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Early Maternal Prenatal Cannabis Use and Child Developmental Delays

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“Importance: Maternal prenatal cannabis use is associated with adverse neonatal health effects, yet little is known about its association with child developmental outcomes.

Objective: To evaluate associations between maternal prenatal cannabis use in early pregnancy and child early developmental delays.

Design, setting, and participants: This cohort study included 119 976 children born to 106 240 unique individuals between January 2015 and December 2019 and followed up to aged 5.5 years or younger (through December 31, 2021) at Kaiser Permanente Northern California. Individuals were screened for prenatal cannabis use via self-report and urine toxicology at entrance into prenatal care (approximately 8- to 10-weeks’ gestation). Data were analyzed from February 2023 to March 2024.

Exposure: Maternal prenatal cannabis use defined as any use (self-reported or by urine toxicology testing) and use frequency.

Main outcomes: Early developmental delays (speech and language disorders, motor delays, global delays) in children up to age 5.5 years defined by International Statistical Classification of Diseases and Related Health Problems, Ninth Revision and Tenth Revision diagnoses codes ascertained from electronic health records.

Results: In this cohort of 119 976 pregnancies among 106 240 unique pregnant individuals, there were 29 543 Hispanic pregnancies (24.6%), 6567 non-Hispanic Black pregnancies (5.5%), 46 823 non-Hispanic White pregnancies (39.0%), 12 837 pregnancies (10.7%) to individuals aged 24 years or younger, and 10 365 pregnancies (8.6%) to individuals insured by Medicaid. Maternal prenatal cannabis use was documented for 6778 pregnancies (5.6%). Daily maternal prenatal cannabis use was reported for 618 pregnancies (0.5%), weekly for 722 pregnancies (0.6%), and monthly or less for 1617 pregnancies (1.3%). No association was observed between maternal prenatal cannabis use and child speech and language disorders (HR, 0.93; 95% CI, 0.84-1.03), global developmental delays (HR, 1.04; 95% CI, 0.68-1.59), or motor delays (HR, 0.86; 95% CI, 0.69-1.06). No association was detected between the frequency of maternal prenatal cannabis use and child early developmental delays.

Conclusions and relevance: In this cohort study, maternal prenatal cannabis use was not associated with an increased risk of child early developmental delays. Future research is needed to assess different patterns of cannabis use throughout pregnancy. Given the association between maternal prenatal cannabis use and other adverse outcomes, pregnant individuals should be educated on those risks.”

https://pubmed.ncbi.nlm.nih.gov/39422907/

 “Is maternal prenatal cannabis use during early pregnancy associated with child early developmental delays (ie, speech and language disorders, motor delays, global delays)?

Findings  In this cohort study of 119 976 mother-child dyads, maternal cannabis use during early pregnancy was not associated with child early developmental delays in children aged 5.5 years or younger.

Meaning  These findings suggest that maternal cannabis use in early pregnancy was not associated with an increased risk of child early developmental delays, but additional research on cannabis use throughout pregnancy, mode of administration, and product strength should be conducted.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2825076#google_vignette


Cannabinoids shift the basal ganglia miRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected Rhesus macaques

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“Epitranscriptomic modifications modulate diverse biological processes, such as regulation of gene expression, abundance, location and function. In particular, N6-methyladenosine (m6A) methylation has been shown to regulate various disease processes, including cancer and inflammation. While there is evidence that m6A modification is functionally relevant in neural development and differentiation, the role of m6A modification in HIV neuropathogenesis is unknown.

Here, we identified direct m6A modifications in miRNAs from BG tissues of Rhesus Monkeys (RMs) that were either vehicle-treated uninfected (VEH), SIV-infected combination anti-retroviral therapy (cART) treated (VEH/SIV/cART), or THC:CBD treated VEH/SIV/cART (THC:CBD/SIV/cART) RMs.

