Cannabinoid derivatives under investigation

Cara Therapeutics Cannabinoid Compound CR701

The cannabinoid compound CR701 is a synthetic cannabinoid receptor agonist being developed by Cara Therapeutics in Stamford, Connecticut. CR701 is indicated for the treatment of neuropathic pain, particularly for hyperalgesia and allodynia.

CR701 was found to bind peripheral CB2 receptors, but not central CB1 receptors, thus mediating anti-inflammatory and antinociceptive pathways without psychotropic effects.1 As is the case with nonsynthetic CBD, CR701 may act synergistically with opioids and nonsteroidal anti-inflammatory drugs, an effect that may be useful when managing pain, that requires smaller doses of medications, and that avoids related adverse effects. 1

Serious adverse effects (ie, catalepsy and hypothermia) were only observed at supratherapeutic doses, and there were no risks for dependence or tolerance associated with CR701.1 Clinicians may not be ready to offer CR701 as a stand-alone option, but its potential synergistic action with other pain treatments may be beneficial for the control of inflammation, nociception, hyperalgesia, and allodynia.

Zynerba Pharmaceuticals ZYN002 Product

ZYN002 is a synthetic CBD gel delivered transdermally. ZYN002 is indicated for use in disorders such as fragile X syndrome, developmental and epileptic encephalopathies, and adult refractory focal epilepsy.

Transdermal CBD modalities can offer a more consistent dose by avoiding first-pass metabolism associated with oral routes, and increasing the bioavailability of active compounds in circulation.2 Furthermore, in a setting of high acidity (eg, the stomach), CBD has been shown to degrade into THC, leading to unwanted psychotropic effects.1 In clinical trials, ZYN002 was found to reduce the frequency of seizures, to display increased antiepileptic effects over time, and to be well tolerated.1

The antiepileptic mechanism of cannabinoids suggest that CBD (more so than THC) modulates the activity of CB1 receptors on presynaptic terminals by enhancing potassium conduction.1 CBD is also thought to slow the breakdown of anandamide, an endogenous neurotransmitter with protective effects against epilepsy.1

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References

1. Urits I, Borchart M, Hasegawa M, Kochanski J, Orhurhu V, Viswanath O. An update of current cannabis-based pharmaceuticals in pain medicine. Pain Ther. 2019;8(1):41-51.

2. Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D, Dosio F. Cannabinoid delivery systems for pain and inflammation treatment. Molecules. 2018;23(10):2478.