Cannabinoids and Posttraumatic Stress Disorder

Cameron C, Watson D, Robinson J. Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J Clin Psychopharmacol. 2014;34(5):559-564. 

Retrospective study of prison inmates with serious mental illness who were prescribed the synthetic cannabinoid nabilone 

The 104 male participants whose records were evaluated in this study were all residents of the St Lawrence Valley Correctional and Treatment Center, Brockville, Ontario, a hybrid mental health and correctional center with a mandate to treat seriously mentally ill adult male offenders. Patients routinely undergo comprehensive psychiatric assessments that include screening for posttraumatic stress disorder (PTSD), sleep disruption, nightmares, and alcohol and substance abuse. Weekly psychiatric sessions during their stay monitor these symptoms. Mean age was 32.7 years. Subjects were diagnosed using The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (revised text), and were found to have a mean of 4.1 Axis I disorders including 95.2% with anxiety disorders comorbid with either alcohol or substance abuse disorders and 12.5% comorbid with psychotic disorders. Subjects were also found to have a mean of 1.3 Axis II disorders, including 75% with antisocial personality disorder and 19.2% with borderline personality disorder.

Nabilone had been used at this treatment facility off-label for treating PTSD for the previous 5 years at the time of the study. No other cannabinoids were used as they were not covered by the Provincial Health Plan (government healthcare plan in Canada). Nabilone does not test positive on urine drug screens while other cannabinoids do. 

 

Nabilone was dosed as powder in water. Mean starting dose was 1.4 mg per day, and the final dose was 4.0 mg per day. Mean length of use was 11.2 weeks for a total of 122.9 weeks of nabilone use for the entire group analyzed. The mean number of indications was 3.5 per patient with the most common being insomnia (97%), nightmares (90%), and chronic pain (65%). None of the patients received nabilone for its on-label indication of chemotherapy-induced nausea.

Pretreatment and posttreatment sleep hours per night, nights with nightmares per week, Posttraumatic Checklist-Civilian Version (PCL-C), and Gobal Assessment of Functioning (GAF)

All pretreatment vs posttreatment measures indicated significant improvement. All subjects reported a significant increase in average number of hours slept, from a mean of 5 hours before and 7 hours after nabilone treatment. Ninety of the subjects reported a significant reduction of nights they had nightmares per week from 5.2 nights to a mean of 0.9 nights. These improvements were typically seen in the initial 1 week to 2 weeks of treatment and were maintained for the balance of the trial. PCL-C scores decreased significantly (n=58) from 54.7 to 38.8 posttreatment, and GAF scores (n=103) increased significantly from serious to moderate impairments in functioning from 45 to 58.2 posttreatment. Of the 68 inmates taking nabilone for chronic pain, 89.6% reported subjective improvement in pain, again typically in the initial 1 week to 2 weeks of treatment, and this was again maintained through the trial. An average of 0.87 other medications were stopped per patient during the course of the trial—90 medications in total—as these other medications were found to be of limited efficacy and deemed to pose greater risk than benefit. The most frequently discontinued medications were antipsychotics and sedative hypnotics.

The findings in this current study are consistent with earlier reports that nabilone is a promising agent in the treatment of PTSD insomnia and nightmares. Nabilone is a synthetic cannabinoid (CB)1 receptor agonist and has been approved for use in Canada for treating chemotherapy-induced nausea since 1982 and in the United States since 1985. It mimics the main psychoactive compound found in cannabis, tetrahydrocannabinol (THC).

 

As a rule, every paper on the medical use of cannabis appears obligated to point out that CB1 receptors, though widely distributed and abundant in the brain, are absent in the cardiorespiratory areas of the brain stem. While agents that act on these receptors may have a wide range of action on brain function, they do not cause cardiorespiratory suppression. As a result, these cannabinoid agonist drugs have relatively high lethal doses, in the range of 1 g per kg body weight for mice and dogs over extended periods of administration.¹

When a person in danger, it is normal to be afraid; these emotions trigger physiological changes in the body to prepare for defense or avoidance—what is commonly called a “fight or flight” response. Somehow in PTSD, this reaction mutates over time, so the emotional and physical components persist when there is no lethal threat. The pathogenesis of PTSD is not due to anxiety (although this is a common symptom) but rather to actual changes in memory processing.^2,3

 

In PTSD sufferers, the memories of “strong” experiences are well consolidated, retrieved frequently into conscious thought, and do not become weaker or disappear over time. To some degree, such strong memories might provide evolutionary advantage: not forgetting where danger lurks may prevent one from stumbling into harm’s way again. In PTSD, however, this process doesn’t work properly. Somehow, a useful mechanism breaks and become maladaptive. 

  

Three kinds of symptoms are necessary for a diagnosis of PTSD:

 

The word persistent is key: The response to trauma persists and doesn’t go away over time as it does in most people.

 

Frequent and excessive retrieval of traumatic memories consolidates and cements them, so they remain and grow in vividness, evoking distress throughout the lifetime.⁵ In PTSD, all 3 phases of memory—consolidation, retrieval, and extinction—malfunction.

 

PTSD is difficult to treat. Although PTSD patients are often generously prescribed a selection of pharmaceutical agents including selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, benzodiazepines, and antipsychotics,⁶ many patients fail to respond adequately to treatment.⁷ Most naturopathic doctors will be quick to point out that these drugs do not actually treat the causes of PTSD, that they merely attempt to limit the symptoms. That may be true, but it is important to remember that these drugs often don’t even treat the symptoms adequately.

