CRx MAGAZINE

Spring 2020

Calming Anxiety With Cannabis

Cannabis can be a first-line and adjunct therapy in personalized anxiety plans.

According to the Anxiety and Depression Association of America, anxiety disorders are the most common mental illnesses in the United States, affecting 40 million Americans age 18 and older—or 18.1% of the population—every year. Although anxiety disorders are considered highly treatable, survey data show that only about 37% of people suffering receive treatment.1 This may be due to misdiagnosed or undiagnosed anxiety, lack of access to health care services, or an aversion to conventional treatments.

The medical use of cannabis in the treatment of anxiety disorders has captured the interest of researchers, health care professionals, and patients alike, and research suggests that cannabis may bring relief to many patients. As more states legalize cannabis for medical purposes and other states revisit their medical use policies, anxiety increasingly is at the top of their lists of approved conditions. That’s been made possible thanks to research into the endocannabinoid system (ECS) and its role in homeostasis. While there aren’t prescriptive recommendations for dosage or timing, clinicians are using cannabis as both a first-line and adjunct therapy in successful personalized anxiety management plans.

Anxiety
Anxiety is both an emotional and a physiological reaction to perceived danger. It’s characterized by a continuum of feelings from general unease to panic, as well as a continuum of physical responses from increased heart rate to running from a threat. Anxiety is considered pathological when the emotional response is disproportionate in duration, frequency, or intensity to the cause and interferes with a person’s ability to live a normal life.2 The ICD-10 definition of generalized anxiety disorder (GAD) (code F41.1) begins with “a condition marked by excessive worry and feelings of fear, dread, and uneasiness that last six months or longer.”3 However, talk to anyone experiencing anxiety and they will tell you it’s not that simple. Anxiety symptoms vary from person to person and can be episodic or chronic. If left untreated, anxiety can interrupt daily life with physical illness symptoms such as abdominal pain and headaches, as well as emotional responses such as not being able to get out of bed in the morning or limiting social interactions.

Anxiety Symptoms
Anxiety disorders fall into a number of diagnostic categories: GAD, panic disorder, social anxiety disorder (SAD), specific phobias, obsessive-compulsive disorder, posttraumatic stress disorder (PTSD), major depressive disorder, and persistent depressive disorder. Regardless of the specific diagnosis, the mental and physical symptoms are similar, yet they vary vastly in intensity and duration and can involve every system in the body.

Nervous System: When the brain perceives a threat, however minor, the brain releases adrenaline, cortisol, and other neurotransmitters to help the body respond. Constant exposure to these chemicals can cause a sense of unease or doom, difficulty concentrating, and panic attacks. Long-term exposure to these hormones and neurotransmitters due to anxious feelings is linked to other physical health problems such as weight gain, depression, and suicide.

Respiratory System: Hormones released into the body due to anxiety can cause rapid, shallow breathing, especially during a panic attack.

Circulatory System: Heart palpitations are often associated with panic attacks but can also occur with general anxiety and may feel more like a vibration in the chest. Blood pressure may increase when anxiety flares up. If not treated, it can result in hypertension.

Immune System: The constant release of stress hormones into the body can weaken the immune system, which increases the risk for viral and bacterial infections and may result in frequent illnesses.

Gastrointestinal System: The role of the brain-gut connection is very apparent in anxiety disorders, as stomach pains, nausea, and diarrhea are often the first signs of long-term generalized anxiety. While historically it was thought that irritable bowel syndrome (IBS) was a symptom of anxiety, experts now agree that IBS has pathophysiology of its own; however, people with IBS frequently suffer from anxiety, which worsens gut symptoms.

Musculoskeletal System: Anxiety may be linked to otherwise unexplainable aches and pains in muscles and joints.

Treatment Options for Anxiety
If left untreated, anxiety can disrupt daily life by making it difficult to concentrate, fulfill job or school responsibilities, complete daily tasks, and establish or maintain personal relationships. For some people, anxiety may make it difficult to leave home or get out of bed. Untreated anxiety has also been linked to more severe conditions such as depression, suicide, and substance abuse and may manifest as physical illness.

