HS-DPL/hemp fabric, in which a portion of the stainless steel ring was included in the irradiated area, and (2) HST-DPL/glass and HST-DPL/hemp fabric—hemp seeds were mixed with turmeric powder, which is known to improve laser interaction and biocompatibility. The FTIR and Micro-FTIR spectroscopy (ATR) performed on thin films compared to the target material confirmed the presence of hemp-derived phenolic compounds, including tetrahydrocannabinol (THC), cannabidiol (CBD), ferulic acid, and coumaric acid, along with other functional groups such as amides. The ATR spectra have been validated against Gaussian 6 numerical simulations. Scanning electron microscopy (SEM) and substance transfer tests revealed the microgranular structure of thin films. Through the analyzes carried out, the following were highlighted: spherical structures (0.3–2 μm) for HS-DPL/glass, HS-DPL/hemp fabric, HST-DPL/glass, and HST-DPL/hemp fabric; larger spherical structures (8–13 μm) for HS-DPL/glass and HST-DPL/glass; angular, amorphous-like structures (~3.5 μm) for HS-DPL/glass; and crystalline-like structures (0.6–1.3 μm) for HST-DPL/glass. Microparticle transfer from thin films on the hemp fabric to the filter paper at a human body temperature (37 °C) confirmed their suitability for TDD applications, aligning with the “whole plant medicine” or “entourage effect” concept. Granular, composite, thin films were successfully developed, capable of releasing microparticles upon contact with a surface whose temperature is 37 °C, specific to the human body. Each of the microparticles in the thin films obtained with the DPL technique contains phenolic compounds (cannabinoids and phenolic acids) comparable to those in hemp seeds, effectively acting as “microseeds.” The obtained films are viable for TDD applications, while the DPL technique ensures industrial scalability due to its low laser energy requirements. Full article

Cannabis sativa L. is a phytochemically rich plant with therapeutic potential across various clinical domains, including pain, inflammation, and neurological disorders. Among its constituents, terpenes are gaining recognition for their capacity to modulate the pathophysiological processes underlying chronic pain syndromes. Traditionally valued for their aromatic qualities, terpenes such as myrcene, β-caryophyllene (BCP), limonene, pinene, linalool, and humulene have demonstrated a broad spectrum of biological activities. Beyond their observable analgesic, anti-inflammatory, and anxiolytic outcomes, these compounds exert their actions through distinct molecular mechanisms. These include the activation of cannabinoid receptor type 2 (CB₂), the modulation of transient receptor potential (TRP) and adenosine receptors, and the inhibition of pro-inflammatory signalling pathways such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Cyclooxygenase-2 (COX-2). This narrative review synthesizes the current preclinical and emerging clinical data on terpene-mediated analgesia, highlighting both monoterpenes and sesquiterpenes, and discusses their potential for synergistic interaction with cannabinoids, the so-called entourage effect. Although preclinical findings are promising, clinical translation is limited by methodological variability, the lack of standardized formulations, and insufficient pharmacokinetic characterization. Further human studies are essential to clarify their therapeutic potential. Full article

Epilepsy is a widespread neurological disorder that remains a critical global public health challenge. While numerous antiepileptic drugs (AEDs) are available, many patients either fail to achieve adequate seizure control or experience significant side effects. One promising alternative is pure cannabidiol (CBD), but using a whole cannabis extract may be equally effective and preferred for some patients. In the current study, we employed the pentylenetetrazole (PTZ)-induced hyperactivity model in zebrafish to compare the effects of CBD with various cannabis extracts. We evaluated three cannabis strains, each subjected to three different extraction methods, and benchmarked the results against the commercially available AED valproic acid (VPA). Our findings revealed that 5.7 µg/mL of CBD and 10 µg/mL of different extracts significantly reduced movement compared to PTZ and VPA. In addition, effective extracts produced effects similar to pure CBD despite containing much lower molecule levels. These results reinforced and expanded previous evidence supporting the clinical potential of both CBD and whole cannabis extracts for seizure control while suggesting a possible entourage effect. Further research is necessary to determine which patients may benefit more from pure CBD versus those who might prefer whole cannabis extracts. Full article

