Vol. 8, Number 1
cheryl riley, James Freire,
Dr. David Bearman,
Gradi Jordan, Ed Glick,
Paul Armentano, Keith Stroup
Sunil K Aggarwal,
Al Byrne, Amanda Reiman,
Jim Greig, Chip Whitley,
Sandee Burbank, Joan Bello
Dr. Ethan Russo, Bryan Krumm
AAMC Rhode Island
Cannabis for posttraumatic stress disorder: A neurobiological approach to treatment - Bryan Krumm, RN
Abstract: The endocannabinoid system is intricately involved in regulation of the neurobiological processes, which underlie the symptomatology of posttraumatic stress disorder (PTSD). This article discusses the neurobiological underpinnings of PTSD and the use of cannabis for treating PTSD in the New Mexico Medical Cannabis Program.
Article: The State of New Mexico has approved posttraumatic stress disorder (PTSD) as an indication for its Medical Cannabis Program, and patients with PTSD currently comprise the largest segment of any approved indication.
Cannabis remains in Schedule I of the Controlled Substances Act (CSA) in the United States, making it illegal to use under federal law. In the case of Krumm vs. Holder, the Drug Enforcement Administration argued that they did not need to defer to state laws regarding scheduling decisions for controlled substances. Due to the federal prohibition against cannabis, research looking into its therapeutic value has faced significant barriers, rendering it nearly impossible to conduct controlled clinical trials of cannabis in treating PTSD. However, the U.S. Supreme Court has upheld that practitioners have a right to recommend cannabis to patients when it is deemed appropriate.
PTSD can occur when a patient is exposed to one or more traumatic events leading to the development of characteristic symptoms following exposure. Patients may exhibit fear-based re-experiencing with emotional and behavioral symptoms. Others may present with anhedonic or dysphoric states and negative cognition. Patients may exhibit arousal and reactive-externalizing, while others may exhibit dissociative symptoms. Some individuals may have combinations of symptom patterns. PTSD is considered the fourth most common psychiatric disorder, affecting 10% of all men and 18% of women, with rates approximately 40% in high-trauma populations, such as soldiers in combat, low-income individuals, and those living in inner cities. PTSD often occurs comorbidly with other psychiatric disorders.4 Originally, PTSD was considered a normative response, related primarily to stressor intensity, but individual response to trauma depends on stressor characteristics as well as neurobiological factors.
The endocannabinoid system appears to be involved in the extinction of aversive memories, and patients with PTSD claim that cannabis use helps alleviate their symptoms. Cannabinoids stimulate receptors in the prefrontal cortex, amygdala, and hippocampus, activating signaling pathways, which appear to inhibit anxiety. Alterations in the endocannabinoid system are seen in depression, including changes in levels of cannabinoid 1 (CB1) receptors and endogenous CB1 receptor ligands. Stimulation of cannabinoid receptors enhances stress-coping behaviors and increases spontaneous firing of serotonergic and noradrenergic neurons in the midbrain.9 Phytocannabinoids, including delta 9 tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabichromene exert antidepressant-like actions and may be useful in the treatment of mood disorders.
High rates of suicidal behavior have been found among patients with PTSD. It appears that sensitization of CB1-receptor-mediated G-protein signaling in the prefrontal cortex contributes to the pathophysiology of suicide and likely contributes to suicidal behavior. The role of the endocannabinoid system in the pathophysiology of PTSD suggests that cannabinoids may be an effective modality to treat both PTSD and suicidal behavior in patients with PTSD. Many patients in New Mexico's Medical Cannabis Program for PTSD have reported reductions in frequency and severity of suicidal thoughts at Medical Advisory Board meetings. Some reported complete cessation of suicidality.
The military is currently facing an epidemic of suicide, and the U.S. Department of Veterans Affairs has called on all mental health and substance abuse healthcare providers to share responsibility for zero tolerance regarding suicide. An estimated 22 veterans die via suicide daily, accounting for at least 22.2% of all reported suicides. There were also 349 suicides among active duty troops in 2012, accounting for more deaths than by enemy fire. Developing new treatment modalities for PTSD is critical given the number of returning veterans who require psychiatric help and are at high risk for suicide.
