The Future of Cannabis for Brain Disorders

The psychotropic properties of the cannabis plant have been known to humans for thousands of years. It’s only during the past few decades that the medicinal properties of cannabinoids have been systematically explored. Plant cannabinoids are compounds that directly or indirectly influence the activity of cannabinoid receptors in the human body. Currently, no one has determined the function of these cannabinoids in plant biology, however, most botanists assume that they are there to protect the plant from herbivores as well as play an important role in seedling development. Humans, as well as many other animal species, also produce a variety of cannabinoids. Their normal physiological functions in humans are not entirely known, but as with plants, they play an important role in stem cell growth and development.

The body contains at least two protein receptors that bind to cannabinoids. Evolutionary evidence suggests that cannabinoids existed long before the emergence of the receptors that bind them. Recent studies have discovered that in the human brain, plant cannabinoids that inhibit the enzyme adenylyl cyclase are always psychoactive. Many naturally occurring cannabinoids, as well as the synthetic cannabinoid N-arachidonoylphenolamine (AM404, the active metabolite of the over-the-counter pain reliever Tylenol), are also neuroprotective in the brain. Several cannabinoids, such as the endogenous anandamide and the exogenous THC, reduce the growth of amoebae, such as Acanthamoeba culbertsoni, the cause of amoebic encephalitis. Future studies may discover additional medical benefits hidden within the cannabis plant.

The following paragraphs summarize what is currently known from human clinical trials about the future therapeutic benefits of these plant- and human-derived cannabinoids.

For the Treatment of Epilepsy

The cannabinoid cannabidiol, CBD, produces anticonvulsant effects in animal models of epilepsy; in contrast, its effectiveness in human trials has been variable. Recent studies have shown that patients with gene variants of aldehyde oxidase or diamine oxidase were more responsive to CBD, while carriers of other gene variants did not respond to CBD treatment. Genetic variabilities may underlie the inconsistent results across clinical trials. CBD was effective in reducing seizures in patients with tuberous sclerosis complex patients. A novel synthetic non-psychoactive cannabinoid (HU-211) has been shown recently to significantly reduce seizure activity.

For the Treatment of Multiple Sclerosis

In clinical studies, oral tetrahydrocannabinol (THC) administration improved muscle spasticity in multiple sclerosis patients and alleviated neuropathic pain. The underlying neurobiology of MS may target the endocannabinoid system. Post-mortem analysis of the brains of MS patients had reduced expression of both known cannabis receptors. In animal studies, THC can induce the regeneration of oligodendrocytes, remyelination of white matter, and improve motor function. THC also initiated axonal remyelination in cerebellar cell cultures. Cannabinoids may play an important role in the treatment of MS symptoms in the future.

For the Treatment of Pain

Human studies with cannabinoids and their effects on pain have been carried out for decades. Both THC and CBD appear to variably affect pain associated with specific conditions including arthritis and chronic neuropathies. The effectiveness of THC on fibromyalgia pain was tested in clinical trials with promising results. THC was not effective for chronic pain in individuals with sickle cell disease. In a randomized, double-blind, placebo-controlled, study, the efficacy of intravenous THC on several painful stimuli was measured in healthy human subjects; THC exhibited no analgesic effects.

Unlike THC, CBD does not directly stimulate cannabinoid receptors at normal physiological concentrations. CBD exhibits anti-inflammatory and immunomodulatory activity and provides modest therapeutic benefits on chronic sciatic nerve constriction (neuropathic pain) and inflammatory pain. Therefore, the efficacy of CBD in pain relief suggests that its effects may be through a different mechanism of action than THC. When oral CBD was tested in clinical studies its effectiveness was highly variable and often disappeared after a few days of continued treatment. In a randomized, double-blind, placebo-controlled trial, the effectiveness of a synthetic version of CBD as add-on pain therapy for osteoarthritis or psoriatic arthritis CBD exhibited no therapeutic effects, nor did it improve depression, anxiety, or sleep quality scores. The difficulty in demonstrating the effectiveness of THC or CBD for pain may be due to the influence of the placebo effect on the experience of pain.

For the Treatment of Neuropsychiatric Disorders

Regional brain activation, electrodermal activity, and anxiety ratings were used to determine the effects of THC and CBD on anxiety. High doses of THC exacerbated anxiety while CBD tended to decrease anxiety. When given to patients taking typical antidepressant medications, CBD add-on treatment reduced their anxiety and depression scores after several weeks of oral therapy.

A single oral dose of CBD led to a trend toward a decrease in psychotic symptoms, suggesting that CBD may be effective in reducing some symptoms of psychosis that do not respond well to typical antipsychotic medications. Cerebrospinal fluid from schizophrenic patients who never used cannabis products contained higher levels of the endogenous cannabinoid anandamide than from healthy individuals and these levels correlated negatively with their psychotic symptoms. In contrast, schizophrenic individuals who reported using cannabis frequently exhibited reduced brain levels of anandamide. This study suggests that endogenous levels of cannabinoids in the brain may play a role in some of the symptoms of schizophrenia and that cannabis may represent a potential therapeutic option for neuropsychiatric disorders.

One of the major challenges for future research is designing synthetic cannabinoids that produce clinical benefits by acting in specific brain regions, but without producing significant cognitive impairments. The non-psychotropic cannabinoid, CBD, holds perhaps more promise as a therapeutic for some neurodegenerative diseases.