How much do we really know about Cannabidiol (CBD)?
There are plenty of convincing theories explaining how CBD produces its anti-inflammatory, anti-anxiety and anti-epileptic effects, but do we know for sure that these are scientific fact?
Dr Manuel Guzmán, Professor of Molecular Biology at Madrid Complutense University, who for the last twenty years has been a trailblazer in the field of cannabinoids and cancer, gives us his take on the great CBD debate.
CBD – ‘a challenging issue’ says Guzmán
“It’s a challenging issue because THC is known”, says Dr Guzmán.
“The locks are well established for CB1 and for THC. But the locks for CBD, if they exist – could be on the inside and not on the surface, and there are not two as they are for THC, but 10 or twenty at a time.
“And it’s very likely that the action of the CBD is not explainable by a single key and lock hypothesis as in the case of THC, but it’s more complex. Because it seems that CBD has low affinity for binding to different proteins, but that there are many proteins that can interact with CBD.
“So it’s very likely that the action of THC is CB1 central, a single avenue or path to effect, but in the case of CBD it involves small effects on different proteins, that when you put together all those small effects you make a bigger one.”
CBD’s classification as a pleiotropic drug, which means it produces many effects through multiple molecular pathways, can help us understand its complex interaction in the body.
CBD binds with non-cannabinoid receptors
In CBD’s case, its ability to bind with non-cannabinoid receptors and Ion channels could explain its wide variety of therapeutic effects.
- Anti-inflammatory/ pain relief: CBD binds to the TRPV-1 receptor, which is known to mediate pain perception, inflammation and body temperature.
- Anti-anxiety: CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor, bringing about an anti-depressant and anti-anxiety effect. This is further compounded by CBD’s ability to activate the Adenosine receptor.
- Antitumoral: Thanks to its activation of the peroxisome proliferator activated receptors, CBD is believed to decrease cancer cell proliferation
- Promote bone mass: By blocking the orphan receptor GPR55’s signaling, CBD may act to decrease bone reabsorption
So, if CBD can bind with other non-cannabinoid receptors, but has low affinity with the endocannabinoid CB1 and CB2 receptors, why does its administration seem to have a direct effect on the endocannabinoid system?
The CBD/ FAAH/ Anandamide connection – a hypothesis based on association?
Scientists have found that CBD increases the levels of the body’s own endocannabinoid, Anandamide. They believe this is because CBD inhibits the production of FAAH (fatty acid amide hydroxylase), the fatty acid involved in Andanamide’s metabolic breakdown. So less FAAH means more Anandamide, which leads to more CB1 receptor activation and greater Endocannabinoid tone.
But according to Dr Guzmán, even this theory remains only that: a hypothesis based on associations and not conclusive proof.
“The clinical trials where endocannabinoids have been measured more thoroughly with CBD are in a couple of trials where CBD was tested as an anti-psychotic,” he says.
Guzman refers here to the stage II double blind, randomised clinical trial carried out at the University of Cologne in 2008, in which 42 in patients with a schizophrenia diagnosis received 200mg – 800mg of cannabidiol over one month.
“In that trial”, says Guzmán, “they could obtain cerebrospinal fluid from schizophrenia patients and they found a good relation between the therapeutic action of CBD and the levels of Anandamide in those samples. In psychotic patients, the levels of Anandamide were low and with cbd – high”.
This seemed to prove the theory that CBD inhibited the levels of FAAH, reducing the breakdown of anandamide, and as a result producing an antipsychotic effect. But to Guzmán this is a case of a theory based on association.
“The FAAH – CBD – Anandamide connection is a hypothesis, we don’t know if it is the whole story. But we do know is that in patients with psychosis, Anandamide levels in cerebrospinal fluid are decreased. When you give CBD to those patients their symptoms improve and anandamide levels go up. So there is an association in between CBD administration and improvement in symptoms of schizophrenia and restoration of normal anandamide levels. They are observations of findings, but we don’t have any absolute proof. It could be true, at least for psychosis, but we don’t know if it’s true for epilepsy, and we don’t know if it’s part of the story in inflammation.”
Just the beginning
In reality, scientific understanding of the Endocannabinoid System is in its infancy, having only been discovered in the 1990s.
Guzmán: “It’s starting to unravel what is the function of the receptors and ligands within our brains and other parts of our bodies, so compared to the opioid system or the insulin system, or the dopamine system or the serotonin system; it’s a very short time.”
But despite this relatively short time frame in endocannabinoid research, progress can still seem desperately slow.
“I’m happy with what we’ve done in the last 20 years”, Guzmán concludes, “but sometimes one feels that things go desperately slowly, especially in regards to moving from the lab to the clinics, so that is something that is frustrating sometimes. We do painstaking approaches to understanding how a compound works in a mouse model, biochemistry and cell biology etc, but then when you realise that maybe there could be something useful for the patients, the gap that is between the bench where we are working and the clinic is massive”.
Dr Manuel Guzman is professor at the Department of Biochemistry and Molecular Biology at Complutense University in Madrid, Spain. He coordinates the Cannabinoid Signalling Group.