Since the discovery of an endogenous cannabinoid system, researchers have been seeking useful drugs that target that system - but developing new medicines has proved harder than anticipated.
Apr 18, 2018 | by Liam Drew
There are documents showing that Cannabis sativa’s medicinal properties have been exploited for, at least, 5000 years. And since the mid-19th Century this curious plant and its ability to relieve numerous disease symptoms has been known to Western medicine.
The plant’s principle psychoactive component – delta-9-tetrahydrocannabinol (THC) – was identified in 1964.1 But by the 1980s, says Roger Pertwee – a pharmacologist who’s studied cannabis and its constituents for 50 years – there was a feeling that “all the obvious things had been done, and that the field was fading.”
In 1988, however, a specific receptor activated by THC and other synthetic cannabinoids was functionally characterized in neuronal membranes.2 And in 1990 the gene for this receptor was cloned.3 There then followed a remarkable burst of discovery that opened a new era of cannabinoid research.
In 1992,4 anandamide was identified as an endogenous activator of the so-called CB1 receptor. In 1993,5 a second receptor, CB2, was identified on immune cells. Then, in 1995,6 a second endogenous activator of these receptors – 2-AG – was discovered. Quickly, the enzymes that synthesized and degraded these two messengers were characterized. “Suddenly,” says Pertwee, “we had this system in our bodies that we’d known nothing about. The field didn’t fade again after that. It’s just grown and grown and grown.”
This endocannabinoid system (ECS) was found to be remarkably pervasive: the CB1 receptor is the most abundant G-protein-coupled receptor in the brain and is spread throughout the central nervous system (CNS). And beyond the CNS, the ECS operates in most, if not all, organ systems.
Consequently, anticipation grew that understanding this system would explain the long-known therapeutic actions of cannabis and would then allow those actions to be refined, and for new drugs targeting the ECS in new ways to be developed for numerous diseases.
Twenty years on, however, there have been a number of high-profile disappointments in the clinic7 and a growing appreciation of just how complex the ECS is. The field remains highly active, but expectations are not what they used to be.
“Things are complicated and this is not easy,” says Pal Pacher, a physician scientist at the NIH, Bethesda.
To survey ongoing research, it’s easiest to view the field of cannabinoid-related medicines in three broad parts. First, there’s the continued use of medical marijuana, which has grown remarkably following its legalisation in increasing numbers of jurisdictions around the globe. Second, there’s research into uses for different compounds extracted from cannabis. And finally, the broadest area of research searches for synthetic compounds that act on the ECS in various ways to achieve clinical benefits.
It’s now widely accepted that cannabis provides bona fide therapeutic relief to certain people with certain conditions. Most notably, cannabis is used by multiple sclerosis (MS) patients to gain relief from pain and spasticity; by chronic pain sufferers to achieve analgesia; by people undergoing chemotherapy to suppress nausea and vomiting; by patients with various wasting diseases, including AIDS, to stimulate their appetites; and by glaucoma patients to reduce intraocular pressure.
But while self-medicating may bring benefits, it marks no conceptual or practical advance. Pacher believes that the marginal oversight and control of this phenomenon means that it’s unlikely to generate interesting new insights. “There are many different strains of cannabis and they are completely different” he says, meaning that it’s nearly impossible to determine what constituents, at what doses, help patients.
Pacher also notes that over the last decade or so the THC content of marijuana has surged by about tenfold, increasing the risk of side effects, which besides well-appreciated psychological ones, include cardiovascular risks.