Volatile organic compounds, colloquially referred to as “terpenes”, have been proposed to impact the therapeutic qualities that are traditionally ascribed to cannabis. However, the contribution of these terpenes in anxiety, at relevant levels and exposure methods common with cannabis use, is lacking empirical assessment. We tested the anxiolytic properties of two prominent cannabis terpenes, linalool and β-myrcene, in male and female mice using short duration vapor pulls to model human inhalation when combusting flower or vaping cannabis oil. We observed sex differences in the locomotor effects in the open field and anxiolytic properties in the elevated plus maze of these terpenes that depended on their exposure characteristics. Both linalool and β-myrcene had anxiolytic effects in female mice when delivered in discrete vapor pulls over the course of 30 min. In male mice, only a single vapor hit containing linalool or β-myrcene had anxiolytic effects. The combination of sub-effective levels of linalool and the phytocannabinoid, cannabidiol (CBD), had synergistic anxiolytic effects in females, but these entourage effects between CBD and terpenes were absent with β-myrcene for females and for either terpene in males. Together, our findings reveal sex differences in the anxiolytic properties of common cannabis terpenes and highlight the potential benefits of unique combinations of CBD and terpenes in expanding the therapeutic dose window. Full article

This study explores the complementary or synergistic effects of medicinal cannabis constituents, particularly terpenes, concerning their therapeutic potential, known as the entourage effect. A systematic review of the literature on cannabis “entourage effects” was conducted using the PRISMA model. Two research questions directed the review: (1) What are the physiological effects of terpenes and terpenoids found in cannabis? (2) What are the proven “entourage effects” of terpenes in cannabis? The initial approach involved an exploratory search in electronic databases using predefined keywords and Boolean phrases across PubMed/MEDLINE, Web of Science, and EBSCO databases using Medical Subject Headings (MeSH). Analysis of published studies shows no evidence of neuroprotective or anti-aggregatory effects of α-pinene and β-pinene against β-amyloid-mediated toxicity; however, modest lipid peroxidation inhibition by α-pinene, β pinene, and terpinolene may contribute to the multifaceted neuroprotection properties of these C. sativa L. prevalent monoterpenes and the triterpene friedelin. Myrcene demonstrated anti-inflammatory proprieties topically; however, in combination with CBD, it did not show significant additional differences. Exploratory evidence suggests various therapeutic benefits of terpenes, such as myrcene for relaxation; linalool as a sleep aid and to relieve exhaustion and mental stress; D-limonene as an analgesic; caryophyllene for cold tolerance and analgesia; valencene for cartilage protection; borneol for antinociceptive and anticonvulsant potential; and eucalyptol for muscle pain. While exploratory research suggests terpenes as influencers in the therapeutic benefits of cannabinoids, the potential for synergistic or additive enhancement of cannabinoid efficacy by terpenes remains unproven. Further clinical trials are needed to confirm any terpenes “entourage effects.” Full article

Cannabis sativa L. has been widely used by humans for centuries for various purposes, such as industrial, ceremonial, medicinal, and food. The bioactive components of Cannabis sativa L. can be classified into two main groups: cannabinoids and terpenes. These bioactive components of Cannabis sativa L. leaf and inflorescence extracts were analyzed. Mice were systemically administered 30 mg/kg of Cannabis sativa L. leaf extract 1 h before lipopolysaccharide (LPS) administration, and behavioral tests were performed. We conducted an investigation into the oxygen saturation, oxygen tension, and degranulation of mast cells (MCs) in the deep cervical lymph nodes (DCLNs). To evaluate the anti-inflammatory effect of Cannabis sativa L. extracts in BV2 microglial cells, we assessed nitrite production and the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The main bioactive components of the Cannabis sativa L. extracts were THCA (a cannabinoid) and β-caryophyllene (a terpene). Cannabis sativa L. leaf extract reduced the immobility time in the forced swimming test and increased sucrose preference in the LPS model, without affecting the total distance and time in the center in the open field test. Additionally, Cannabis sativa L. leaf extract improved oxygen levels and inhibited the degranulation of MCs in DCLNs. The Cannabis sativa L. extracts inhibited IL-1β, IL-6, TNF-α, nitrite, iNOS, and COX-2 expression in BV2 microglia cells. The efficacy of Cannabis sativa L. extracts was suggested to be due to the entourage effect of various bioactive phytochemicals. Our findings indicate that these extracts have the potential to be used as effective treatments for a variety of diseases associated with acute inflammatory responses. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized. Full article

Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds—cannabinoids, terpenes, and flavonoids. While major cannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis’s bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis’s sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis’s complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis’s full therapeutic potential within the realm of natural plant-based medicine. Full article