There are a range of treatment options for anxiety disorders that may be chosen based on symptoms and severity. The most standard approaches that have proved effective are medication (discussed in-depth below), therapy, complementary and alternative medicine, and transcranial magnetic stimulation (TMS). While therapy is considered the most effective treatment for anxiety disorders, doctors often prescribe antidepressants or antianxiety medications in conjunction with therapy or other complementary treatment. When determining a treatment plan, it’s important to consider all available modalities, including cannabis.

Therapy
The most common and effective form of therapy for anxiety is cognitive behavioral therapy, which focuses on identifying, understanding, and changing thinking and behavior patterns.1 Therapy of any type requires the patient to be actively involved in learning the skills necessary to control anxiety. While therapy traditionally involves in-person sessions with a therapist, advances in technology allow patients to interact with therapists by phone, video call, or even text message.

Complementary & Alternative Medicine
There’s growing scientific evidence that complementary and alternative medicine approaches may be useful in the treatment of anxiety symptoms.4 Some examples of these methods include meditation, yoga, and acupuncture.

TMS
TMS (also called repetitive TMS or rTMS) may be a safe, effective, and noninvasive option for people who have depression that has not improved with medication and other treatments. TMS creates a magnetic field to induce a small electric current in a specific part of the brain; the current comes from the magnetic field created by an electromagnetic coil that delivers pulses through the scalp. TMS is an FDA-approved treatment.1

Medication for the Treatment of Anxiety
Medications for anxiety disorders are generally considered safe and effective and, for short- or long-term treatment, may be used alone or in combination with other forms of treatment. For most patients, it takes patience and time to find the drug that works best for their symptoms. According to the 2009–2010 Medical Expenditure Panel Survey, more than 1 in 6 Americans take a psychiatric drug such as an antidepressant or a sedative.5 It’s helpful to understand the mechanism of action of these medications in order to understand how cannabis can affect the anxiety response. There are four major classes of medications used to treat anxiety disorders.

Selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline) relieve symptoms by blocking the reuptake of serotonin by certain nerve cells in the brain. Serotonin-norepinephrine reuptake inhibitors (SNRIs) (venlafaxine and duloxetine) have a dual mechanism of action. They increase the levels of neurotransmitters serotonin and norepinephrine and inhibit their reuptake into cells in the brain. Benzodiazepines (alprazolam, clonazepam, diazepam, and lorazepam) are used for short-term management of anxiety or as an add-on strategy for treatment-resistant anxiety disorders. They work by enhancing the effect of gamma-aminobutyric acid and thus have sedative, hypnotic, and anxiolytic (anxiety reducing) properties. Tricyclic antidepressants (amitriptyline, imipramine, and nortriptyline)—one of the oldest classes of antidepressant medications—increase levels of norepinephrine and serotonin and block the action of acetylcholine.1

Until recently, it was thought that there were very few things that could alter the release of neurotransmitters and stress hormones other than pharmaceuticals. However, in recent years, research into exercise and meditation have proved effective in reducing the stress response and/or the symptoms caused by systemic overload. More important, the discovery of the ECS elucidated new mechanisms by which the brain influences total body homeostasis.

The ECS and Anxiety
The ECS was discovered in 1992 at the Hebrew University in Jerusalem. It’s described as a signaling system made up of the cannabinoid receptors CB1 and CB2; their ligands, the endocannabinoids anandamide (N-arachidonoylethanolamide, or AEA) and 2-AG (2-arachidonoylglycerol); and associated transport proteins and degradative enzymes. The ECS performs multiple tasks, but its goal always is to maintain a stable environment despite fluctuations in the external environment.6 Research continues to support the involvement of the ECS in a variety of biological functions including energy expenditure, food intake, pain perception, inflammation, cognition, and stress responses such as anxiety. The high level of expression of CB1 receptors in the brain areas involved in the regulation of cognition and mood functions (amygdala, prefrontal cortex, and hippocampus) implies that the ECS is involved in emotional processing and mood and anxiety regulation, which means that dysregulation of the ECS may be an underlying cause of anxiety disorders.7

Both CB1 receptor agonists and inhibitors of AEA hydrolysis increase the firing activity of the specific neurons that are the major source of serotonin. Enhancing serotonin neurotransmission produces an anxiolyticlike effect.8,9 Similarly, stimulation of the CB1 receptor has been shown to increase firing activity of noradrenergic neurons and the release of norepinephrine in the prefrontal cortex.9,10 Thus, phytocannabinoids can influence regulation of the ECS to control anxiety, as do pharmaceuticals mentioned previously.

