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138. Li N, Liu JY, Timofeyev V, Qiu H, Hwang SH, Tuteja D, et al. Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches. J Mol Cell Cardiol. (2009) 47:835–45. doi: 10.1016/j.yjmcc.2009.08.017

165. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med. (2015) 373:1048–58. doi: 10.1056/NEJMra1407304

67. Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HHQ, et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, ΨGPR53 and GPR55: GPR55 is extensively expressed in human brain. Mol Brain Res. (1999) 64:193–8. doi: 10.1016/S0169-328X(98)00277-0

Funding

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87. Wei D, Dinh D, Lee D, Li D, Anguren A, Moreno-Sanz G, et al. Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment. Cannabis Cannabinoid Res. (2016) 1:81–9. doi: 10.1089/can.2015.0008

The ECS is an important signalling axis for inflammatory pathways throughout the body. Many children affected by ASD, FXS, and 22QS suffer from epileptic/non-epileptic seizures that stem from detrimental mutations responsible for their disorders (5, 7, 105–107). 10–30% of people with ASD have comorbid epilepsy and several synaptic plasticity pathways appear to be involved in both disorders (105). As such, affected children are at increased risk of serious seizure-related accidents and have their neurodevelopment further impaired by frequent seizures (108). In recent years, epilepsy has been surmised to be strongly correlated with neuroinflammation (104, 109). Additionally, abnormally high levels of neuroinflammation have been associated with ASD (110); Vargas et al. (110) and Jyonouchi et al. (111) found higher levels of proinflammatory cytokines (e.g., tumour growth factor–β1) in the brain tissue, cerebrospinal fluid and peripheral blood of ASD patients (including children) (110, 111).

While CBD might not interact strongly with CB1R and CB2R when administered at therapeutical levels (166), it has been reported to regulate calcium ion homeostasis in neurons (167) and increase inhibitory neurotransmission via interactions with GPR55 (164). CBD therapy has been correlated with an increase in AEA blood levels and a reduction in the psychotic symptoms of treated schizophrenic patients vs. placebo-control patients (35); the mechanism behind CBD’s beneficial effect in this instance could be due to an increase in AEA levels found to be lower in the cerebrospinal fluid of epileptic patients (168) and in the blood of ASD children (169, 170). Of note, the mechanism by which CBD increases AEA levels seems to differ between species; Elmes et al. reported that, in humans, this effect may be due to CBD binding preferentially to the fatty acid binding proteins on which AEA depends to be transported into cells for FAAH catalysis rather than the CBD-induced FAAH inhibition observed in rodents (171). This interaction between CBD and AEA metabolism in humans vs. rodents (171, 172), highlights that the differences in xenobiotics metabolism between species can limit the utility of animal models in cannabinoid research.

Intriguingly, CBD has been shown to desensitise non-cannabinoid TRPV1s (75) and related TRPV2s, hence blocking the release of calcium ions outside cells and dampening hyperexcitability (contributor to aberrant neuronal activity) in neurons, suggesting another potential regulatory mechanism (172, 183). CBD has been reported to enhance microglial phagocytosis in rodent microglia partially via the activation of TRPV1 and probably TRPV2 receptor channel of the microglial cells (112); however, Hassan et al. cautioned that increasing microglial phagocytosis might not be a positive strategy for combating neuroinflammation, but their results might not be applicable to human physiology.

Conclusion

We would like to thank the CCTRND, in particular Mr. Michael Duhig and the clinical staff for their help with KKC’s research project.

Activation of the cannabinoid receptors by endocannabinoids can trigger downstream signalling, such as ion channel openings, changes in intracellular calcium ion concentrations and regulation of inflammatory pathways (71). The two most well-studied endocannabinoids are N-arachidonoyl-ethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG). AEA acts as a high-affinity, partial agonist of CB1R, and barely interacts with CB2R while 2-AG is a full agonist at both CBRs with low-to-moderate affinity, with both endocannabinoids being GPR55 agonists (68, 72, 73). At the end of their normal lifecycle, AEA is mostly degraded to arachidonic acid (AA) and ethanolamine by fatty acid amide hydrolase (FAAH) (71), while 2-AG is majorly converted to AA and glycerol by monoacylglycerol lipase (MAGL) (74). Interestingly, AEA is also a full agonist (with a different affinity than for CB1R) of a non-ECS receptor named the Transient Receptor Potential Vanilloid 1 (TRPV1) that regulates extracellular calcium ion secretion and neuronal excitability (75).

