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Selective Inhibition Shows Promise as Marijuana Treatment

by Diana Martinez, MD, and Pierre Trifilieff, PhD | August 15, 2014

THC Molecule 

A promising treatment option for addiction to marijuana may emerge through selective inhibition of a specific signaling pathway in the brain. While recent clinical trials have shown little luck in targeting serotonin, dopamine or norepinephrine systems to treat marijuana dependence, a new approach that would block the brain’s cannabinoid receptor itself – much like naltrexone blocks the µ-opioid receptor in heroin dependence – could become a viable pharmacological treatment.

Recent clinical trials investigating the potential effectiveness of dronabinol (a synthetic cannabinoid) or antidepressants like fluoxetine, venlafaxine and buspirone have failed at reducing cannabis use (Cooper; Haney, 2014). Furthermore, human laboratory studies that have modeled relapse have not shown great success with these medications that target the serotonin, dopamine or norepinephrine systems (Cooper; Haney, 2014). While smaller studies have shown some success with medications such as gabapentin ([Mason, 2012), quetiapine (Mariani, 2014), and N-acetylcysteine (Gray, 2012), larger studies are still needed to confirm these preliminary results.

Another approach that appears promising is to block the brain cannabinoid receptor itself. Previously, this method proved effective at inhibiting the intoxicating effects of marijuana by using rimonabant to block the cannabinoid receptor, but it was not practical as a treatment option due to rimonabant’s serious side effects, such as increased risk for depression and suicide (Huestis, 2001).

More recently, however, a study led by Pier Vincenzo Piazza, at the University of Bordeaux, revisited the treatment approach (Vallée, 2014). They discovered an endogenous compound that was able to partially block the activity of the cannabinoid receptor and therefore inhibit the intoxicating effects of marijuana in animals while leaving active other pathways that were blocked by rimonabant. This may lead to a new treatment approach for marijuana dependence that inhibits only the “high” of marijuana without other side effects that were seen with the use of rimonabant.

The study by Vallée, et al showed that the levels of the endogenous neurosteroid hormone pregnenolone are tremendously increased in the brain after tetrahydrocannabinol (THC) administration, which is not seen with other drugs of abuse such as ethanol, nicotine, cocaine or morphine. The authors hypothesized that pregnenolone could be a cellular negative feedback mechanism, where the brain increases pregnenolone production to counteract the effects of excessive THC. The study proves this theory, demonstrating that pregnenolone administration prevents the behavioral and physiological effects of THC, such as increase in food intake, memory deficits, hypolocomotion, hypothermia or catalepsy. Importantly, the authors also showed that pregnonolone inhibits cannabinoid self-administration in rodents.

How can pregnenolone exert such effects? Vallée, et al were able to show that pregnenolone directly impacts the signaling in the neurons that occurs after THC binds to the cannabinoid receptor.

There are two main types of cannabinoid (CB) receptors: CB1, which is expressed in the brain and peripheral organs, and CB2, which is mostly in peripheral organs. The CB1 receptor is found in almost every brain structure, and modulates well-known processes such as mood, appetite, and pain, but also has neuro-protective effects. The CB1 receptor is activated by endogenous neurotransmitters (compounds made by the brain itself) and by THC from marijuana intake.

Once activated, the CB1 receptor affects at least two intracellular signaling pathways within the neuron (MAPK/ERK and cyclic AMP pathways) and each pathway can have different effects within the neuron. Activating the CB1 receptor with THC could be compared to flipping a switch that turns on one light (the MAPK/ERK pathway) and turns off another light (the cyclic AMP pathways). If the receptor is fully blocked, then THC cannot affect either pathway (or light), but the normal function of the receptor from endogenous neurotransmitters is also blocked.

Vallée, et al showed that pregnenolone prevents THC from turning on the MAPK/ERK pathway, but doesn’t prevent THC from turning off the other pathway (cyclic AMP). This is an important finding, since most medications available today do not allow the selective inhibition of a specific signaling pathway within a neuron. As a result, these medications may have a beneficial effect, but will also have side effects that cannot be avoided – an example would be antipsychotics, which improve psychosis but also cause cognitive and movement problems. The medications that block a drug’s effect on all intracellular pathways are referred to as orthosteric antagonists.

Pregenolone on the other hand, acts as an allosteric inhibitor, meaning that it doesn't fully block the receptor, but modifies it in such a way that only one signaling pathway is blocked. Such “biased” antagonistic effect could account for the selective impact of pregnenolone on the intoxicating effects of THC, but not the other, more beneficial, effects of normal signaling at the CB1 receptor. Thus, pregenolone could potentially block the high of marijuana without causing the side effects seen with rimonabant (depression and suicidality).

But this selective effect at the CB1 receptor remains to be shown in humans, and even though pregnenolone is available over the counter, it cannot be used as a treatment right away. Pregnenolone is an endogenous steroid hormone that is found in the brain and many other organs, and it serves as a precursor to a number of hormones that regulate electrolyte balance, stress response, and sex steroids (androgen and estrogen). Because pregnenolone is converted into these other hormones, its administration has side effects that include irritability/mood changes, insomnia, headache, facial hair growth with head hair loss, and increased risk of heart disease.

Consider then the work by Vallée, et al as opening new routes for developing an analog of pregnenolone that could provide the partial blockade of the CB1 receptor and would allow some effects to be inhibited but not others. Currently, Dr. Piazza’s lab is developing an allosteric inhibitor for the CB1 receptor called C3,17-NMPD for use in humans. Medications like this, selective allosteric inhibitors, are a new class of medication that could greatly improve pharmacologic treatments of many disorders, including addiction. The design of such drugs would require a better understanding of the cellular and molecular bases of psychiatric disorders, which can only be achieved by conducting fundamental research that further our understanding of the signaling pathways.

Diana Martinez, MD

Dr. Martinez is an Associate Professor at Columbia University/New York State Psychiatric Institute. She is a psychiatrist and imaging researcher whose work has focused on using Positron Emission Tomography (PET) imaging in drug addiction. PET imaging allows the measurement of dopamine receptors and dopamine release in the human brain, and her work focuses on using this imaging technique, based on animal models of addiction, to better understand the neurochemistry of substance use disorders. Through these types of studies, her work is geared toward developing innovative treatments for addiction.

Pierre Trifilieff, PhD

Dr. Trifilieff is an Assistant Professor at INRA in the University of Bordeaux. His research focuses on the role of the mesolimbic dopaminergic transmission in physiologic and pathological conditions. Since the activity of the dopaminergic D2 receptor is altered in various psychiatric disorders that involve a dysregulation of the reward system, his work aims at unraveling the role of D2 receptor-dependent signaling in the modulation of reward processing and motivation. This includes studying the impact of D2 receptor manipulations on goal-directed behaviors as well as identifying environmental factors that impact D2-dependent signaling and related behaviors.

 

References

  1. Balter, R.E., Z.D. Cooper, and M. Haney, Novel Pharmacologic Approaches to Treating Cannabis Use Disorder. Curr Addict Rep, 2014. 1(2): p. 137-143.
  2. Mason, B.J., et al., A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology, 2012. 37(7): p. 1689-98.
  3. Mariani, J.J., et al., Open-label pilot study of quetiapine treatment for cannabis dependence. Am J Drug Alcohol Abuse, 2014. 40(4): p. 280-4.
  4. Gray, K.M., et al., A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry, 2012. 169(8): p. 805-12.
  5. Huestis, M.A., et al., Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry, 2001. 58(4): p. 322-8.
  6. Vallée, M., et al., Pregnenolone can protect the brain from cannabis intoxication. Science, 2014. 343(6166): p. 94-8.

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