Specifically, CBD has been shown to decrease the activity of the enzyme that breaks down AEA; this results in more AEA present, thus enhanced serotonin activity, which produces anxiolyticlike effects. And THC has been shown to directly affect CB1 receptors, therefore stimulating the release of norepinephrine. In combination, CBD and THC act a bit like an SNRI used to treat anxiety and depression.

However, a biphasic effect of cannabis on anxiety has been demonstrated in animal models and observed in humans.11,12 In general, anxiolyticlike effects are produced after low doses of phytocannabinoids are consumed, while higher doses result in a heightened anxiety (anxiogenic) response.

The Biphasic Nature of Cannabis in the Treatment of Anxiety
The No. 1 reason people give for trying medical cannabis is to relax; however, anxiety is also reported as a common adverse effect of cannabis use in medical contexts, with panic attacks or paranoia being reported after high doses of THC consumption.13 When considering the ECS’s involvement in balancing a patient’s reaction to stimuli, it’s no surprise that cannabis may be both anxiogenic and anxiolytic. Generally, low doses induce anxiolyticlike effects, whereas high doses cause the opposite.14

Much of the research into the role of cannabinoids in anxiety treatment have been done with single molecule, synthetic cannabinoids such as nabilone (synthetic THC analog and CB1 agonist), which has been shown to be effective in the treatment of anxiety.15 The evidence suggests that the CB1 receptor is involved in the pathophysiology of anxiety, and its activation appears to be inversely correlated to symptoms of anxiety. Preclinical studies on GAD suggest that CBD possesses both anxiolytic and antipsychotic properties.16 High doses of CBD (100 mg/kg) were ineffective in relieving anxiety symptoms in animal models of GAD, while low doses (10 mg/kg) were found to have anxiolyticlike effects.17 While observational studies demonstrate the biphasic nature of cannabis in the treatment of anxiety, researchers agree that more work needs to be done to elucidate the mechanisms of action, which may be very complex.

CBD Oil for Anxiety
CBD oil has received a lot of attention recently as the nonintoxicating cannabinoid that can potentially alleviate myriad symptoms and conditions. Of those, anxiety is at the top of the list. In a survey of 2,000 American adults, the top three reasons given for trying CBD oil were relaxation, anxiety relief, and improved sleep.18 A small 2011 study found that CBD reduced symptoms of social anxiety in people with SAD. Brain scans of participants revealed changes in blood flow to the regions of the brain linked to feelings of anxiety. In this study, CBD not only made participants feel better but also changed the way their brains responded to anxiety.19 In 2015, a review of research published in the journal Neurotherapeutics concluded that CBD oil holds promise as a treatment for numerous forms of anxiety, including GAD.20 However, this review also identified dosing as a caveat to current treatment recommendations because most research has been done in acute administration; thus the impact of chronic CBD dosing needs further investigation before clinical recommendations can be established.

Practice Points for Clinicians
Like most topics in the clinical use of cannabis, more research is needed to determine population recommendations for CBD:THC ratio, dose, and timing for the treatment of anxiety disorders. That said, research is mounting to support the use of cannabis as a first-line and adjunct therapy for the treatment of anxiety. As with other conditions, the goal of anxiety therapy is the maximum reduction in symptoms with the minimum tolerable intoxicating effects. That means personalization is crucial.