 

A more effective target of treatment would be to block the pathology related to the consolidation and retrieval of memories of the initial trauma while encouraging the extinction of those initial memories. Thus recent reports that cannabinoids might be useful in treating PTSD are of particular interest as they may potentially treat the maladaptive memory function that characterizes PTSD. 

 

The cannabinoid system was discovered by chemists Yechiel Gaoni and Raphael Mechoulam in 1964 after they had isolated the active ingredient in marijuana, THC. Obviously, the brain did not evolve just to have cannabis-derived chemicals influence its function. Gaoni and Mechoulam identified the receptors in the brain that THC binds to and then discovered that THC mimics the action of an endogenous chemical that they named anandamide. The chemicals that bind to these receptors and the system that they modulate are all named after the plant that led the way to their discovery, cannabis.

 

Both THC and anandamide, our endogenous hormone, bind to cannabinoid receptors and act in the brain via retrograde action. Endogenous cannabinoids are released from postsynaptic cells and travel backward or upstream to the presynaptic cell binding onto CB1 receptors and inhibiting the release of many excitatory and inhibitory neurotransmitters. THC acts on the brain by influencing the intrinsic neuronal signaling system, mimicking anandamide, the natural player, and basically hijacking the system. Since this whole system was discovered via research on cannabis and because it was these exogenous cannabinoids that led to this system being discovered, the system of regulatory pathways are referred to as the “endogenous cannabinoid system,” or “endocannabinoid system” (ECS).

 

Bradley E. Alger, PhD, professor of physiology at the University of Maryland School of Medicine, Baltimore, described the ECS as 

 

Physiologically, the ECS works via 2 major cannabinoid binding sites referred to as CB1 and CB2. CB1 is the primary binding site in the central nervous system (CNS), though binding sites exist outside the CNS as well. CB2 binding sites are only found outside the CNS. The idea that nabilone, a synthetic THC that binds CB1 receptors in the brain, might play a role in treating PTSD makes sense as the ECS plays a major role in memory.

 

The roles of CB1 plays in learning and memory have been well documented via rodents in various memory tests; the ECS is required in the acquisition and/or extinction of memory. In particular, the activation of CB1 receptor-mediated signaling is centrally involved in the facilitation of behavioral adaptation after the acquisition of aversive memories.⁹ CB1 receptors must be activated in the extinction of fear that has been conditioned in a patient, which means these receptors are essential in emotional learning and memory on the neuronal level.¹⁰Given this understanding, targeting the ECS to treat PTSD makes sense.¹¹

 

Of course, we must acknowledge that the historical and legal issues surrounding recreational and medical cannabis use have made research on these chemicals somewhat controversial over the years, and advocates tend to be viewed with some suspicion. Even so, there are several intriguing publications that corroborate the findings of the study reviewed here.

 

Fraser reported nabilone useful in treating PTSD nightmares in a retrospective study in 2009. Adjunctive treatment with nabilone had been initiated in 47 patients with PTSD who experienced continuing nightmares despite conventional antidepressant treatment and were referred to a psychiatric specialist. Seventy-two percent of the patients receiving nabilone experienced cessation of nightmares or a significant reduction in nightmare intensity. Patients also reported subjective improvement in sleep time, quality of sleep, and reduction of daytime flashbacks.¹²

 

Knowing that endocannabinoids play a role in the stress response, are elevated during acute stress regulation, and also play a role in stressful memories, Hauer et al measured levels of these hormones in patients with PTSD,  reporting in May 2013 that PTSD was associated with distinct changes in plasma endocannabinoid hormones.¹³

 

Using sophisticated brain scans of people with PTSD, Neumeister et al (2013) reported that they could correctly identify PTSD patients from healthy controls merely by uncovering deficiencies of endogenous hormones, in particular anandamide, that should have bound onto the cannabinoid sites in the brain but hadn’t done so.¹⁴

 

Marijuana abuse has long been stereotyped as part of PTSD, and this idea has been reinforced by reports of a high comorbidity between cannabis abuse and PTSD. Kessler reported in 1995 that adults suffering from PTSD were 3 times more likely to have cannabis dependence compared to adults without PTSD.¹⁵ The more acute the PTSD symptoms, the more likely the patient is to use cannabis. The strongest motivating symptom for someone to turn to cannabis appears to be insomnia.¹⁶

 

Combat-exposed male veterans use marijuana in quantities that correlate directly to the magnitude of their PTSD symptoms and interestingly also to the degree they think marijuana will relieve their symptoms.¹⁷ Cannabis users are typically overloaded with anxiety, social phobias, PTSD, and more than their share of other concomitant mood disorders.¹⁸ In one study of military veterans suffering from PTSD who completed in-patient treatment programs, subsequent cannabis use was proportional to how little benefit the patients felt they received from their in-patient treatment.¹⁹

 

This concomitant use of marijuana by those suffering from PTSD is often described as another negative aspect of their condition, part of the long-term consequences of PTSD. This current study by Cameron, Watson, and Robinson reveals another posibility—that PTSD patients may simply be self-medicating with a treatment that is actually uniquely effective for their condition. It is not that cannabis abuse leads to PTSD; it may be that sufferers of PTSD find enough relief using cannabis that they seek it out.