Between the lines, these investigators are saying that mixtures of phytocannabinoids can have effects that differ from those of the the dratted enemy, THC, alone. Half of the neuro world reads/writes, time after time, that THC is pro-psychotic. The literature is therefore full of bullshit re. "pot" and downside.
It's just like obesity, and the rationale for developing rimonabant in the first place.... pot smokers get the munchies. Never mind that they are also skinny with great fasting insulin levels.
REAL WORLD? Patients seek out that magic mixture of cannabinoids that goes well beyond a mix of THC and CBD. That mixture even includes at least one CB1R antagonist. And THC alone might be pro-psychotic in animal models, but it's time that researchers understand that marijuana-experienced patients would self medicate, in a heart beat, with THC alone. It's like none of these people have actually EVER SPOKEN to a patient with schizophrenia. They run away from them on the street, so that they can get to the lab and study them.....
Curr Pharm Des. 2013 Jun 14. [Epub ahead of print]
Cannabinoids and Schizophrenia: Therapeutic Prospects.
Robson PJ, Guy GW, Di Marzo V.
Cannabinoid Research Institute, GW Pharmaceuticals plc, Porton Down Science Park, Salisbury SP4 0JQ.
Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic drugs (APs). Some of these may prove responsive to clozapine, but non-response to APs remains an important clinical problem and cause of increased health care costs. In a significant proportion of patients, schizophrenia is associated with natural and iatrogenic metabolic abnormalities (obesity, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus), hyperadrenalism and an exaggerated HPA response to stress, and chronic systemic inflammation. The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health. ECS modulates emotion, reward processing, sleep regulation, aversive memory extinction and HPA axis regulation. ECS overactivity contributes to visceral fat accumulation, insulin resistance and impaired energy expenditure. The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have emerged in pre-clinical and clinical models as potential APs. Since the likely mechanism of action does not rely upon dopamine D2 receptor antagonism, synergistic combinations with existing APs are plausible. The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established and are summarised below. Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the schizophrenia phenotype.
Hepatology. 2013 Jul 6. doi: 10.1002/hep.26606. [Epub ahead of print]
Hepatic CB1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long chain ceramides.
Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, Harvey-White J, Kunos G.
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Obesity is associated with increased activity of two lipid signaling systems - endocannabinoids (ECs) and ceramides - with both being implicated in insulin resistance. Cannabinoid-1 receptor (CB1 R) antagonists reverse obesity and insulin resistance, but have psychiatric side effects. Here we analyzed the role of ceramide in CB1 R-mediated insulin resistance in C57Bl6/J mice with high-fat diet-induced obesity (DIO), using JD5037, a peripherally restricted CB1 R inverse agonist. Chronic JD5037 treatment of DIO mice reduced body weight and steatosis, and improved glucose tolerance and insulin sensitivity. Peripheral CB1 R blockade also attenuated the diet-induced increase in C14:0, C16:0, C18:0 and C20:0 ceramide species with either C16 or C18 sphingosine-base in the liver. Decreased ceramide levels reflected their reduced de novo synthesis, due to inhibition of the activity of serine-palmitoyl transferase (SPT) and the expression of its SPTLC3 catalytic subunit, as well as reduced ceramide synthase (CerS) activity related to reduced expression of CerS1 and CerS6. JD5037 treatment also increased ceramide degradation due to increased expression of ceramidases. In primary cultured mouse hepatocytes and HepG2 cells, the EC anandamide increased ceramide synthesis in an eIF2a-dependent manner, and inhibited insulin-induced akt phosphorylation by increased serine phosphorylation of IRS1 and increased expression of the serine/threonine phosphatase Phlpp1. These effects were abrogated by JD5037 or the SPT inhibitor myriocin. Chronic treatment of DIO mice with myriocin or JD5037 similarly reversed hepatic insulin resistance, as verified using a euglycemic/hyperinsulinemic clamp. Conclusions: ECs induce CB1 R-mediated, ER stress-dependent synthesis of specific ceramide subspecies in the liver, which plays a key role in obesity-related hepatic insulin resistance. |
