Building Emotional Resilience:The Emerging Role of

Cannabinoids for Mental Health & Emotional Pain

Dr. Reef KarimBoard Certified Psychiatrist; Board Certified Addiction Medicine Physician International Speaker, Author, UCLA Clinical Faculty, CMO Vitality Healthtechreef@vitalitybio.com

Conflict of interest

Chief Medical Officer, Vitality Healthtech

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Stress

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Terminology

Hypothalamic-Pituitary-Adrenal (HPA) Axis: Neuroendocrine central stress system, responsible for creation of cortisol. Also plays a role in mood, digestion, and immune function

Cortisol: Primary stress hormone. End product of the HPA axis’ stress response

Endocannabinoid System (eCB or ECS): Our endogenous cannabinoid system, located diffusely throughout the body

- "Almost all body processes can involve endocannabinoid signaling” - Piazza et al., 2017

- Helps us “relax, eat, sleep, forget, & protect” - Di Marzo et al., 1998

Chronic pain: Pain that lasts longer than 3-6 months, becomes its own disease state

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Terminology cont.

Cannabinoid Receptors: Both G protein-coupled receptors

- CB1R: Widespread, common in CNS, psychoactivity, pain relief, modulates neurotransmission throughout the body, responsible for THC “high”

- CB2R: Mainly on immune cells, anti-inflammation, muscle relaxant, less understood

Endocannabinoids: The body’s naturally occurring cannabinoids

- AEA (Anandamide): Primarily activates central CB1, weak peripheral CB2- 2-AG (2-Arachidonoylglycerol): Full agonist of CB1 & CB2, primary ligand of CB2

Phytocannabinoids: Primary cannabinoids present in cannabis sativa

- THC: Primary psychoactive component in cannabis. Effective in reducing pain, nausea, and inflammation. Increases appetite, anxiety at high doses. CB1R & CB2R agonist

- CBD: Non-intoxicating. Reduces THC-high, muscle tension, anxiety, and convulsions

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HPA axis & the stress response

1.First, a stressor causes the hypothalamus to release corticotropin-releasing factor (CRF)

2.CRF binds to receptors in the anterior pituitary gland, causing release of adrenocorticotropic hormone (ACTH)

3.ACTH binds to receptors in the adrenals (kidneys) that generate cortisol

4.Cortisol finally acts back on the hypothalamus, downregulating the system and hopefully returning it to equilibrium. Negative feedback loop

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HPA axis dysfunction

▪ Prolonged and repeated stressors create a constant “fight or flight” response usually meant for short bursts

▪ Chronic stress weakens the immune system, strains the circulatory system, and puts constant cognitive strain on individuals

▪ Stress-induced dysregulation and sensitization of HPA axis similar across PTSD, chronic fatigue syndrome, chronic pain, fibromyalgia, and IBS

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Understanding the problem: Over 58 million Americans suffer

from anxiety disorders1

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● Only 36.9% of this population seek and receive treatment 1

● 20% of American adults feel they do not do enough to manage their stress 2

● Gen Z and Millennials reported highest levels of stress 2

● Gen Z (youngest generation) most likely to report poor mental health 2

1 ADAA.org & US 2017 Census2 APA: 2018 Stress in America survey

Standard-of-care treatments

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Current SOC for Stress & Anxiety

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Benzodiazepines Increases effects of GABA, the primary inhibitory neurotransmitter, resulting in anxiety relief, muscle relaxation, and sedation

CBT, ACT, MBSR Psychosocial treatments aimed at changing habits, beliefs, and behaviors of patients from the top-down

Antidepressants (SSRIs, SNRIs, etc)

Block reuptake of serotonin and/or norepinephrine to prolong and increase availability of both in synapses, lift mood, and decrease stress & anxiety

Is cannabinoid stress reduction a possible

treatment option?

