Potential Cannabinoid Treatments for Psychiatric Illness
A summary of “Targeting the Endocannabinoid System in Psychiatric Illness” by Martin A. Katzman, BSc/MD/FRCPC, Melissa Furtado, BSc, and Leena Anand, BA, 2016.
Certain interactions with the endocannabinoid system have lead to improved outcomes in a variety of disorders. Since its discovery, the endocannabinoid system (ECS) has been identified a key component in many physiological and pathophysiological processes throughout the body. Such processes include, but are not limited to, immune function, inflammation, metabolism, memory, stress, pain, and psychiatric disorders.
Mental health disorders remain extremely persistent worldwide. These disorders exert encumbrance not only on the individual, but also on society. A large burden of psychiatric illness is the loss of work productivity. In the United States, approximately 200 million workdays are lost entirely due to depression.
Since the treatment outcomes of such illnesses remain to be less than ideal, new treatment methods are being explored to increase and improve outcomes in the psychiatric population. The endocannabinoid system has been of high interest in identifying pharmacological interactions to treat disorders such as schizophrenia, attention-deficit hyperactivity, anxiety, posttraumatic stress, and depressive disorders. This paper discusses these psychiatric disorders from the systematic review ‘Targeting the Endocannabinoid System in Psychiatric Illness’ (Katzman, Furtado, & Anand, 2016).
Something to address before reviewing the research on treating psychiatric disorders with cannabinoids, is the casual association between cannabis use and symptoms of psychosis. Previous evidence indicates a connection between the use of cannabis and the development of psychiatric illnesses. This conclusion is starting to be questioned, as the casual relationship is ambiguous and confounded by genetic variables.
A Swedish study examined the suspected association between cannabis abuse and being diagnosed with schizophrenia later in life. The study compared schizophrenic patients with documented cannabis abuse prior to the diagnosis to matched healthy controls. The study did find an increased risk of schizophrenia diagnosis in cannabis abusers. However, when the degree of sharing genetic factors increased, meaning increase in family history or having a gene associated with schizophrenia, there was a significant decrease in the association between schizophrenia and cannabis abuse. After correcting for familial confounding variables, the casual relationship decreased by about two thirds. This applies to more psychiatric symptoms and illnesses than schizophrenia, such as manic depression.
Individuals diagnosed with schizophrenia experience a significant loss in quality of life and this leads to premature death. There has been much research on this psychiatric illness, yet the cause of the disease is still unclear to this day. Schizophrenia is represented by: hallucinations, delusions, unorganized or repetitive movements, lack of emotional expressiveness, and lack of attention or intuition.
Following the recommended course of treatments with antipsychotics, there is only a remission rate of about thirty-five percent. Nearly seventy-five percent of schizophrenia patients discontinue their medications primarily because of the adverse side effects. Due to the large population that decides to discontinue medication or does not achieve remission, further research on effective and tolerable treatment is needed.
A neural post mortem study in schizophrenic patients compared to controls revealed interesting findings. The study discovered that schizophrenic patients had a rather large distribution of CB1 receptors in a part of the limbic lobe known as the anterior cingulate cortex (ACC). The ACC and CB1 receptors are suspected to play important roles in cognitions, motivation, and attention. Therefore, specific changes within the endocannabinoid system of the ACC may be a potential cause of the lack of motivation and attention in individuals diagnosed with schizophrenia.
The fatty acid neurotransmitter anandamide has been investigated in the ECS’s role in schizophrenia. Anandamide has roles in higher-level functions such as reward anticipation, decision-making, impulse control, and emotion. Changes in this endocannabinoid mediator are exhibited in schizophrenic individuals, and signaling is proposed to be hyperactive in these patients. One study found that cerebrospinal fluid (CSF) levels of anandamide were about 8-fold higher in schizophrenic patients compared to healthy controls.
Anadamide was further researched to determine if the amount of cannabis consumed in schizophrenia individuals altered the levels of anadamide in the CSF. First episode schizophrenia and healthy controls were divided into two groups: high or low frequency cannabis user. Statistical analysis of the results revealed that the low frequency using schizophrenia patients had a greater than 10-fold increase in CSF anandamide levels compared with healthy low and high frequency using controls, and with high frequency using schizophrenic patients. This finding is extremely important and exciting clinically, because the results suggest that increased cannabis use in schizophrenic patients may cause downregulation of anadamide signaling.