Raphael Mechoulam, PhD, perhaps the world's leading authority on cannabinoids and the endocannabinoid system, points out the following:
The neurobiological basis of PTSD
After exposure to a traumatic event, patients may experience recurring memories of the event, including distressing dreams, dissociative reactions/flashbacks, or increased stress responses to external cues and physiological reactions to external cues resembling aspects of the traumatic event. They try to avoid distressing memories or external reminders of the event. They experience negative changes in mood and cognition associated with the event in addition to marked alterations in arousal and reactivity, beginning or worsening after the traumatic event. These disturbances continue for over 1 month and cause significant disturbances in social, occupational, or other important areas of function. These disturbances cannot be attributable to the physiological effects of substances or other medical conditions.
The broad range of symptoms seen in PTSD have made treatment challenging. PTSD involves central neurotransmitter imbalances and neuroanatomical disruptions, with potential dysregulation of immune, autonomic, endocrine, and cardiovascular function. Recent neuroimaging studies have helped elucidate the underlying neurobiological processes involved in the symptomatology of PTSD as well as the role of the endocannabinoid system in managing these neurobiological pathways. CB1 receptor availability is upregulated in an amygdala-hippocampal-cortico-striatal neural circuit implicated in PTSD and in brain regions outside this circuit. This may result from a combination of both receptor upregulation and low receptor occupancy by anandamide, an endogenous cannabioid. This suggests that abnormal CB1 receptor-mediated anandamide signaling is implicated in the PTSD etiology.
PTSD is associated with amygdala dysfunction, the anterior cingulate cortex (ACC), the medial prefrontal cortex (mPFC), and the hippocampus. Structural impairments include decreased hippocampal volume and decreased ACC volume. Dysregulation in threat-related processing in response to trauma exposure leads to a cascade of neural changes, causing a state of amygdala hyperresponsivity, which triggers hyperarousal and vigilance. Inadequate top-down control by the mPFC and ACC perpetuates the state of amygdala hyperresponsivity, increasing attention to trauma-related stimuli.
The hypothalamic-pituitary-adrenal (HPA) axis coordinates neuroendocrine stress response systems and has been a major focus of scrutiny in patients with PTSD. Exposure to stress triggers neurons in the hypothalamic paraventricular nucleus to secrete a corticotropin-releasing hormone, which stimulates the production and release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal cortex, which modulate metabolism, immune function, and brain function to manage stressors. Sustained glucocorticoid exposure leads to reduced dendritic branching, loss of dendritic spines, and impaired neurogenesis of the hippocampus.
Role of the endocannabinoid system in PTSD
THC has a significant and selective impact on amygdala reactivity to threat signals in humans. Endocannabinoids are crucial for the extinction of aversive memories. Activation of CB1 receptors in the amygdala blocks reconsolidation of aversive memories, which suggests that cannabinoids might help patients with PTSD prevent relapse after a stressful experience.
The endocannabinoid system plays a significant role in the function of the prefrontal cortex. The PFC receives and modulates information processing throughout the brain and projects to subcortical arousal systems, regulating monoamine and cholinergic inputs. Activation of cannabinoid receptors in the mPFC enhances serotonin 5-hydroxytryptamine (5-HT) neurotransmission, eliciting potent antidepressant effects. Disinhibition of excitatory projections from the mPFC to serotonergic neurons in the dorsal raphe may underlie antidepressant activity in the mPFC. The endocannabinoid system may be involved not only in the extinction of conditioned fear but also adaptation to aversive situations in general.
Cannabinoids have diverse effects on hippocampal memory and plasticity. The effects of cannabinoids on anxiety appear to be biphasic, with low doses being anxiolytic and high doses being ineffective or possibly anxiogenic. However, chronic high-dose cannabinoid treatment has been shown to induce hippocampal neurogenesis, which may contribute to the anxiolytic and antidepressant effects of cannabinoids. Modulation of hippocampal memory and plasticity by targeting the endocannabinoid system may aid in the treatment of impaired extinction-like processes seen in PTSD.
