New Drug Can Treat Cannabis Use Disorder, Researchers Say

A new class of drugs could be the answer to improving treatment for cannabis use disorder (CUD), according to new research published today in Nature Medicine.

In the new paper, a multi-institutional team of researchers reports the development of a new drug class, which they have named the “signaling-specific inhibitors of the cannabinoid receptor 1”, or CB1-SSi.

Based on data from pre-clinical animal models and phase 1 and 2a trials, the researchers believe that AEF0117, the first drug of this class to be studied, could help facilitate the treatment of cannabis addiction.

In these trials, AEF0117 appeared to be safe and well tolerated at multiple doses. Giving AEF0117 before administering cannabis also reduced the amount of cannabis being self-administered in a trial involving adults with CUD, without inducing withdrawal.

Encouraged by these findings, the researchers say that they are currently operating a longer three-month study of CB1-SSi drugs in patients seeking treatment for CUD.

New drug proven safe in phase 1 trials

Cannabis’ effects on human behavior are largely caused by THC activating the endocannabinoid system’s CB1 receptor.

Previously, the same research team found that the steroid pregnenolone is released in response to high concentrations of THC in the body. Once released, the steroid inhibits CB1-mediated changes in mitogen-activated protein kinase (MAPK) phosphorylation and in mitochondrial respiration. But notably, it does not inhibit any of the CB1-mediated changes in cyclic adenosine monophosphate (cAMP) that are normally seen.

Because of this signaling-specific action, pregnenolone is able to block many of THC’s effects and protect the brain against CB1 receptor overactivation, without causing significant adverse effects or impairing other endocannabinoid system functions.

In that earlier paper, the researchers hypothesized that such a signaling-specific compound could have useful implications in treating conditions such as CUD, as it could potentially nullify the pleasant aspects of cannabis and encourage abstinence. However, pregnenolone’s short half-life and low bioavailability make it largely unsuitable for use as a therapeutic drug.

Now, the researchers report the development of a new pharmacological class of drugs, CB1-SSis, which appear to act in a similar way to pregnenolone but with better bioavailability.

The latest paper includes details of multiple preclinical proof-of-concept studies using the CB1-SSi drug AEF0117, which show that the drug can inhibit THC’s behavioral effects in mice and non-human primates without disrupting normal behavior of psychological metrics.

Additionally, they report the results from two phase 1 clinical trials. The first of these was a single ascending dose (SAD) trial involving 64 healthy human volunteers who were given a single dose of either 0.2, 0.6, 2, or 6 milligrams of AEF0117. The second was a multiple ascending dose (MAD) trial using the same dosing amounts, but with the drug being administered once per day for up to seven days. In both trials, the participants reported no serious adverse events thought to be related to the drug.

Drug reduces cannabis use with no withdrawal symptoms

The new Nature Medicine paper also includes data from a phase 2a trial of AEF0117 in 29 volunteers with CUD. This trial group was not treatment-seeking and used cannabis on average for 6.9 days per week. Around 35% of the group had been diagnosed with mild CUD, 45% with moderate CUD, and 20% with a severe case of CUD.

The phase 2a trial was a randomized, double-blind, placebo-controlled, crossover, multiple-dose escalation trial testing the effects of 0.06 mg and 1 mg AEF0117 taken daily for five days.

Each volunteer took part in two five-day experimental sessions, one using the AEF0117 and one using a placebo drug, with a significant washout period between the sessions. On the first day, volunteers would take their AEF0117 or placebo as instructed. Around 3.5 hours later, they were asked to smoke a controlled amount of cannabis containing a consistently set amount of THC. On each following day, the participants would take the AEF0117 or placebo as normal, and then have the opportunity to self-administer cannabis of a randomly chosen strength until they felt satisfied. At regular intervals, the participants were also asked to rate the subjective effects of their cannabis usage using a 44-item visual analog scale and on a separate ‘cannabis rating form’.

The trial results indicated that AEF0117 decreased volunteers’ ratings of cannabis’ positive subjective effects and decreased cannabis self-administration relative to placebo. Crucially, while the volunteers with CUD reduced their cannabis usage, they did not report any significant signs of cannabis withdrawal or any disruptions to their regular sleep, food, or mood patterns over the experimental sessions.

“Because these drugs reproduce the effects of a natural mechanism to counteract CB1 overactivation, they can inhibit the effects of THC without altering the basal activity of the CB1,” the researchers wrote.

“Therefore, these compounds seem to have no effect on normal behavior and physiological activity while decreasing cannabis’ abuse-related and reinforcing effects, resulting in a well-tolerated and potentially efficacious therapy for CUD.”

The researchers say their next step is to conduct a similar trial comprised of individuals with CUD who are treatment-seeking. Additional studies looking at long-term safety are also recommended.

Cannabis use disorder treatment

There is currently no accepted pharmacotherapy option for assisting CUD treatment, but there are a handful of past studies that suggest that cannabinoids themselves could also be a useful strategy for bolstering cannabis abstinence.

A previous randomized controlled CBD trial published in Lancet Psychiatry found that individuals with CUD who regularly took CBD reported more cannabis-abstinent days than their peers who were given a placebo.

“We know that CBD has contrasting effects to THC on the endocannabinoid system,” Dr Tom Freeman, an addiction researcher at the University of Bath and lead author of the Lancet Psychiatry study, told Analytical Cannabis after its publication. “We know that THC is a partial agonist at cannabinoid receptors. But CBD has minimal direct activity at cannabinoid receptors.”

“At the same time, it does have properties that could be helpful in treating cannabis use disorder, such as inhibiting the effects of other ligands acting on the CB1 receptor and increasing endocannabinoids. And this is a potential mechanism through which it could be acting to alleviate the cannabis use disorder and help people cut down their use.”