Cognitive function in schizophrenic patients was also assessed by 16 different task tests. Lifetime (regular) users of cannabis were compared to non-regular (non-users) in schizophrenic patients and healthy controls. A meta-analysis exhibited cognitive improvements associated with cannabis. It is expected, and was demonstrated, that all schizophrenic patients showed significant deficiencies in every cognitive functioning tasks compared to the healthy controls. However, when just comparing the two schizophrenic groups, cognitive improvements were demonstrated by regular cannabis use. The non-using group was considerably impaired on 15 out of 16 tasks, while the regular using group was only impaired selectively on 9 tasks.
Research on the use and efficacy of cannabidiol (CBD) versus the antipsychotic amisulpride in schizophrenic individuals has also been evaluated. A double-blind randomized trial revealed that the use of CBD and the antipsychotic produced the same desired result. More interesting, CBD was associated with significantly less adverse side effects. This study provides a very exciting conclusion that CBD is just as successful at improving psychotic symptoms as the antipsychotic drug amisulpride.
Another psychiatric illness with poor remission rates is depressive disorder. It has been documented that only one third of patients with major depressive disorder (MDD) receiving recommended medication achieve remission. The ECS has previously been shown to be involved in the causation of depression.
The ECS role in MDD has been investigated genetically in regards to treatment response. The CNR1 gene is located on chromosome 6 and encodes for the CB1 receptor. This gene can have many variations in its sequence, but one was found to have an affect in the response to treatment, the CNR1 rs1049353 G allele. This lines up with the previous research that demonstrated that individuals who carry only this G allele display decreased reactivity in certain brain regions in response to positive facial expressions.
Genomics is very important in medicine, and in my own opinion it is the future of healthcare. It is helping health care providers meet the needs of treatment in specific individuals. Further studies on the CNR1 gene will help in the development of specific medications to prescribe to patients with depression who have the G allele.
Serotonin is a primary neurotransmitter that affects mood and the antidepressant action. What we have learned to this date is that CB1 receptors are greatly expressed in the prefrontal cortex (PFC) of the brain. The PFC is involved in transmitting excitatory signals to the dorsal raphe, which is a structure in the brainstem responsible for a majority of serotonin. The relationships between these are worth further investigation.
Another brain region to consider in the evaluation of the ECS and MDD is the ventral tegmental area found in the midbrain. This area contains dopaminergic neurons, which are neurons that are responsible for the release of the neurotransmitter dopamine. Dopamine is responsible for the reward system, cognition, and motivation. Recently, it has been discovered that these midbrain dopamine neurons can release 2-AG, a primary endocannabinoid ligand.
The release of 2-AG affects the sensory input of neurons. 2-AG is synthesized and released from a postsynaptic neuron, and then 2-AG binds to CB1 receptors on the presynaptic neurons, which inhibits the release of dopamine. Opposed to this mechanism are THC and other synthetic endocannabinoids. They act as agonists to the CB1 receptor and increase the firing rate and activity of these dopamine neurons. This all results in the increase of dopamine in the PFC and nucleus accumbens, which are areas that are important in depression. Increased dopamine levels serves to boost one’s self esteem. Higher dopamine results in increased mood, better concentration, and an enhancement in prosocial behavior.
It is extremely common for individuals who are diagnosed with depression to simultaneously suffer from anxiety or attention-deficit hyperactivity disorder. The comorbidity of MDD and anxiety was assessed to try and further understand the ECS in MDD patients. The subjects in the study, healthy controls and women with MDD, underwent a Trier Social Stress Test (TSST) and blood samples were drawn at many points throughout to compare serum levels of different endocannabinoids.
The study found that after administering the TSST, certain serum endocannabinoid levels were significantly increased in the MDD individuals. This revealed the effect stress exposure has on the ECS in MDD patients. Social stress in MDD causes alterations in signaling within the ECS, this gives researcher one more reason why further examination about managing MDD through the therapeutic effects of cannabinoids is needed.
Anxiety, particularly social anxiety disorder (SAD), has high prevalence in the general population. However, like many other psychiatric illnesses, the remission rate of symptoms after treatment remains very low. These extremely unsatisfactory remission rates have lead to the need of new beneficial and more effective treatment methods.
Previous research has demonstrated that CBD can potentially reduce anxiety in patients suffering from SAD. A double blind, and placebo-controlled, study examined how CBD affected generalized SAD patients compared to healthy controls using a Simulation Public Speaking Test (SPST). The study confirmed the anxiolytic effects of CBD in SAD patients. CBD treatment resulted in significantly reduced anxiety, cognitive impairment, discomfort, and almost completely eliminated negative self-evaluation in SAD patients.
CBD’s anxiolytic effect was also evaluated at a neural level. Special tomography imaging known as SPECT was used with a radiopharmaceutical to determine CBD’s effects in the brain. CBD primarily impacted the limbic and paralimibic neural areas of the brain, which are proposed to be responsible for the mediation of fear and anxiety.