Endocannabinoid signaling negatively modulates function of the HPA axis. Short-term activation of the HPA axis is beneficial to survival; however, long-term activation can impact mood, cognition, and metabolism. Chronic activation of the HPA axis is associated with a variety of neuropsychiatric disorders.
Cannabinoids, through action on both limbic and paralimbic brain areas, reduce activity of the amygdala and hypothalamus. Retrograde endocannabinoid signaling in the hypothalamus is responsible for regulating HPA output. Acute administration of exogenous cannabinoid ligands also activates the HPA axis indirectly through an increase in serotonergic and noradrenergic neurotransmission. Chronic exposure to desipramine (and perhaps other antidepressants and therapies) has been shown to upregulate the endocannabinoid system, which, in turn, dampens the stress axis in a manner similar to habituation. Endogenous cannabinoid signaling is essential for stress adaptation and is fundamental to the intrinsic regulation of the HPA axis.
Because PTSD is often difficult to treat with a single medication, it is common to see the use of “drug cocktails,” which may cause significant adverse reactions. This may include treatment with combinations of antidepressants, antipsychotics, benzodiazepines, anticonvulsants, sedative/hypnotics, and antihypertensives. Cannabis may address symptoms across all 3 major symptom clusters in PTSD with few clinically significant adverse reactions.
A review by Grant and colleagues found that inhaled cannabis is a rapid and efficient method of delivery for THC, allowing for self-titration of medication. Although cannabis may cause dizziness, anxiety, paranoia, dry mouth, fatigue, or weakness, tolerance to adverse reactions develops rapidly. There are no reports of fatal overdose with cannabis, and long-term use is not associated with increased risk of lung or gastrointestinal cancers. There is little evidence of important CYP 450 system drug-drug interactions, and the acute medical risks of THC as used in clinical trials are low.
Inhaled cannabis is generally well tolerated and has been shown to reduce the pain intensity, decrease anxiety, and improve sleep. Cannabinoids may reduce or entirely eliminate nightmares; patients using cannabinoids report improvement in sleep time, quality of sleep, and reduction of daytime flashbacks and night sweats.
Alcohol abuse has been significantly linked to PTSD, and cannabis has been shown to act as a substitute for alcohol. Many patients with PTSD struggle with alcohol abuse, often in an attempt to self-medicate. The majority of these patients referred to the Medical Cannabis Program, who have co-occurring alcohol abuse issues, have reported significantly decreased use, and in many cases, complete cessation of alcohol. A patient survey conducted by Berkeley Patient's Group, a medical cannabis dispensary in Berkeley, CA, found that 65% of those surveyed reported using cannabis as a substitute because it has less adverse reactions than alcohol and illicit or prescription drugs.
Cannabinoids have been shown to reduce aggressive behavior, which has important implications in PTSD. Patients commonly report significant reductions in irritability and anger. Patients are often accompanied by family members, friends, and/or treatment team members who confirm reductions in aggressive behavior.
Many patients with PTSD have co-occurring psychotic disorders. Although use of cannabis in patients with schizophrenia has typically been reported to worsen psychosis, increases in population cannabis use have not been followed by increases in psychotic incidence. THC has been shown to improve symptoms in treatment-refractory patients with schizophrenia, including reduction in core psychotic symptoms, with no clinically significant adverse effects. When compared to non-using patients, patients with schizophrenia who use cannabis and patients with a history of cannabis at first episode of psychosis have superior neuropsychological functioning. Medical cannabis patients with co-occurring psychotic disorders often report reductions in both positive and negative symptoms of schizophrenia, which have failed to resolve with traditional antipsychotic medications, consistent with the findings of Schwarcz and colleagues.
Strains of cannabis-containing CBD in addition to THC may prevent the psychotic-like symptoms sometimes caused by strains with high levels of THC but a lack of CBD. Cannabis of the sativa and ruderalis biotypes typically contain higher levels of CBD and lower levels of THC, while indica biotypes tend to have higher levels of THC and more variable levels of CBD. Unfortunately, finding consistent access to CBD-rich strains is difficult for many patients, and finding the best strain for any individual is largely a matter of trial and error.