Although cannabidiol and tetrahydrocannabinol in Cannabis species exert their pharmacological effects via the endocannabinoid system, it is believed that other phytochemicals, particularly terpenes, can modulate therapeutic outcomes through the entourage effect. Therefore, to gain a better understanding of the pharmacological effects of Cannabis, obtaining information on phytochemical compositions, including mono-, di-, and sesqui-terpenes in Cannabis species is essential. Applying a sophisticated analytical method is indispensable. In this study, headspace-gas chromatography/mass spectrometry (HS-GC/MS) was employed to identify major terpenes in the leaves and inflorescences of hybrid Cannabis species. The incubation time and temperature conditions for HS-GC/MS were optimized. This method was successfully applied to the leaves (n = 9) and inflorescences (n = 7) of hybrid Cannabis species. A total of 26 terpenes in Cannabis species were detected, and six major components, such as α-pinene (9.8–2270 μg/g), β-pinene (2.6–930 μg/g), myrcene (0.7–17,400 μg/g), limonene (1.3–300 μg/g), β-caryophyllene (60–3300 μg/g), and α-humulene (40–870 μg/g), were quantified. Each sample showed different terpene compositions, but six major terpenes among all the terpenes detected were consistently found in both the leaves and inflorescences of hybrid Cannabis species. In this study, the six major terpenes’ potential in hybrid Cannabis species was evaluated as biomarkers to distinguish hybrid Cannabis species samples. This study contributes to a better understanding of the entourage effect of Cannabis-based botanical drugs. Full article

Hemp bioproducts hold great promise as valuable materials for nutraceutical and pharmaceutical applications due to their diverse bioactive compounds and potential health benefits. In line with this interest and in an attempt to valorize the Lazio Region crops, this present study investigated chemically characterized hydroalcoholic and organic extracts, obtained from the inflorescences of locally cultivated Felina 32, USO 31, Ferimon and Fedora 17 hemp varieties. In order to highlight the possible chemopreventive power of the tested samples, a bioactivity screening was performed, which included studying the antimutagenic activity, radical scavenging power, cytotoxicity in human hepatoma HepG2 cells, leakage of lactate dehydrogenase (LDH) and modulation of the oxidative stress parameters and glucose-6-phosphate dehydrogenase (G6PDH) involved in the regulation of the cell transformation and cancer proliferation. Tolerability studies in noncancerous H69 cholangiocytes were performed, too. The organic extracts showed moderate to strong antimutagenic activities and a marked cytotoxicity in the HepG2 cells, associated with an increased oxidative stress and LDH release, and to a G6PDH modulation. The hydroalcoholic extracts mainly exhibited radical scavenging properties with weak or null activities in the other assays. The extracts were usually well-tolerated in H69 cells, except for the highest concentrations which impaired cell viability, likely due to an increased oxidative stress. The obtained results suggest a possibility in the inflorescences from the Felina 32, USO 31, Ferimon and Fedora 17 hemp varieties as source of bioactive compounds endowed with genoprotective and chemopreventive properties that could be harnessed as preventive or adjuvant healing strategies. Full article

Cannabinoids: cannabidiol (CBD), cannabidiolic acid (CBDA), and cannabichromene (CBC) are lipophilic compounds with limited water solubility, resulting in challenges related to their bioavailability and therapeutic efficacy upon oral administration. To overcome these limitations, we developed co-dispersion cannabinoid delivery systems with the biopolymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and magnesium aluminometasilicate (Neusilin US2) to improve solubility and permeability. Recognizing the potential therapeutic benefits arising from the entourage effect, we decided to work with an extract instead of isolated cannabinoids. Cannabis sativa inflorescences (Henola variety) with a confirming neuroprotective activity were subjected to dynamic supercritical CO₂ (scCO₂) extraction and next they were combined with carriers (1:1 mass ratio) to prepare the co-dispersion cannabinoid delivery systems (HiE). In vitro dissolution studies were conducted to evaluate the solubility of CBD, CBDA, and CBC in various media (pH 1.2, 6.8, fasted, and fed state simulated intestinal fluid). The HiE-Soluplus delivery systems consistently demonstrated the highest dissolution rate of cannabinoids. Additionally, HiE-Soluplus exhibited the highest permeability coefficients for cannabinoids in gastrointestinal tract conditions than it was during the permeability studies using model PAMPA GIT. All three cannabinoids exhibited promising blood-brain barrier (BBB) permeability (P_app higher than 4.0 × 10⁻⁶ cm/s), suggesting their potential to effectively cross into the central nervous system. The improved solubility and permeability of cannabinoids from the HiE-Soluplus delivery system hold promise for enhancement in their bioavailability. Full article