THC, the psychoactive component of cannabis, and its effects on anxiety have also been investigated. One study demonstrated, in healthy individuals (not suffering form SAD), that THC increased the feeling of anxiety in both low and high THC strains. A second study compared the effects of 10 mg of THC, 600 mg of CBD, and a placebo on anxiety levels. The subjects were randomly assigned to THC, CBD, or placebo and underwent fMRI (a type of imaging) while viewing images that provoked different levels of anxiety.
This study demonstrated how CBD and THC target different neural areas of the brain and thereby differ in symptomatic responses. It was demonstrated that THC increased anxiety and acted as an activating modulator in the frontal and parietal regions of the brain. Comparatively, CBD reduced anxiety and produced thin bold signals in the amygdala and the anterior and posterior cingulate cortex. The differences between these two compounds in cannabis are noteworthy. CBD has been shown to reduce anxiety, while THC can cause an increase in one’s anxieties.
Another psychiatric illness that has seen positive outcomes in cannabinoid treatments is Posttraumatic Stress Disorder (PTSD). The symptoms of PTSD include nightmares, flashbacks, problems falling asleep or staying asleep, and negative changes in mood and thoughts. The current issue is that the recommended treatment methods have proven to inefficient.
Certain areas of the brain, such as the hippocampus and amygdala, are thought to be involved in the cause of PTSD. These are also areas in which the ECS interacts with. Some animal model studies have already inferred to treating PTSD with cannabinoids. There have also been several studies that help solidify this conclusion.
Nabilone, a synthetic cannabinoid, has most commonly been used to study treating PTSD with cannabis. Three studies discussed all resulted in positive outcomes for the patients, except for some adverse side effects. There a few individuals from one investigation that withdrew due to experiencing dizziness, headaches, and forgetfulness. Beyond that, all three studies showed that treating individuals suffering from PTSD with nabilone helped significantly reduce or completely eliminate the symptoms of this psychiatric illness. Beyond relief of symptoms, nabilone also led to an increase in overall well being.
The final psychiatric disorder to discuss is attention-deficit hyperactivity disorder (ADHD). ADHD has recently gained a spotlight in the world of science. ADHD impairs attention and proper functioning in patients. These symptoms cause serious impairments in one’s life. Currently, stimulants are prescribed to individuals with ADHD. However, stimulants’ safety is in question. Stimulant drugs can lead to unwanted psychological effects and long-term use causes a build in tolerance.
There has yet to be research studies directly in patients diagnosed with ADHD, but other findings have concluded the ECS’s effect on an individual’s executive functioning. A study examined the use of THC and how it affected one’s ability to perform continuous tasks, along with brain imaging by fMRI to confirm conclusions. The study concluded that the subjects dispensed THC had impaired performance compared to the placebo. The fMRI images confirmed that the ECS affected areas associated with executive function, specifically by exciting the activity within the default mode network (DMN).
Although this particular trial used healthy individuals, it is important to note that patients with ADHD suffer from the weakened ability to suppress the activity within the DMN. This study is mostly important because it demonstrated the effect THC has on the ECS in a sense of concentration and focus. Therefor, for future research investigations the amount of THC or type of cannabinoid being studied should be highly controlled.
Many of the research studies discussed in this paper are of small sample size, and therefor further research is required. In the future, research designs should be repetitive and of larger sample sizes to reduce any limitations or biases. Never the less, there is much promising research that supports the use of cannabinoids in treating specific psychiatric illnesses. Furthermore, the different affects of THC and CBD have been documented. This is important because as we progress, research will become more definite as the appropriate cannabinoid will be directly studied.
Some considerations for the future would be how certain cannabinoids, such as CBD, affect the metabolic processes of other drugs an individual may consume. Long-term effects of using cannabis as medicine also needs more attention, along with the investigating the most efficient and healthy method of consuming the cannabinoid.
The future is promising for medicinal cannabis, especially in the treatment of psychiatric disorders that have such poor remission rates. A large majority of the general population suffers from some type of psychiatric illness or disorder. You most likely know a handful of people that fall in this category, maybe even yourself. Mental health is easily forgotten about by individuals whom are not affected it, but it is just as important, if not more important than physical health. It is imperative that pros and cons of medicinal cannabis are not weighed lightly, as it puts many in jeopardy of achieving remission and relief of symptoms.
Katzman, M. A., Furtado, M., & Anand, L. (2016). Targeting the Endocannabinoid System in Psychiatric Illness, 36(6), 691–703. https://doi.org/10.1097/JCP.0000000000000581