A comprehensive study of 4 legal, medical cannabis patients in the federal Investigational New Drug Program found only mild changes in pulmonary function associated with long-term, heavy use. No functionally significant adverse effects were noted in any other physiologic system examined in the study. Although changes in pulmonary function can be seen with chronic high use of cannabis, occasional and low cumulative marijuana use of up to 1 joint a day for 7 years is not associated with adverse effects on pulmonary function.
New Mexico incorporated a definition of “practitioner” that allows advanced practice nurses with prescriptive authority to refer patients to the Medical Cannabis Program. Unfortunately, most states with medical cannabis programs do not allow advanced practice nurses to refer patients. Many providers are not able to refer patients to medical cannabis programs due to institutional regulations. Some providers may have concerns about potential adverse reactions reported with cannabis. However, for those who are able and willing to refer patients to medical cannabis programs, these programs offer a unique opportunity to investigate the safety and efficacy of cannabis while providing relief from pain and suffering.
Marijuana as medicine
Cannabis is effective in treating PTSD, even when there are other co-occurring psychiatric and/or medical disorders. The broad range of therapeutic effects seen in treating PTSD with cannabis suggests that it may be beneficial in treating other disorders as well. Rather than targeting neurotransmitter systems and their agonists, cannabinoids target the underlying neurobiological processes that lead to imbalances in these neurotransmitter systems, helping to return them to a state of homeostasis.
As with any medication, caution must be used when recommending medical cannabis. Patients should be warned of potential risks, including the potential legal and occupational repercussions that can arise the use of cannabis. Some patients may experience increased levels of sedation, anxiety, or paranoia, and cannabis may induce psychosis in certain individuals. Many patients may opt to use cannabis in spite of these risks.
“Based on evidence currently available, the Schedule I classification is not tenable; it is not accurate that cannabis has no medical value or that information on safety is lacking.” (Medical marijuana: clearing away the smoke). Healthcare providers have an obligation to provide the best possible care based on the best available scientific evidence. Until cannabis is removed from Schedule I of the federal CSA, the barriers to controlled clinical trials of cannabis in treating PTSD and other medical conditions will remain.
The Cannabis sativa Versus Cannabis indica Debate - Daniele Piomelli Interviews Ethan Russo, MD
Cannabis and Cannabinoid Research (Dr. Daniele Piomelli: CCR): I would like to start with a few questions that should not be too contentious. First off, what is the geographic origin of the Cannabis plant?
Dr. Russo: Cannabis originated in Central Asia and perhaps the Himalayan foothills. There are converging lines of evidence, including a center of biological diversity there, and biochemical data that support this. There is no trace of its presence in the Western Hemisphere before the 16th century.
CCR: What chemical(s) are the major contributors to the psychoactive effects of Cannabis? D9- tetrahydrocannabinol, cannabidiol, or others?
Dr. Russo: D9-tetrahydrocannabinol is, of course, the pre-eminent psychoactive component of Cannabis. D8-tetrahydrocannabinol, a more heat-stable component, is probably slightly less psychoactive, but is present only in trace amounts or as an artifact of laboratory analysis. Cannabinol is the nonenzymatic oxidative breakdown product of tetrahydrocannabinol (THC), seen in aged Cannabis, and is about 25% of the potency of THC. Tetrahydrocannabivarin (THCV) is a neutral antagonist at CB1 at low doses, but an agonist at high doses, and is certainly psychoactive, but rarely seen in high titer in commonly available Cannabis strains. Finally, although cannabidiol (CBD) is nonintoxicating, it certainly has antianxiety, antipsychotic, and even antidepressant effects, so properly they must be considered psychoactive with these qualifications.
CCR: What about other medicinal properties of the plant? For example, the local anti-inflammatory actions extolled by some ancient writers?
