SCIREQ recently attended this year’s Society of Toxicology (SOT 2021) Annual Meeting and ToxExpo! While the toxicological science of drugs of abuse has not been a major theme at previous SOT conferences, this year’s virtual event gave space for more focused sessions and discussions surrounding this topic. In particular, the impacts of cannabis exposure on human health and our understanding of the endocannabinoid system. Here are some highlights of what we learned from this year’s sessions!

The current state of cannabis research

While humans have been consuming cannabis and its derivatives for centuries, the recent legalization of its use and growth in North America has increased widespread consumption of this substance among populations. This social reality further supports the need for studying the potential benefits of cannabis on health as therapeutic treatment but also the possible deleterious effects that may come with it’s use.

With an already wide variety of ways of cannabinoid uptake into the body (Cannabidiol; CBD and Tetrahydrocannabinol; THC being the major active compounds), the rise in popularity of e-cigarette devices and cannabidiol incorporation into products has also broaden the different routes through which CBD and THC can be inhaled and consumed. Many researchers are tackling the challenge of unravelling the endocannabinoid system pathways and how CBD and THC affect our bodies at the physiological and neurological levels.

Consequences of parental cannabis exposure in offspring neurological development

The excellent Symposium Session on “Identifying and Communicating Adverse Neurological Outcomes from Parental Cannabis Use” had presenters delve into the various neurodevelopmental outcomes in offspring following parental cannabis exposure.

Clinical studies report that marijuana use during pregnancy and breastfeeding, to help reduce nausea and anxiety, is very common and legalization has further expanded its use. With THC crossing the placental barrier and the increase risk of child secondhand cannabis smoke exposure following legalization, researchers have been interested in studying the impact of these exposures in early life and development.

Dr. Bara’s group, at the Icahn School of Medicine at Mount Sinai, presented data from various studies using preclinical rodent models looking at behavioral and neurobiological disturbances in offspring following parental CBD/THC exposure. In one particular study where mice were placed in a heroin self-administration environment, they found that subjects exposed to THC had an increased drug-seeking behavior, with significantly reduced time before these subjects were driven to press a lever to self-administer a heroin dose. Another study showed that daily maternal exposure to THC during pregnancy resulted in alterations to rat placentas as well as impaired neuroplasticity in offspring, followed by depression-like behavior. They also performed several other behavioral studies of motivation, depression-like phenotypes and post-natal stress sensitivity, which showed that prenatal exposure to THC has an impact on reward and motivational processes in offspring.

Interestingly, Dr. Levin’s group also investigated preconception exposure to THC but focusing mainly on the paternal component. They hypothesized that the exposure could modify the epigenetic imprinting of sperm, translating in generational toxicant effects on the offspring’s phenotypes. In their studies, the group exposed young adult male rats to three different doses of THC daily for 28 days (0, 2 or 4 mg/kg/day) and bred them with unexposed females. Male and female offspring were then tested for neurobehavioral and cognitive functions (i.e. novel object recognition, suppressed feeding, locomotor activity, memory, attention). Their results showed a variety of alterations in offspring following exposure, for example significant impairment in attention function tests, more rapid habituation in locomotor activity test, suppressed feeding initiation even when hungry in fear tests, greater risk taking and significant delays in learning through 16-arm radial mazes experiments. To try and understand the mechanism behind these changes, the group also conducted a sperm epigenetic study looking at sperm methylation changes caused by THC exposure in male rats. They found that these DNA methylation changes overlapped with the same markers affected in human marijuana smokers. Another study also linked paternal THC exposure with cholinergic synaptic function deficits in the offspring.

CBD-mediated immune modulation

Other research groups are focusing on the potential health benefits of CBD/THC. Various studies are looking specifically at the immune modulation of CBD and its potential for therapeutic treatment of autoimmune inflammatory diseases.

Dr. Kaminski, from the Michigan State University, gave an excellent Merit Award Lecture, presenting their studies focusing on elucidating the molecular mechanisms behind cannabinoid-mediated immune modulation and the therapeutic potential it holds. One interesting study looked at the effect of CBD treatment on the immune response of human monocytes activated by infection with bacteria and viruses. Monocytes are activated by pathogens through biding to TRL receptors 1-9, which then causes secretion of inflammatory factors that modulate the innate and adaptive immune systems. In their study, the monocytes were isolated and incubated for 22 hours following CBD treatment. Secretion profiles and cytokines produced were then quantified. Their results showed that CBD treatment selectively suppressed monocyte-derived IL-1β and IL-6 from monocytes activated through TLR 1-9. These cytokines are critically involved in inflammatory responses and thus the study suggests that CBD presents benefits for reducing inflammation associated with bacterial and some viral infections which are recognized by the innate immune system.

Dr. Kaplan’s research, from the Mississippi State University, is also focused on CBD-induced immune suppression both in vivo and in vitro. In a workshop session for “Cannabidiol 2021: Science, Safety, and Societal Issues”, Dr. Kaplan presented their work on the effects and mechanisms of CBD immune function suppression in an animal autoimmune encephalomyelitis (EAE) model of multiple sclerosis. They hypothesized that CBD treatment can inhibit IFN-gamma production, which is a cytokine whose activity is crucial to promote macrophage activation, regulate T cell balance and promote TH1 immunity through inflammation, cell-mediated immunity and responses against intracellular pathogens. In these in vivo experiments, CBD was administered through oral gavage for 5 days following EAE disease induction. Their results showed significant reduction in disease severity at 18 days. Further, they observed a significant reduction of IFN-gamma production by CBD treatment in the spleen at day 10, which was followed by suppression of inflammation in the spinal cord and cerebellum at day 18. Their study supports the immune suppressive effect of CBD thought inhibition of IFN-gamma which suggests there may be a therapeutic potential for autoimmune diseases, but also an associated risk of immune suppression with uncontrolled use of the cannabinoid.

CBD & COVID-19: Potential for treatment of inflammatory diseases

Finally, with the recent COVID-19 pandemic, researchers have also been interested in developing therapeutic treatments for Acute Respiratory Distress Syndrome (ARDS). ARDS models are useful as safer alternatives to working with virus samples and mimic the cytokine storm presented by severe SARS-Cov-2 infected patients.

Dr. Nagarkatti’s group, at University of South Carolina School of Medicine, investigated the potential of CBD to treat a Staphylococcal enterotoxin B (SEB) induced ARDS mouse model, given CBD has been known to show anti-inflammatory and immune regulatory effects. C3H/HeJ mice exposed to dual doses of SEB were administered CBD for 3 days pre and post SEB dosing. While controls had a 0% survival rate within 5 days post SEB infection, they found that the survival rate of the CBD treated mice attained 100% indefinitely. To understand the molecular pathways through which CBD was leading to this amelioration, they evaluated whole single cell data in both groups. CBD treated mice showed an increase in TNF-α and IL-β, cytokines which expression is known to be associated with the presence and activation of inflammatory macrophages and neutrophils leading to respiratory disease and inflammation present in ARDS. These results paralleled a noticeable increase in MicroRNAs regulating the activity of the cytokine’s expression. This study shows the promising potential of CBD as therapeutic treatment for inflammatory diseases through immune cell regulation.

SCIREQ’s preclinical systems provide researchers with intervention tools to create standardized and reproducible exposure animal models as well as platforms to measure detailed lung function, allowing to track disease progression and test efficacy of potential drug therapies.