There are three choices when considering products to treat anxiety: high CBD, 1:1 CBD:THC, and CBD only. Since cannabinoid analysis is not required in most states where cannabis is legal, these can be difficult to find in flower or whole plant products. That’s why practicing clinicians recommend tinctures and vape concentrates for the treatment of anxiety; these products generally come with clear labeling about what percentage of the product is CBD, THC, and other cannabinoids. They do not recommend edibles because first-pass liver metabolism changes the active metabolites in the body and titration of dose is difficult. Other concentrates, such as dabs, wax, and shatter, are also more difficult to titrate and generally deliver too much THC for anxiety treatment.

As a rule of thumb, clinicians start anxiety patients on low doses that deliver 2 to 20 mg of cannabinoids in one dose before bed and increase from there. For patients concerned about the intoxicatingeffect of THC, it’s appropriate to start with CBD only. As with any cannabis recommendations, it’s important for patients with anxiety to keep a detailed diary of dose, timing, symptom relief, and adverse effects. Taking note of higher levels of anxiety after dosing is especially important to determine the sweet spot for anxiety relief. Once effective night-time dosing has been established, considered the “sweet spot,” CBD can be used at that dose during the day to treat episodic and/or chronic anxiety symptoms.

Microdosing
Microdosing—a growing trend in cannabis use where less is more21—involves taking small amounts of cannabis for medical purposes to avoid the intoxicating effects of THC that may interfere with daily life. Microdosing is especially appealing to patients who want to treat anxiety disorders because of its limited intoxicating effect and the ability to treat anxiety in multiple small doses throughout the day. In a 2014 study, incarcerated individuals were given low (4 mg) doses of nabilone (synthetic THC and a CB1 agonist) to help treat their PTSD and anxiety symptoms. The results showed significant improvements in PTSD-associated insomnia, nightmares, general anxiety symptoms, and even chronic pain.22 Because cannabinoid metabolism varies greatly from person to person, it’s hard to give specific microdosing recommendations. Sublingual tinctures are the most recommended products for microdosing because the ratio of CBD to THC is well controlled and dosing is exact. Clinicians usually start patients on 2 to 2.5 mg 1:1 CBD:THC products for a few days and increase from there if necessary. For patients who prefer to inhale, one puff at a time is considered a microdose. While edibles can be split into microdoses, it’s not recommended because it’s difficult to get consistent CBD:THC throughout the product, and first-pass liver metabolism will change the cannabinoid metabolites in the body.

Conclusion
As more attention is paid to cannabis in the treatment of conditions such as anxiety disorders, it’s imperative that health care professionals learn the basics in order to confidently and accurately answer patient questions. If not, patients will turn to friends, the internet, and budtenders (some of whom may not be adequately educated) for recommendations and validation. Cannabis can be an effective first-line or adjunct treatment if used as part of a personalized care plan.

— Bonnie Johnson, MS, RDN, is a registered dietitian nutritionist, food industry consultant, speaker, and certified cannabis consultant. She spends much of her volunteer time educating a variety of audiences about the benefits and potential risks of using cannabis to treat chronic pain, anxiety, insomnia, and other ailments. As a consultant, she works with the food and cannabis industries to bring science-based education to health care professionals and category-changing products to market.

7 Misconceptions About Using Cannabis for Anxiety

1. Medical cannabis doesn’t produce a “high.” While the goal is maximum symptom relief with minimal intoxicating effect, too much THC will produce a “high” and may interfere with normal daily activities.
2. CBD alone is a helpful treatment. Pure CBD oil has been shown to be effective in the treatment of anxiety symptoms. However, THC is the phyto-equivalent of anandamide, which has the greatest affinity for CB1 receptors, therefore it significantly enhances serotonin neurotransmission.
3. High doses of cannabis aren’t harmful. If there’s one place where cannabis researchers agree, it’s on the biphasic nature of cannabinoids. Low doses produce anxiolyticlike effects, and high doses produce anxiogeniclike effects, including paranoia and psychotic episodes.
4. All natural is better than pharmaceuticals. Some patients think that cannabis is better than pharmaceuticals because it’s “natural.” However all forms of treatment should be considered in a personalized anxiety treatment plan.
5. Continuous use is necessary. The primary role of the endocannabinoid system (ECS) is balance. When there’s ECS dysfunction, cannabis can be a way to bring the body back into homeostasis. Once balance is reestablished, cannabis use may not be necessary.
6. Cannabis can’t make it worse. It’s critical to keep records of how cannabis reacts with your body and stop using it if symptoms get worse.
7. Clinicians aren’t necessary in the use of medical cannabis. Experienced health care professionals can provide education and guidance on how to use medical cannabis effectively. They also evaluate positive and adverse reactions and make further recommendations for successful use.