Dr. Russo: CBD is a versatile anti-inflammatory analgesic through numerous distinct mechanisms, and various other minor cannabinoids and terpenoids in Cannabis certainly may contribute notably to the therapeutic profile of Cannabis. Numerous basic science and even clinical trial data support the concept of herbal synergy in Cannabis beyond the effects of single components. We are only seeing the very beginnings of the therapeutic potential of this plant!
CCR: Can you explain what is meant by entourage effect as it pertains to Cannabis?
Dr. Russo: This concept was first espoused by Drs. Mechoulam and Ben-Shabat more than 15 years ago to explain how certain components of the endocannabinoid system boost the therapeutic effects of its main players, anandamide and 2-arachidonylglycerol. Thus, it is akin to a symphony, in whichmanymusicians support and harmonize the melody provided by the soloists. The same analogy fits well the synergistic phenomena observed in Cannabis, whose various components boost and compliment those of its better known ones, THC and CBD.
CCR: People have been selecting Cannabis strains for quite some time now. One would expect human selection to have substantial effects on Cannabis’ psychoactive and medicinal properties. Is this true?
Dr. Russo: Absolutely! While there have always been very potent Cannabis strains to be found, they are certainly more commonly available today due to selective breeding and culture techniques that produce ganja, or sinsemilla, that is, unfertilized female flowers. The plant puts all its energy into production of cannabinoids and Cannabis terpenoids instead of producing seeds. Unfortunately, until recently, almost all the effort in breeding has been toward higher potency THC strains rather than on the safer and arguably much more therapeutically versatile mixed or CBD predominant strains. Selective breeding for medicinal efficacy is a relatively new phenomenon that is now accelerating.
CCR: Now, moving onto something more controversial. Here is a statement one can find on the Web: ‘‘It is widely accepted that marijuana has two different species: Cannabis indica and Cannabis sativa.’’ This was of course also the opinion of the great 18th century naturalist, Jean-Baptiste Lamarck, but would academic botanists today agree with this statement?
Dr. Russo: Botanical taxonomists never agree on anything for very long! To paraphrase and expropriate an old Yiddish expression: 12 botanical taxonomists, 25 different opinions. Many classical botanists would argue for Cannabis as one polymorphic species based on the ability of all its types to interbreed. However, if this were true, hundreds of neotropical gesneriads (Gesneriaceae, members of the African violet family) would all be one species since they readily hybridize and produce fertile offspring. It is clear that there are many chemotypes of Cannabis: THC predominant, CBD predominant, and mixed types. This is a good basic classification, but it has also been possible to selectively breed for other chemotypes expressing high titers of THCV, cannabidivarin, cannabichromene, and even ones producing 100% of its cannabinoids as cannabigerol, or others with no cannabinoids at all. The debate continues. Some espouse Cannabis as a single species, while others describe up to four: Cannabis sativa, Cannabis indica, Cannabis ruderalis, and Cannabis afghanica (or kafiristanica).
CCR: Some users describe the psychoactive effects of Cannabis indica and sativa as being distinctive, even opposite. But are they really? Beyond self-reports from users, is there any hard evidence for pharmacologically different species of Cannabis?
Dr. Russo: There are biochemically distinct strains of Cannabis, but the sativa/indica distinction as commonly applied in the lay literature is total nonsense and an exercise in futility. One cannot in any way currently guess the biochemical content of a given Cannabis plant based on its height, branching, or leaf morphology. The degree of interbreeding/hybridization is such that only a biochemical assay tells a potential consumer or scientist what is really in the plant. It is essential that future commerce allows complete and accurate cannabinoid and terpenoid profiles to be available.
CCR: Sativa is often described as being uplifting and energetic, whereas indica as being relaxing and calming. Can you speculate on what could be the basis for these perceived differences?