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). Full article

Currently, much effort is being placed into obtaining extracts and/or essential oils from Cannabis sativa L. for specific therapeutic purposes or pharmacological compositions. These potential applications depend mainly on the phytochemical composition of the oils, which in turn are determined by the type of C. sativa and the extraction method used to obtain the oils. In this work, we have evaluated the contents of secondary metabolites, delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD), in addition to the total phenolic, flavonoids, and anthraquinone content in oils obtained using solid–liquid extraction (SLE) and supercritical fluid extraction (SCF). Different varieties of C. sativa were chosen by using the ratio of THC to CBD concentrations. Additionally, antioxidant, antifungal and anticancer activities on different cancer cell lines were evaluated in vitro. The results indicate that oils extracted by SLE, with high contents of CBD, flavonoids, and phenolic compounds, exhibit a high antioxidant capacity and induce a high decrease in the cell viability of the tested breast cancer cell line (MCF-7). The observed biological activities are attributed to the entourage effect, in which CBD, phenols and flavonoids play a key role. Therefore, it is concluded that the right selection of C. sativa variety and the solvent for SLE extraction method could be used to obtain the optimal oil composition to develop a natural anticancer agent. Full article

After a stroke incident, physical inactivity is common. People with stroke may perceive several barriers to performing physical activity (PA). This study aimed to document the PA level and understand the barriers and facilitators to engaging in PA for community-dwelling stroke survivors in Benin, a lower middle-income country. A cross-sectional study was conducted in three hospitals in Benin. Levels of PA were recorded by means of the Benin version of the International Physical Activity Questionnaire long form (IPAQ-LF-Benin), which is validated for stroke survivors in Benin. The perceived exercise facilitators and barriers were assessed by the Stroke Exercise Preference Inventory-13 (SEPI-13). A descriptive analysis and associations were performed with a Confidence Interval of 95% and <0.05 level of significance. A total of 87 participants (52 men, mean age of 53 ± 10 years, mean time after a stroke of 11 (IQR: 15) months and an average of 264.5 ± 178.9 m as distance on the 6 min walking test (6MWT) were included. Overall, stroke survivors in Benin reached a total PA of 985.5 (IQR: 2520) metabolic equivalent (METs)-minutes per week and were least active at work, domestic, and leisure domains with 0 MET-minutes per week. The overview of PA level showed that 52.9% of participants performed low PA intensity. However, 41.4% performed moderate PA or walking per day for at least five days per week. Important perceived barriers were lack of information (45.3%), hard-to-start exercise (39.5%), and travelling to places to exercise (29.9%). The preference for exercise was with family or friends, outdoors, for relaxation or enjoyment (90.2%), and receiving feedback (78.3%). Several socio-demographic, clinical, and community factors were significantly associated with moderate or intense PA (p < 0.05) in stroke survivors in this study. Our findings show that the PA level among chronic stroke survivors in Benin is overall too low relative to their walking capacity. Cultural factors in terms of the overprotection of the patients by their entourage and/or the low health literacy of populations to understand the effect of PA on their health may play a role. There is a need for new approaches that consider the individual barriers and facilitators to exercise. Full article

Acute respiratory distress syndrome (ARDS) is a serious inflammatory lung disorder and a complication of SARS-CoV-2 infection. In patients with severe SARS-CoV-2 infection, the transition to ARDS is principally due to the occurrence of a cytokine storm and an exacerbated inflammatory response. The effectiveness of ultra-micronized palmitoylethanolamide (PEA-um) during the earliest stage of COVID-19 has already been suggested. In this study, we evaluated its protective effects as well as the effectiveness of its congener, 2-pentadecyl-2-oxazoline (PEA-OXA), using in vitro models of acute lung injury. In detail, human lung epithelial cells (A549) activated by polyinosinic–polycytidylic acid (poly-(I:C)) or Transforming Growth Factor-beta (TGF-β) were treated with PEA-OXA or PEA. The release of IL-6 and the appearance of Epithelial–Mesenchymal Transition (EMT) were measured by ELISA and immunofluorescence assays, respectively. A possible mechanism of action for PEA-OXA and PEA was also investigated. Our results showed that both PEA-OXA and PEA were able to counteract poly-(I:C)-induced IL-6 release, as well as to revert TGF-β-induced EMT. In addition, PEA was able to produce an “entourage” effect on the levels of the two endocannabinoids AEA and 2-AG, while PEA-OXA only increased PEA endogenous levels, in poly-(I:C)-stimulated A549 cells. These results evidence for the first time the superiority of PEA-OXA over PEA in exerting protective effects and point to PEA-OXA as a new promising candidate in the management of acute lung injury. Full article