We detected m6A modifications across all BG tissues. SIV infection promoted an overall hypomethylated m6A profile. While the overall hypomethylated m6A profile was not significantly impacted by THC:CBD treatment, specific miRNAs, particularly those predicted to target proinflammatory genes showed markedly reduced m6A methylation levels compared to the VEH treated RMs. Additionally, we found that specific BG tissue miRNAs bearing m6A epi-transcriptomic marks were also transferred to BG-derived extracellular vesicles (EVs). Mechanistically, we identified the DRACH motif of the seed region of miR-194-5p to be significantly m6A hypomethylated, which was predicted to directly target STAT1, an important interferon-activated transcription factor known to drive neuroinflammation, in diseases ranging from Alzheimer to Parkinson and Huntington disease.

Notably, THC:CBD treatments significantly reduced m6A methylation of 43 miRNA species directly involved in regulating CNS network genes, thus providing a possible mechanist explanation on the beneficial effects of THC:CBD treatments noted in several disease involving neuroinflammation.

Our findings also underscore the need for investigating the qualitative, posttranscriptional modification changes in the RNA profiles along with the more traditional, qualitative alterations in pathological conditions or after various treatment regimens.”

https://pubmed.ncbi.nlm.nih.gov/39416016/

https://www.biorxiv.org/content/10.1101/2024.10.11.614514v1

Prenatal Cannabis Use and Offspring Attention Deficit Hyperactivity Disorder and Disruptive Behavior Disorders: A Retrospective Cohort Study

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“Objective: To examine whether maternal cannabis use during early pregnancy is associated with offspring attention deficit hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD).

Methods: We conducted a population-based retrospective birth cohort study of children (N = 141,570) born between 2011 and 2018 to pregnant individuals (N = 117,130) in Kaiser Permanente Northern California universally screened for any prenatal cannabis use at the entrance to prenatal care (at ∼8-10 wk gestation). Prenatal cannabis use was defined as (1) self-reported use and/or a positive toxicology test, (2) self-reported use, (3) a positive toxicology test, and (4) self-reported use frequency. Cox proportional hazards regression models adjusting for maternal characteristics (sociodemographics, other substance use and substance use disorders, prenatal care initiation, comorbidities) examined associations between prenatal cannabis use and offspring ADHD and DBD diagnosed by age 11 years.

Results: The sample of pregnant individuals was 27.2% Asian/Pacific Islander, 5.7% Black, 24.5% Hispanic, and 38.8% non-Hispanic White, with a mean (SD) age of 30.9 (5.2) years; 4.6% screened positive for any cannabis use (0.4% daily, 0.5% weekly, 1.1% monthly or less, 2.7% unknown frequency); 3.92% had a positive toxicology test and 1.8% self-reported use; 7.7% of offspring had ADHD and 6.8% had DBD. Maternal prenatal cannabis use was not associated with ADHD (adjusted hazard ratio [aHR]: 0.84, 95% CI, 0.70-1.01), and there was an inverse association with DBD (aHR: 0.83, 95% CI, 0.71-0.97), which remained when cannabis was defined by toxicology testing but not by self-report. Frequency of use was not associated with outcomes.

Conclusion: Maternal prenatal cannabis use was not associated with an increased risk of offspring ADHD or DBD.”

https://pubmed.ncbi.nlm.nih.gov/39400201/

https://journals.lww.com/jrnldbp/abstract/9900/prenatal_cannabis_use_and_offspring_attention.212.aspx

Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-κB pathways in mice

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“Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice.

Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7th to the 14th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7th to the 14th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed.

Findings/results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants.

Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.”

https://pubmed.ncbi.nlm.nih.gov/39399730/

“This study confirmed that CBD attenuates As-induced nephrotoxicity in mice. CBD led to the strengthening of antioxidant defense, reduction of lipid peroxidation, inflammation and expression of proteins of NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3. The dose of 10 mg/kg of CBD showed better results than 5, and 2.5 mg/kg. Finally, the findings of the present study provide evidence that CBD may serve as a potential therapeutic agent for the prevention and treatment of arsenic-induced nephrotoxicity. “

https://journals.lww.com/rips/fulltext/2024/19040/cannabidiol_attenuates_arsenic_induced.8.aspx

Cannabidiol Finds Dihydrocannabidiol as Its Twin in Anti-Inflammatory Activities and the Mechanism

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“Ethnopharmacological relevance: The hemp (cataloged at the “Medicinal Plant Names Services” as Cannabis sativa L.) extracts, cannabinoids have been used for centuries in Southeast Asia as folk medicines and now authorized by about 50 countries for application in medicine, health care products and cosmetics. As the most consumed cannabinoid, cannabidiol (CBD) has been recognized due to its various bioactivities, including anti-inflammatory and antibacterial properties.