The lipoxygenase (LOX) enzyme pathway is another metabolic route for endocannabinoids and other related fatty acids (149). The LOX pathway starts with the change of AA into leukotriene A4 by the 5-LOX enzyme (expressed on cell types such as neurons). Leukotriene A4 (LTA4) is rapidly catalysed into LTB4 and cysteinyl leukotrienes (i.e., Cys-LTs, which comprises LTC4, LTD4 and LTE4) (149, 150). LTD4 has been linked to blood-brain barrier dysfunction (151), a contributing factor of neuroinflammation (152), as evidenced by exposure of microglial Cys-LT1 and Cys-LT2 receptors to LTD4 resulting in microglial secretion of pro-inflammatory IL-1β in mice (153). In brief, the ongoing research on eicosanoids (collective term for the endocannabinoids and the many metabolites of the ECS) indicates that the ECS is thoroughly implicated in regulation of neuronal activity and neuroinflammation. But until the signalling pathways involved are thoroughly investigated, particularly in the human brain, how neuroinflammation is exactly linked to ECS dysfunction and psychiatric impairments remains to be elucidated. Interestingly, inflammation in the GIS could substantially affect the gut-microbiome-brain axis and subsequent neuronal activity as ASD individuals have been reported to suffer from gastrointestinal issues (such as diarrhoea and constipation) (154–157) and dysbiotic microbiota compared to neurotypical individuals (158). Perturbations in gut microbial diversity has been found to influence neuroinflammation (159) as some gut microbes can secrete pro-inflammatory metabolites and cytokines (160) that cross the blood-brain barrier. CB1R, TRPV1 and PPAR-α can modulate the permeability of the gut-vascular barrier that prevents the entry of intestinal bacteria into the bloodstream; if the GVB’s selective permeability is compromised, the bacteria themselves can enter the bloodstream and cross the BBB, causing an inflammatory response (161).

Agonism of CB1R and CB2R have shown anti-inflammatory effects in human and animal models (120–123). Antagonism/non-expression of GPR55 also resulted in a reduction in neuronal and microglial inflammation (116, 124, 125). However, agonism of GPR55 in animal and human neural stem cells was found to elicit a neuroprotective effect and rescued neurogenesis after inflammatory insult (126). Additionally, activation of microglial GPR55 by the endogenous ligand l-α-lysophosphatidylinositol limited neuronal damage in rats (127). As Hill et al. suggest, the actions of GPR55 probably strongly depend on the cell type and cause of inflammation (126). Cyclooxygenase enzymes (COX) synthesise signalling intermediaries known as prostanoids, often derived from AA. The constitutive isoform of COX, COX-1, found in numerous cell types, regulates physiological responses, while the inducible isoform, COX-2, is induced rapidly in several cell types (including neurons and glial cells) after biochemical stimuli, such as cytokines and pro-inflammatory molecules (128). COX-2 is involved in the conversion of a minor proportion of AEA and 2-AG to prostaglandin ethanolamides (PG-EAs) (74) and prostaglandin glycerol esters (PG-Gs) (129), respectively—both of which can contribute to inflammatory responses (128). Other prostaglandins derived from AA by COX-1 and COX-2, prostaglandin E2 (PGE2) and prostaglandin F (PGF), have neurotoxic properties (125, 130, 131). Suppression of MAGL activity (which leads to a downregulation in AA synthesis) has shown neuroprotective effects in mice (132). COX-2 levels have been found to be greatly increased in the brains of patients with epilepsy, compared to non-epileptic patients (133) and in animals that experience prolonged seizures (134), suggesting a relationship between epilepsy and neuroinflammation.

The people behind spiked vapes leave few clues about who makes them or what’s inside.

“People have started to see the market grow and there are some fly-by-night companies trying to make a quick buck,” said Marielle Weintraub, president of the US Hemp Authority, an industry group that certifies CBD cosmetics and dietary supplements.

Through interviews and documents, AP tracked Green Machine pods that reporters bought to a warehouse in Philadelphia and then a Manhattan smoke shop and the entrepreneur behind the counter, Rajinder Singh, who said he is Green Machine’s first distributor.

Juul trying to recoup millions from brazen entrepreneurs

Maloney also said Mathco does not “engage in the manufacture, distribution or sale of any illegal products.” She said the Yolo products in Utah “were not purchased from us” and the company can’t control what happens to products once they are shipped. AP-commissioned testing of two CBD vape cartridges marketed under Maloney’s Hemp Hookahzz brand found no synthetic marijuana.

After several Georgia high school students passed out from vaping last year, authorities began scrutinizing local tobacco shops. One of the CBD vape brands they targeted was called Magic Puff.

Packaging doesn’t identify the companies and their brands have little online presence. Newcomers can simply design a label and outsource production to a wholesaler that deals in bulk.

Back in the car, Jenkins tried it first. Things “got hazy,” then terrifying.