The term ‘phytocannabinoids’ describes all the cannabinoids that naturally occur in plants. Traditionally, attention has focused on THC and THC preparations, some using extracted THC, others using a synthetic version, and these have been widely approved by regulatory bodies. These preparations are widely used for the indications listed above for marijuana use, while potential new indications include Parkinson’s disease – where cannabinoids may both help control symptoms as well as be neuroprotective – and possibly post-traumatic stress disorder. Additionally, GW Pharmaceuticals market Sativex® – a 1:1 ratio of extracted THC and extracted cannabidiol (CBD), another very abundant cannabinoid in cannabis. Sativex is an oromucosal spray, which delivers a much more sustained dosing of these cannabinoids than smoking them. Sativex is approved for use in several countries worldwide for adults with spasticity associated with MS.8 It is also approved for additional indications in select countries; as a treatment for adults with neuropathic pain associated with MS and as an analgesic treatment in adult patients with advanced cancer.
While there is little doubt that THC is predominately responsible for cannabis’ psychoactive effects, there has been increasing interest in the possibility that other phytocannabinoids contribute to marijuana’s medicinal effects and that these may be potential drugs in their own right. Not least, CBD, which has recently received renewed attention.
In a 2016 open label study of treatment-resistant epilepsy in children9 and subsequently in a 2017 double-blind trial for Dravet Syndrome,10 CBD was found to roughly halve the frequency of convulsive seizures. For a horribly unmet clinical need, CBD has suddenly been pushed to the fore.
Remarkably, however, no one is sure how CBD acts. Unlike THC, CBD doesn’t activate CB receptors (though it may modulate CB1). In the lab, it’s been shown to affect over thirty different targets – albeit some only at high concentrations – and it remains to be determined which are important for this anti-epileptic effect. “It may be effective because it is a very dirty drug,” Pacher says, “and maybe that’s good. But the problem is that you cannot really develop analogues if you don’t know the target.” This could make drug companies wary of investigating its effects, but GW Pharmaceuticals continue to develop a CBD preparation toward the clinic for epilepsy.
Beyond THC and CBD, cannabis contains more than 120 further cannabinoids. And these structurally similar compounds have fascinatingly diverse pharmacological profiles. (Plus, if you count structurally dissimilar compounds cannabis has hundreds more constituents.) Some of these chemicals appear to have effects complementary to one another, whereas others are mutually antagonistic, highlighting what a complex drug unprocessed marijuana is.
“Cannabis is like a treasure chest,” says Pertwee. He’s currently studying a phytocannabinoid called delta-9-tetrahydrocannabivarin,11 or THCV, that blocks CB1 receptors but activates CB2 receptors. THCV may be useful for treating kidney disease –indicative of how widespread the search for conditions that may be usefully modulated by cannabinoids has become.
“But”, says Pertwee, “there’s an awful lot of preclinical data, and the question is how much is hype? And how much is genuine as far as potential new medicine is concerned?”
He says that now, “What’s needed urgently are clinical studies with patients. But with great care needed to avoid having bad results.”
The Endocannabinoid System
When the main components of the ECS were mapped out in the 1990s, it was widely hoped that this knowledge would allow the drug’s medical properties to be recapitulated by new drugs that lacked its psychoactive properties.12
Early on, pain-relief became a major focus, and when it was established that CB1 receptors outside of the CNS contributed to cannabis’s analgesic effects, CB1 agonists that did not cross the blood brain barrier (BBB) were developed. Astra Zeneca tested such drugs in Phase 2 clinical trials but discovered that they were only moderately successful analgesics. More problematically, though, the drugs caused major falls in blood pressure and substantial weight gain – side-effects that halted their development.7
Another event that deflated the cannabinoid community came after a CB1 antagonist was widely approved as an anti-obesity drug. Given the appetite-stimulating effects of THC, it was reasoned that blocking CB1 would supress appetite and promote weight loss. Although the CB1 blocker Rimonabant never received FDA approval,13 it was marketed in many countries, including across Europe (from 2006) and in Brazil (from 2007). But in 2008 its use was suspended after it had induced anxiety and suicidality, including numerous fatalities, in many people taking it.14
Interestingly, however, this centrally and peripherally acting CB1 inhibitor hadn’t caused weight loss by solely blocking central receptors and reducing appetite. Blocking peripheral CB1 receptors, it was discovered, enhances metabolic rates in peripheral organs, such as fat, liver, muscle. Consequently, peripherally restricted CB1 antagonists are now being developed as potential therapies for targeting obesity and diabetes.