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"There is wide consensus that ECS signaling generally reduces anxiety and fear responses.” -

Piazza et al., 2017

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Lutz et al., 2015

Moreira & Wotjak, 2010

Morena et al., 2016

Riebe & Wotjak, 2011

CB1 receptors are present throughout the HPA axis

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● Depending on the dosage, ratio, & situation, cannabinoids can be anxiolytic or anxiogenic● Low doses of endocannabinoids dull stress, while high doses of ECBs increase stress● Larger doses of THC => more anxiety

1 Rodríguez de Fonseca et al. 1996 2 Martin et al., 2001 3 Hilliard et al., 2018

ECS & stress

▪ We will see how eCB signaling generally reduces anxiety, fear responses, and provides buffering from chronic stress

▪ eCB activity dulls anxiety in less stressful situations to help prevent chronic stress

▪ During highly stressful stimuli, the ECS can increase anxiety responses

2019 North American Cannabis Summit 14Corcoran et al., 2015; Hohmann et al., 2005; Suplita et al., 2005; Valverde et al., 2000; Lutz et al., 2015; Dlugos et al, 2012; Hill et al, 2010; Moreira and Wotjak, 2009; Morena et al., 2016; Riebe and Wotjak, 2011

eCBs & stress

▪ Chronic stress reduces the # of CB1 receptors, although it can recover after a few days

▪ Loss of CB1Rs is likely due to activation of glucocorticoid receptors, because a glucocorticoid antagonist (RU486) blocks reduction in CB1Rs

▪ In all populations, lower levels of circulating AEA correlate with higher anxiety

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Morena et al., 2016

Morena et al., 2016; Rossi et al., 2008; Wamsteeker et al, 2010; Dlugos et al, 2012; Hill et al, 2008c

Chronic

CB1 & the HPA axis

▪ eCBs regulate unnecessary glucocorticoid secretion in response to chronic homotypic stress

▪ This plays a protective role against developing chronic stress syndrome

▪ “In more general terms, the hypothesis can be put forward that the eCB system facilitates the activation of resilience factors during and/or after stress exposure." - Russo et al., 2012

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Hill et al., 2010

ECS at CB1 functions as stress-recovery system

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● eCB system regulates habituation to homotypic stressors, not heterotypic ones○ Homotypic Stressors: Stressors of the

same variety vs. a barrage of many different kinds of stressors (ex: Marital problems, work problems, health, poverty)

● 2-AG release increased in response to repeated stress (Patel et al., 2005b, Rademacher et al., 2008)

1 Patel & Hillard, 2008 2 Patel et al., 2005b 3 Rademacher et al., 2008

eCB system the “gatekeeper” of the HPA axis

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● A disrupted endocannabinoid system is associated with failure to adapt to chronic stress

● Data suggests deficient eCB system may be implicated in affective disorders such as depression

● CB1 antagonists increase corticosterone secretion and enhance neuronal activity in the PVN, indicating higher stress responses in the HPA-axis

● Typical antidepressants have a downstream effect on eCB signaling in the limbic brain and that alteration contributes to their effectiveness

Gorzalka et al., 2008; Pi-Sunyer et al., 2006; van Gaal et al., 2005

Acute vs. chronic stress

▪ In response to acute stress, 2-AG levels do not tend to change much

▪ Repeated stress exposure, or chronic stress, causes an increase in 2-AG and downstream reduction in amygdala fear activity, driving habituation to stress.‒ A similar phenomenon happens in fear

extinction, which has also been shown to be mediated by the ECS

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Hill et al., 2010

Chronic stress, the hippocampus, & eCBs

▪ Chronic stress conditions causes significant downregulation of CB1 and decreases 2-AG content in the hippocampus

▪ This creates deficits in behavioral flexibility in rodents, ‒ This signals a potential role in

pervasive and unhealthy behaviors in mental health conditions including anxiety & depression

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Hill et al., 2005

Resilience

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“Maintenance of positive adaptation (to stress) by individuals despite experiences of adversity”

Improvement in resilience correlated with stress & pain reduction

(Friborg et al., 2005; Luthar et al., 2000)

The endocannabinoid system in stress resilience

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Cannabinoids & resilience

▪ eCBs regulate HPA axis’ long-term response to stress, improve coping, and improve stress habituation

▪ Deficient eCB systems increases risk of developing PTSD & depression

▪ CB1R agonists in vmPFC help reduce anxiety, fear expression, and active coping responses to stress.