2-AG: 2-arachidonoylglycerol
AEA: Anandamide or N-arachidonoylethanolamide
Anxiogenic: Causing anxiety, stimulating feelings of anxiety
Anxiolytic: Controlling anxiety, reducing feelings of anxiety
ECS: Endocannabinoid system
GABA: Gamma-aminobutyric acid
GAD: Generalized anxiety disorder
IBS: Irritable bowel syndrome
MDD: Major depressive disorder
PDD: Persistent depressive disorder
PTSD: Posttraumatic stress disorder
SAD: Social anxiety disorder
SNRIs: Serotonin-norepinephrine reuptake inhibitors
SSRIs: Selective serotonin reuptake inhibitors
TMS: Transcranial magnetic stimulation

References

1. Facts & statistics. Anxiety and Depression Association of America website. https://adaa.org/about-adaa/press-room/facts-statistics. Accessed on July 31, 2019.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2018.

3. World Health Organization. International Classification of Diseases, 10th Revision. Geneva, Switzerland: WHO Press; 2019.

4. van der Watt G, Laugharne J, Janca A. Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry. 2008;21(1):37-42.

5. Shirneshan E, Bailey J, Relyea G, Franklin BE, Solomon DK, Brown LM. Incremental direct medical expenditures associated with anxiety disorders for the U.S. adult population: evidence from the Medical Expenditure Panel Survey. J Anxiety Disord. 2013;27(7):720-727.

6. Moore M. How the endocannabinoid system was discovered. Labroots website. https://www.labroots.com/trending/cannabis-sciences/8456/endocannabinoid-system-discovered. Published April 5, 2018. Accessed July 31, 2019.

7. Lutz B, Marsicano G, Maldonado R, Hillard C. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16(12):705-718.

8. Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci. 2007;27(43):11700-11711.

9. Gobbi G, Bambico FR, Mangieri R, et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci U S A. 2005;102(51):18620-18625.

10. Oropeza VC, Page ME, Van Bockstaele EJ. Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex. Brain Res. 2005;1046(1-2):45-54.

11. Hill MN, Gorzalka BB. The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurol Disord Drug Targets. 2009;8(6):451-458.

12. Lafenêtre P, Chaouloff F, Marsicano G. The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction. Phamacol Res. 2007;56(5):367-381.

13. Hall W, Solowij N. Adverse effects of cannabis. Lancet. 1998;352(9140):1611-1616.

14. Kamal BS, Kamal F, Lantela DE. Cannabis and the anxiety of fragmentation — a systems approach for finding an anxiolytic cannabis chemotype. Front Neurosci. 2018;12:730.

15. Fabre LF, McLendon D. The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety. J Clin Pharmacol. 1981;21(S1):377S-382S.

16. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl). 1990;100(4):558-559.

17. Silveira Filho NG, Tufik S. Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behavior. Res Commun Psychol Psychiatr Behav. 1981;6(3):251-266.

18. Kopf D, Avins J. New data show Americans are turning to CBD as a cure-all for the modern condition. Quartz website. https://qz.com/1590765/survey-shows-americans-use-cbd-to-treat-anxiety-and-stress/. Published April 15, 2019. Accessed July 31, 2019.

19. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121-130.

20. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015;12(4):825-836.

21. Hoffman A. Microdosing cannabis: benefits without the buzz. Leafly website. https://www.leafly.com/news/cannabis-101/microdosing-weed-guide. Published May 25, 2017. Accessed July 31, 2019.

22. 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.

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