Aims of the study: The utilization of CBD is limited due to its potential conversion to psychoactive Δ9-tetrahydrocannabinol in strong acidic environment, demanding to excavate safer alternatives with clarified bioactivities. Yet the anti-inflammatory and antibacterial properties of CBD still remain unknown, in both of the performances and the corresponding mechanisms. Previously, a synthetic CBD analogue, H2CBD (Dihydrocannabidiol) was found to be effective as CBD does towards some antioxidantive activities and mouse seizure mitigation. Therefore, it is wondering if H2CBD also acted similarly as CBD does in the aspect of anti-inflammatory performance and mechanism, and the safety.

Material and methods: The anti-inflammatory properties of CBD and H2CBD were revealed with enzymatic assays, proteins denaturation and lipopolysaccharide (LPS) stimulated RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. Their anti-inflammatory mechanism was revealed with ELISA and Western blot assay. The antibacterial properties of CBD and H2CBD were also investigated towards E. faecalis and B. cereus along with their synergistic effect with commercial antibiotics.

Results: CBD and H2CBD exhibited almost same (P> 0.05) performance in all the assayed anti-inflammatory properties, yet their anti-inflammatory efficiencies positively correlated to their antioxidantive activity. Moreover, both of CBD and H2CBD presented anti-inflammation to LPS stimulated RAW264.7 cells through NF-κB and AKT pathway. Furthermore, CBD and H2CBD also supplied strong and very similar (P>0.05) antibacterial activities, comparable to tetracycline in same dose and strength. The erythrocyte hemolytic assay indicates CBD and H2CBD possessing the same safety. All the combinations of H2CBD with other cannabinoids or antibiotics present no antagonism against the bacteria, but nice synergistic or additive effect in some cases.

Conclusion: CBD and H2CBD presented very similarly in all the assayed anti-inflammatory performances, undergoing same inflammatory mechanism with NF-κB and AKT pathway; they also expressed similar antibacterial activity, like twins. These findings will supply CBD a sustainable, safer and economic alternative with same excellent performances.”

https://pubmed.ncbi.nlm.nih.gov/39389390/

“To assess the hypothesis or query that CBD could also find H2CBD performing similar anti-inflammatory properties and mechanism, as well as the safety, this experiment reveals the anti-inflammatory properties of CBD, H2CBD and H2THC using serval enzymatic assays, proteins denaturation assay and LPS-RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. The results indicate that both of CBD and H2CBD significantly inhibited NO production from the LPS-stimulated RAW.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874124012108?via%3Dihub

Antifungal properties of Abnormal Cannabinoid derivatives: Disruption of Biofilm Formation and Gene Expression in Candida Species

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“Abnormal cannabinoids (including comp 3) are a class of synthetic lipid compounds with non-psychoactive properties and regioisomer configurations, but distinct from traditional cannabinoids since they do not interact with the established CB1 and CB2 receptors. Previous research showed the cardioprotective and anti-inflammatory potentials of comp 3 and more recently its antimicrobial effect on methicillin-resistant Staphylococcus aureus (MRSA).

Given the escalating challenges posed by Candida infections and the rise of antifungal drug resistance, the exploration of novel therapeutic avenues is crucial. This study aimed to assess the anti-Candida properties of newly synthesized AbnCBD derivatives. AbnCBD derivatives were synthesized by acid catalysis-induced coupling and further derivatized. We evaluated the potential of the AbnCBD derivatives to inhibit the growth stages of various Candida species.