2019 North American Cannabis Summit 23Hill et al., 2009; Hillard et al., 2018, Martin et al., 2002; Bluett et al., 2017; Worley et al. 2017 ; Moldrich & Wenger, 2000, Worley et al., 2017

Evidence for cannabinoid treatment of pain & mental

health

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Current evidence: cannabinoid treatment

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Lynch & Ware, 2015: 7/11 controlled studies show sig. pain ↓, QOL ↑ (sleep, anger, anxiety, and depression) Degenhardt et al., 2015: Cannabis + opioids > opioids alone for pain: ↑ QOL, ↓ pain, ↓ opioid usage Agarwal et al., 2007:Endogenous CB1 receptor (thus THC) primarily responsible for pain reduction

Withdrawal symptoms relieved by cannabinoids:Anxiety, sleep problems, GI pain, nausea, & muscle pains Haroutounian et al., 2016: 44% ↓ in opioid usage over 6 months with cannabis Ware et al., 2003: 59% of cannabis-using patients reported reduction in other medication taken

Bergamaschi et al., 2011 CBD reduces anxiety while public speaking in healthy naive individuals Greer et al., 2014: Cannabis therapy effective in reducing symptoms for 75% of PTSD patients Phan et al., 2008: THC dampens amygdala response to stress

PainOpioid dependenceMental illness & stress

Cannabinoid treatments for anxiety/stress

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Chronic Stress Cannabinoids help regulate the amount of unnecessary glucocorticoid secretion in response to chronic stress

Depression/anxietyCBD shown to be effective as an anxiolyticDeficient eCB system in patients with depressionQOL, incl. depression, improved with low THC cannabis

PTSDCannabinoid therapy effective in reducing symptoms for 75% of PTSD patients

Hill & Tasker, 2012; Hill et al., 2010, Greer et al., 2014; Ware et al., 2010; Bluett et al., 2017; Hohmann et al. 2005

The Opioid Epidemic

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Understanding the problem: Over 100 million Americans

suffer from chronic pain1

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● Cannabinoids’ biochemically and neurologically reduce nociception 2

● Cannabinoids also improve secondary symptoms of pain likely to improve resilience. 3○ This includes sleep disturbances, inflammation, nausea, anxiety, and

depression, providing another novel opportunity for treatment

1 2016 National Survey on Drug Use and Health2 Agarwal et la., 20073 Campbell et al., 2001; Haroutounian et al., 2016; Lynch & Ware, 2015; Martin-Sanchez et al., 2009

What is a modern definition of pain?

Is it exclusively biomedical?

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Pain: the biological

▪ Pain is first sensed by nociceptors throughout the body▪ The signal travels through the spinal cord, crossing to

the opposite side of the body▪ Afterwards, the signal travels through multiple lower

levels of the brain until it is projected to the primary sensorimotor cortex via the thalamus

▪ The limbic system mediates emotional and rewarding properties of pain

▪ Takeway: pain is in and always from the brain▪ Nonetheless, biology alone cannot explain all of the

variance in pain

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Pain is a biopsychosocial phenomenon:

Stress and anxiety shape the pain experience, especially when chronic

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Keefe et al., 1999

Gatchel et al., 2007

Turk et al., 2002

Campbell et al. 2003

Medical cannabis as medicine, not recreation

Misconceptions:

▪ Not just another excuse to get high. The high is not the point

▪ Most medical doses do not need to cause prolonged intoxication, especially after tolerance is built

▪ “Sativa,” “indica,” and “hybrid” are a taxonomy that inadequately describe variance in cannabis

▪ THC-induced high and side effects can be reduced by including CBD

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Cannabis dosing strategies for stress

▪ Start low, go slow, stay low▪ Cannabis medicine is individualized; dose finding

and adjustments are common▪ CBD is consistently anxiolytic, doses of 5-10mg,

starting once daily, up to 3x a day ▪ Lower amounts of THC can also be anxiolytic (1-

5mg). ▪ Be sure to combine THC & CBD for maximal

anxiety relief and attenuated high▪ Tinctures & edibles for long-term relief (4-8 hours,

15-90 min onset), vaporization for immediate relief (2-4 hours, 5-10 min onset)

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Future directions

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● First and foremost, more research!○ THC/CBD ratios for different conditions○ Nature of “Entourage Effect” with

terpenes, other cannabinoids (CBN, CBG, etc)

○ Long-term side effects○ Drug interactions

● De-scheduling from Schedule 1 to allow for research of medical effects

● Integration with the healthcare system. ○ CME for doctors, healthcare professionals○ Development of cannabinoid

pharmaceuticals○ Patient education

The Team/Acknowledgements

Karl Neumann

Clinical Research Associate Vitality Biopharma &

Vitality Healthtech

Robert Brooke

CEO & Co-founder Vitality Biopharma & Vitality

Healthtech

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