Dr. Russo: We would all prefer simple nostrums to explain complex systems, but this is futile and even potentially dangerous in the context of a psychoactive drug such as Cannabis. Once again, it is necessary to quantify the biochemical components of a given Cannabis strain and correlate these with the observed effects in real patients. Beyond the increasing number of CBD predominant strains in recent years, almost all Cannabis on the market has been from high- THC strains. The differences in observed effects in Cannabis are then due to their terpenoid content, which is rarely assayed, let alone reported to potential consumers. The sedation of the so-called indica strains is falsely attributed to CBD content when, in fact, CBD is stimulating in low and moderate doses! Rather, sedation in most common Cannabis strains is attributable to their myrcene content, a monoterpene with a strongly sedative couch-lock effect that resembles a narcotic. In contrast, a high limonene content (common to citrus peels) will be uplifting on mood, while the presence of the relatively rare terpene in Cannabis, alpha-pinene, can effectively reduce or eliminate the short-term memory impairment classically induced by THC.
CCR: How do you think one could address the sativa/ indica dichotomy in a scientifically sound manner?
Dr. Russo: Since the taxonomists cannot agree, I would strongly encourage the scientific community, the press, and the public to abandon the sativa/indica nomenclature and rather insist that accurate biochemical assays on cannabinoid and terpenoid profiles be available for Cannabis in both the medical and recreational markets. Scientific accuracy and the public health demand no less than this.
CCR: Thank you, Dr. Russo. We all appreciate your insight into this controversial, complex, and very important topic.
Full article (with references)
Alabama: Considering a medical marijuana law.
Arkansas: Considering a medical marijuana law.
Idaho: Considering a medical marijuana law.
Indiana: Considering a medical marijuana law.
Iowa: Considering a medical marijuana law.
Missouri: Considering a medical marijuana law.
North Carolina: Considering a medical marijuana law.
Ohio: Medical marijuana law on November ballot.
Pennsylvania: Considering a medical marijuana law.
South Carolina: Considering a medical marijuana law.
South Dakota: Medical marijuana petition drive underway.
Tennessee: Considering a medical marijuana law.
Texas: Considering a medical marijuana law.
Wisconsin: Considering a medical marijuana law.
Featured Recipe - Marble Madness by Jay R. Cavanaugh, PhD
A Canny Bus Quick Treat
Some of the best things in life are so easy. Here’s a recipe that is ready in minutes and tastes just delightful. The only problem with this desert treat is the urge to eat more than is really good for you. The trick to this recipe is getting the consistency right. Whenever you use cannabutter in place of dairy butter the result will be that the product is more crumbly. For stand up firm cookies and cakes it is best to go to a 50/50 mixture of butters but Nancy Wife and I prefer straight cannabutter for potency. As usual, feel free to improvise and use what ratio is right for you.
Now, some believe that when your cake crumbles that the calories leak out and it’s less fattening. Of course, this is true. You eat this cake by using a fork to push down on the moist blond/green/chocolate crumbs sticking them to the back of the fork or you can use your fingers and lots of licking. We used a special cannabutter for this recipe (see Kicked Up Better Bud Butter).
A word of caution about this cake you’re about to make: Don’t leave it out for the kids! They will eat it and you will be in trouble!
¾ cups of Kicked Up Better Bud Butter
Melt the cannabutter in a sauce pan over low heat and pour it into a bowl containing the sugar and stir to mix. Beat in the eggs and vanilla and the liqueur of your choice.
Use a double boiler to melt your chocolate chips. Stir often. This step is what gives you the “marble” effect. If you’re lazy (and I am) you can just add the chips to the final batter.
In another bowl sift the dry ingredients together then mix with the wet ingredients then drizzle in the chocolate forming swirls or just mix in chips (some of you may prefer butterscotch chips or even white chocolate).
Place the batter in a baking pan that has been lightly oiled and floured. Bake at 325 degrees (I know that’s low) for about 20-40 minutes. You can tell when the cake is done by sticking a toothpick in the cake. When the toothpick comes out relatively clean, the cake is ready. Remove from the oven and let the cake cool for a bit before attempting to remove from the pan. The cake is going to be crumbly so it’s tough to cut out nice squares but we don’t mind J
Recommended Beverage: 20 year old Tawny Port served room temperature or Hennessy VSOP Cognac served slightly warmed.
Recommended Activities: Getting a good nights sleep
May 21-23, 2015
West Palm Beach, Florida USA
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