By in vitro colorimetric assays and in vivo mice experiments, we have shown that AbnCBD derivatives induce differential inhibition of Candida growth. The AbnCBD derivatives, especially comp 3, comp 10, and comp 9 significantly reduced the growth of C. albicans, including FLC-resistant strains, and of C. tropicalis and C. parapsilosis but not of C auris compared to their controls (FLC and 0.5% DMSO). Comp 3 also disrupted C. albicans biofilm formation and eradicated mature biofilms. Notably, other derivatives of AbnCBD disrupted the biofilm formation and maturation of C. albicans but did not affect yeast growth. In a murine model of VVC, comp 3 demonstrated significant fungal clearance and reduced C. albicans burden compared to vehicle and FLC controls.

These findings highlight the potential of AbnCBDs as promising antifungal agents against Candida infections.”

https://pubmed.ncbi.nlm.nih.gov/39368567/

https://www.sciencedirect.com/science/article/pii/S1043661824003864?via%3Dihub

Identification of the TRPA1 Cannabinoid-Binding Site

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“Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood.

The principal phytocannabinoids, the psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors.

Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies.

Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations.

Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.”

https://pubmed.ncbi.nlm.nih.gov/39368566/

https://www.sciencedirect.com/science/article/pii/S104366182400389X?via%3Dihub

Nanocarriers for Cannabinoid Delivery: Enhancing Therapeutic Potential

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“Medical cannabis has potential therapeutic benefits in managing pain, anxiety, depression, and neurological and movement disorders. Phytocannabinoids derived from the cannabis plant are responsible for their pharmacological and therapeutic properties. However, the complexity of cannabis components, especially cannabinoids, poses a challenge to effective medicinal administration. Even with the increasing acceptance of cannabis-based medicines, achieving consistent bioavailability and targeted distribution remains difficult. Conventional administration methods are plagued by solubility and absorption problems requiring innovative solutions. After conducting a thorough review of research papers and patents, it has become evident that nanotechnology holds great promise as a solution. The comprehensive review of 36 research papers has yielded valuable insights, with 7 papers reporting enhanced bioavailability, while others have focused on improvements in release, solubility, and stability. Additionally, 19 patents have been analyzed, of which 7 specifically claim enhanced bioavailability, while the remaining patents describe various formulation methods. These patents outline effective techniques for encapsulating cannabis using nanocarriers, effectively addressing solubility and controlled release. Studies on the delivery of cannabis using nanocarriers focus on improving bioavailability, prolonging release, and targeting specific areas. This synthesis highlights the potential of nanotechnology to enhance cannabis therapies and pave the way for innovative interventions and precision medicine.”

https://pubmed.ncbi.nlm.nih.gov/39356097/

https://www.eurekaselect.com/article/141807

Rooted in therapeutics: comprehensive analyses of Cannabis sativa root extracts reveals potent antioxidant, anti-inflammatory, and bactericidal properties

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“Following the legalization of recreational Cannabis in Canada in 2018, the associated waste, including Cannabis roots, has significantly increased. Cannabis roots, comprising 30%-50% of the total plant, are often discarded despite their historical use in Ayurvedic medicine for treating inflammatory and infectious disorders.

This study evaluates the phytochemical and therapeutic properties of Cannabis root extracts from a high tetrahydrocannabinolic acid, low cannabidiolic acid cultivar (variety Alien Gorilla Glue).

We performed ultra high-performance liquid chromatography coupled with mass spectrometry (UPLC-QTOF-MS) to identify the chemical components of the Cannabis roots. Extracts using water, ethanol and acid-base solvents were tested for antioxidant activity through free radical scavenging, metal chelation, and lipoperoxidation inhibition assays. Mitochondrial membrane protection was assessed using flow cytometry with the MitoPerOx probe in THP-1 monocytic leukemia cells. Anti-inflammatory potential was evaluated by measuring interleukin-6 levels in lipopolysaccharide-stimulated THP-1 cells. Bactericidal/fungicidal efficacy against Escherichia coli, Staphylococcus aureus, and Candida albicans was determined using the p-iodonitrophenyltetrazolium assay. Additionally, we investigated the anticholinesterase activity of Cannabis root extracts, given the potential role of plant alkaloids in inhibiting cholinesterase, an enzyme targeted in Alzheimer’s disease treatments. UPLC-QTOF-MS analysis suggested the presence of several phenolic compounds, cannabinoids, terpenoids, amino acids, and nitrogen-containing compounds.

