Addiction

In one study in rats, chronic stimulation of the endocannabinoid system (Anandamide) reduced addictive behavior (cocaine seeking), suggesting a role for the endocannabinoid system in suppressing Addiction (Chauvet et al., 2014).

anorexia

2AG and AEA are involved in food intake regulation (Fride, Bregman, & Kirkham, 2005).

anxiety

DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and anxiety responses (Jenniches et al., 2016).

Autism

Hippocampal Anandamide, OEA and PEA were increased after social exposure (Kerr et al., 2013) once more stipulating the involvement of the endocannabinoid system in Autism.

cancer

Bone Cancer

CB2 agonists as Anandamide or THC affect the inflammatory process of bone cancer cells by modulating interleukin, tumor necrosis factor α and nuclear factor-κB expression and cofilin-1 protein (Hsu et al., 2007; Lu et al., 2015; Yang et al., 2015).

Cervical Cancer

cannabinoid receptors CB1, CB2 and TRPV1 are expressed in the cervix. Anandamide bind to those receptors and has multiple functions on them (Ayakannu et al., 2015).

One of the effects of Anandamide (and THC) is to overexpress TIMP-1 with anti invasive and apoptotic functions on cancer cells (Ramer and Hinz, 2008).

However, the specific mechanism of the endocannabinoid system is not clear. Some studies suggest that Anandamide anti cancer properties depend on TRPV1 and not on CB1 or CB2 (Contassot et al., 2004; Ramer and Hinz, 2008).

COPD

In human patients, Anandamide was found to strongly inhibit bronchospasms and coughing (caused by chemical irritants) through activation of CB1 receptors (Calignano et al., 2000). 

Cystitis

In a rat study, Anandamide was found to induce bladder inflammation pain through TRPV1 suggesting this receptor might be a therapeutic target (Dinis et al., 2004). Interestingly, the opposite was found in another study where boosting Anandamide levels by preventing its breakdown exerted potent analgesic and anti-inflammatory effects (Wang et al., 2015). FAAH was responsible of breaking down Anandamide. Several studies found that CB2 was upregulated with Cystitis (Merriam et al., 2008; Tambaro et al., 2014) and that activation of CB2 with Anandamide or PEA attenuated pain and inflammation (Jaggar et al., 1998; Wang et al., 2013, 2014).

depression

Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).

Diabetes

Anandamide and CB1, CB2 and GPR55 receptors are implicated in the pathophysiology of Diabetes type 2 (Jenkin et al., 2014; Jourdan et al., 2014; Troy-Fioramonti et al., 2014).

Eczema

In an experimental mouse model of Eczema endocannabinoids AEA and PEA were increased and TRPV1 and PPARα were upregulated (Petrosino et al., 2010). PEA enhances AEA activity at CB1, CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1, CB2 or PPARα-dependent way.

epilepsy

Anandamide reduces burst-firing in neurons (Evans et al., 2008).

Functional Gastro-Intestinal Disorders

Patients with Crohn’s Disease have significantly reduced levels of Anandamide, but not 2AG or PEA, supporting a role for the endocannabinoid system in Crohn’s Disease (Di Sabatino et al., 2011). Intracerebrovascular application of Anandamide and 2AG appeared gastro-protective in ethanol-induced ulcers suggesting the involvement of endocannabinoids in the central nervous system (Gyires and Zádori, 2016).

Hypoxic-Ischemic Encephalopaty

cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013). AEA modulates the function of the glia increasing its pro-inflammatory response in the brain (Vázquez et al., 2015).

insomnia

CB1 receptors mediated sleep effects caused by Anandamide in a rat model with in vivo microdialysis (Murillo-Rodriguez et al., 2003). Anandamide may interact with oleamide processes to induce sleep. CBD would act as an inhibitor of Anandamide uptake through TPRV1 receptor, suggesting a role in sleep (Bisogno et al., 2001; Mechoulam et al., 1997). Administration of a synthetic inhibitor of Anandamide uptake showed increased sleep in rats and enhanced c-Fos expression in sleep related brain areas (Murillo-Rodríguez et al., 2008).

Malaria

Anandamide reduced parasitaemia and increased the survival rate of infected mice through the acceleration of eryptosis of infected erythrocytes (Bobbala et al., 2010).

Migraine

Pre-administered Anandamide significantly reduced nociceptive behavior in rats, suggesting that migraine may actually be a manifestation of a dysfunctional endocannabinoid system (Greco et al., 2011), which in turn offers interesting possibilities for endo- and plant cannabinoids in the treatment of migraine.

obesity

endocannabinoids are derived from Poly Unsaturated Fatty Acids (PUFAs) with Anandamide and 2AG coming from Ω-6 PUFAs and EPA and DHA coming from Ω-3 PUFAs. The typical Western diet is low on PUFAs and has a low Ω-3/Ω-6 ratio. Shifting the balance to a higher Ω-3 content leads to weight loss, presumably through differential activation of the endocannabinoidsystem (Watkins and Kim, 2014)

OCD

In line with this the endogenous CB1 agonist Anandamide stimulates marble seeking behavior (Umathe et al., 2012).

pain

In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic cannabinoid but also displaying endocannabinoid activity), which in turn blocks re-uptake of Anandamide (Mallet et al., 2008). The analgesic effect of paracetamol thus seems to be due to increased ambient levels of Anandamide. Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006). Similarly, ibuprofen was found to block the breakdown/hydrolysis of Anandamide (Fowler et al., 1999), which may contribute to the analgesic effect of ibuprofen (and similar substances).

Parkinson´s

In one study, Anandamide was found to reduce dopamine release via TRPV1 receptors (de Lago et al., 2004) suggesting their involvement in movement behaviour.

Psoriasis

Similarly, the endocannabinoid Anandamide strongly suppresses keratinocyte proliferation and induces cell death via sequential activation of CB1 and TRPV1 (Tóth et al., 2011), suggesting the endocannabinoid system normally keeps keratinocyte proliferation in check.

psychosis and schizophrenia

Regarding the molecular mechanisms of the comorbidity between cannabis and schizophrenia, the endocannabinoid system has been related to schizophrenia. endocannabinoids like Anandamide and 2-AG play an important role on psychosis (Manseau and Goff, 2015). Some studies point to an Anandamide imbalance associated to psychosis (Leweke, 2012). In unmedicated patients with acute psychosis one of the body’s main endocannabinoids, Anandamide, is elevated 8-fold. This elevation is absent in patients on anti-psychotics and is inversely correlated with psychotic symptoms, suggesting Anandamide actually functions to suppress psychotic behavior (Giuffrida et al., 2004).

PTSD

Similar to chronic stress, people with PTSD have 15-20% lower CB1 levels and more than 50% reduced Anandamide levels (Neumeister et al., 2013) which may form a mechanistic insight in the development of PTSD and/or depression.

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