This Special Issue features fourteen original research articles across a wide range of topics and includes 10 reports on phytocannabinoids, 2 studies examining the endocannabinoid system, and 2 papers using synthetic cannabinoids. Three of these studies looked at the role of cannabinoids at mediating pain, two studies examined cannabinoids for treating mental illness, two studies addressed the potential safety of cannabinoids, two looked at cannabinoids as treatment options for gastrointestinal inflammation, and two studies examined the impact of cannabinoids on neurodevelopmental diseases. Other studies examined the impact of cannabinoids on cancer cell growth, anti-inflammatory activity in fibroblasts from patients with rheumatoid arthritis, regulation of matrix metalloproteases and cell proliferation, and regulation of neuroprotective genes in the brain. These various topics highlight the wide-ranging potential benefit of cannabis and cannabinoids to treat an array of human illness and disease.

In a study by Moreno-Sanz and colleagues, the impact of inhaled cannabis to treat pain and anxiety was examined [4]. The authors found that inhalation of pharmaceutical-grade cannabis flower provides patient-reported improvements to pain, mood, anxiety, and sleep. Perhaps most importantly the study reports an overall increased quality of life in a treatment-resistant group of patients. Sepulveda et al. found that pure THC, unlike pure CBD, is capable of reducing hyperalgesia in a murine model of chemotherapeutic-induced peripheral neuropathy [5]. This study also provides support for an “entourage” effect because a high CBD hemp extract, unlike the pure CBD, was able to reduce hyperalgesia when normalized to CBD levels; however, high THC extract and pure THC were found to offer the maximum reduction in sensitivity. In a study by Trevino and collaborators, the authors report that levels of the endocannabinoid 2-arachidonoylglcerol (2-AG) in the plasma at time of injury are positively correlated with chronic pain [6]. This suggests that increased activation of the endocannabinoid system can contribute to the development of chronic pain following an injury.

In addition to the Moreno-Sanz study described above, one other study examined cannabinoids in mental illness. A study by Zer-Aviv et al., found that inhibition of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) produces a stress-protective effect through activation of β-catenin in the nucleus accumbens region of the brain [7]. The study also found that the increase in anandamide levels, from inhibition of FAAH, acts through the cannabinoid receptor 1 to increase nuclear levels of β-catenin.

Hajjar and colleagues examined the use of prescription and non-prescription medications in patients using medical cannabis, as self-reported by patients [8]. The study found that patients frequently switch medical cannabis products, which may be due to the need to find a dose and product that work well for the patient. The study also found that despite the use of medical cannabis, the majority of patients taking antidepressants and anxiolytic medications did not change their medications or the dose of these medications. Bouassa et al., found that THC and CBD were well-tolerated by patients with HIV on anti-retroviral therapy [9]. Their study did find that patients on high doses of CBD (800 mg/day) should be monitored for liver pathology.

Bacalia et al. examined the impact of CBD on intestinal inflammation, and they found that in female mice, CBD suppresses inflammation in the absence of estradiol, but it enhances inflammation in animals with estradiol [10]. Yekhtin and colleagues found that both THC and CBD reduced nitric oxide production by lipopolysaccharide (LPS)-stimulated peritoneal macrophages [11]. Interestingly, only CBD was able to reduce cytokine production in LPS-stimulated macrophages, suggesting differences in the anti-inflammatory properties of these two cannabinoids. Both cannabinoids were equally beneficial at improving clinical outcomes in the dextran sodium sulfate murine model of colitis.

Gáll and collaborators found that CBD increases the latency to the first seizure and decreased the mortality associated with the pentylenetetrazol (PTZ)-kindling model of epilepsy in rats [12]. However, no impact was observed for seizure frequency or duration in this model. In a placebo-controlled trial of cannabinoids (CBD and THC at a 20:1 ratio using both extracts and pure compounds), Schnapp et al. found no impact on sleep parameters in patients with autism spectrum disorder [13].

In another study that examined the anti-inflammatory activity of cannabinoids outside of the gastrointestinal tract, Lowin et al. found that the impact of THC on inflammation in synovial fibroblasts from rheumatoid arthritis (RA) patients is dose dependent [14]. Therefore, using THC to treat RA may require titrating the dose to find an effective dose for each patient. Golan and colleagues found that a novel compound (HU-585), a synthetic derivative of anandamide and oleic acid, induces apoptosis and senescence in treatment-resistant neuroblastoma cells [15]. Greiner et al. report that activation of the cannabinoid receptor 2 produces protective effects in vascular smooth muscle cells and cardiac myocytes, and the opposite effect is observed when cannabinoid receptor 1 is activated in these cells [16]. Finally, in a study by Mottarlini and colleagues, it was found that cannabidiol administered via intraperitoneal injection is able to be detected in the prefrontal cortex of the brain, and that CBD treatment modulates the expression of brain-derived neurotropic factor (BDNF) [17]. BDNF plays a role in neurodevelopment, neuroplasticity, and neuroprotection, and the authors propose that CBD may prove beneficial in these areas when taken as a supplement.