Our results indicated significant antioxidant, bactericidal, and anticholinesterase properties of Cannabis root extracts from both soil and hydroponic cultivation.

Extracts showed strong antioxidant activity across multiple assays, protected mitochondrial membrane in THP-1 cells, and exhibited anti-inflammatory and bactericidal/fungicidal efficacy. Notably, soil-cultivated roots displayed superior anti-inflammatory effects.

These findings demonstrate the remarkable antioxidant, anti-inflammatory, and anti-microbial activities of Cannabis roots, supporting their traditional uses and challenging their perception as mere waste. This study highlights the therapeutic potential of Cannabis roots extracts and suggests avenues for further research and application.”

https://pubmed.ncbi.nlm.nih.gov/39351095/

“In conclusion, this study sheds light on the chemical profile and significant therapeutic potential of Cannabis root extracts, confirming the validity of their traditional uses and challenging their conventional status as waste products of Cannabis cultivation.

The results presented in this work add evidence to the broad spectrum of biological systems in which Cannabis-sourced derivatives have a potential effect, not only because of cannabinoids, but also because of the possible action of phenolic and nitrogen-containing compounds. Through comprehensive investigation, we have demonstrated their remarkable antioxidant, anticholinesterase, and anti-inflammatory activities, along with their ability to protect mitochondrial membranes.

These findings underscore the importance of reevaluating the utilization of Cannabis roots in various therapeutic contexts, potentially offering new avenues for drug discovery and development. By recognizing the value of these often-overlooked plant components, we may uncover novel treatments for a range of medical conditions, thereby contributing to the advancement of natural product pharmacology and healthcare innovation. Further research in this area is warranted to elucidate the underlying mechanisms and explore the full therapeutic potential of Cannabis root extracts.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1465136/full

Repeated Administration of a Full-Spectrum Cannabidiol Product, Not a Cannabidiol Isolate, Reverses the Lipopolysaccharide-Induced Depressive-Like Behavior and Hypolocomotion in a Rat Model of Low-Grade Subchronic Inflammation

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“Background: Mounting evidence suggests that the phytocannabinoid cannabidiol (CBD) holds promise as an antidepressant agent in conditions underlined by inflammation. Full-spectrum CBD extracts might provide greater behavioral efficacy than CBD-only isolates and might require lower doses to achieve the same outcomes due to the presence of other cannabinoids, terpenes, and flavonoids. However, investigations in this area remain limited. 

Methods: We evaluated the behavioral response to the administration for 7 days of 15 and 30 mg/kg of a CBD isolate and a full-spectrum CBD product in a rat model of subchronic lipopolysaccharide (LPS, 0.5 mg/kg/day/7 days, intraperitoneal)-induced depressive-like and sickness behavior. The forced swim test was used to assess depressive-like behavior, the open field test (OFT) to assess locomotion, and the elevated plus maze to assess anxiety-like behavior. 

Results: The full-spectrum CBD extract at both doses, but not the CBD isolate, reversed the LPS-induced depressive-like behavior in the forced swim test. Moreover, the full-spectrum CBD extract at the higher dose but not the CBD isolate restored the subchronic LPS-induced hypolocomotion in the OFT. Repeated administration of both formulations elicited an anxiogenic-like trend in the elevated plus maze. 

Conclusion: Full-spectrum CBD products might have greater therapeutic efficacy in resolving inflammation-induced depressive and sickness behavior compared to a CBD-only isolate.”

https://pubmed.ncbi.nlm.nih.gov/39347620/

https://www.liebertpub.com/doi/10.1089/can.2024.0086