While Pacher sees these drugs as potentially very useful, he is concerned that gaining regulatory approval will be difficult given Rimonabant’s withdrawal – “Normally, you consider that less than 5% entering through the BBB as safe, but since CB1 is the most abundant GPCR in the brain, a couple of percent may induce problems.”
Pacher is more optimistic about CB2 agonists, which to date appear to have a much better safety profile – at least, when given acutely. This subfield has had its problems too – certain CB2 agonists have had opposite effects in mice and humans, and the lack of good antibodies has caused confusion regarding where exactly CB2 receptors are expressed. However, it’s now agreed that activating CB2 has anti-inflammatory effects, which may be useful for limiting tissue injury after acute insults. While, immunosuppressant effects could be a concern with chronic usage, it’s thought that transient agonist use might restrict the detrimental consequences of a stroke, myocardial infarction, eye inflammation or kidney disease.
A Subtler Approach?
The model of the ECS that’s emerged in the last two decades, is of a system where unstable endogenous messengers are made on demand. Besides being unstable, anandamide and 2-AG are lipids that will not diffuse far due to their membrane solubility; plus, they are quickly broken down by abundant degradative enzymes, meaning that normally they signal only briefly.
Administering agonists that constantly activate receptors throughout the body can seem like the antithesis of this finally balanced system – a none-too-subtle carpet bombing of the target in whichever cell types it exists. Therefore, another major approach to manipulating the ECS has been to develop inhibitors of the degrading enzymes, with the hope and expectation that such drugs would boost endogenous cannabinoid tone; thereby only enhancing CB1 or CB2 signaling that was caused by intrinsic activity in the ECS.
Anandamide is broken down by FAAH (fatty acid amide hydrolase) and 2-AG by MAG lipase (monoacylglycerol lipase). Inhibitors of each enzyme have been produced – but again, the development of neither drug class has been straightforward.
First, a clinical trial for an FAAH-inhibitor for osteoarthritic knee pain failed to have a significant analgesic effect despite increasing anandamide levels in the joint by up to tenfold.14 But much more problematically, there was the notorious Bial Pharmaceuticals trial in which an experimental FAAH-inhibitor killed one participant and left four permanently brain-damaged.16
It remains unclear if the cerebral haemorrhaging and brain tissue death resulted from FAAH-inhibition directly or from an off-target effect, but the trial unsurprisingly prompted numerous drug developers to halt FAAH-inhibitor programs. Whether it will be conclusively proven that this tragedy was due to an off-target effect, and whether FAAH inhibitors might be one day usefully developed, remains moot.
The problem with MAG-lipase inhibitors is that targeting this route to increasing 2-AG levels has encountered the full complex web of biochemical interactions by which the body generates its lipid mediators. Most problematically, blocking MAG lipase causes a pronounced dysregulation of prostaglandin signaling.
This inability to separate one biological pathway from another seems emblematic of the cannabinoid field. The ECS’s role in so many systems continues to fuel interest in targeting it for medical gain. But this very ubiquity is what makes it such a difficult system to safely disrupt. “You have to think beyond your primary target,” says Pacher, “because you are giving it to patients and you will expose all organs. We still know relatively little about this and the consequences.”
There remain other avenues left to explore – some of them perhaps promising, such as allosteric modulators of CB1 and CB2 receptors, plus drugs that target the EC synthesising enzymes. But in Pacher’s assessment the initial excitement is over, the science has matured. “There will not be a blockbuster drug,” he says. “But it is a very exciting field, still. And if we go after some specialized indications very carefully, then I think it will be successful. This is a very important system; now, the question comes up of whether we will be clever enough to develop something.”
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