Cannabidiol, Essential Oils, and CAMs

Tracy L. Skaer, PharmD, FASHP, FASCP

Professor Emeritus of Pharmacotherapy

Nicole Perea, PharmD

Academic Fellow in Pharmacotherapy

Disclosure

We have no actual or potential conflict of

interest in relation to this program /

presentation.

2

Objectives

Describe the potential

uses, benefits, and

safety concerns related

to the use of

cannabidiol (CBD) and

essential oils for the

treatment of pain

Identify other CAMS

that may be beneficial

for the treatment of

post-op pain to help

minimize reliance on

opioid

pharmacotherapy.

Cannabinoids Background

Cannabis plant 100+ different

cannabinoids

Primary active compounds: CBD and

THC

CBD: non-psychoactive; THC –

psychoactive

Hemp: seeds, stems, non-flower parts

of cannabis plant made into rope or

clothing; for sale online.

Hemp is mostly CBD and can contain

no more than 0.3% THC.

Image Source: Natural

Center for Complementary

and Integrative Health

Controlled Substances Act (CSA) Exempts sterilized seeds, fiber, and stalk from

definition of marijuana as a Schedule I drug

Contains no standardized definitions for “medical

marijuana”, “high-CBD,” or “low-THC”; no

regulation among products

State laws on medical marijuana and cannabis

products vary

CBD Versus THC

Anti-nauseant

Appetite Stimulant

Analgesic

Muscle spasms

Causes: euphoria,

drowsiness, mood

changes, impaired

memory, changes in

cognition and problem

solving, dependence,

addiction

Anti-inflammatory

Analgesic

Neuroprotective

Antiepileptic

Anti-nauseant

Anxiolytic

No Euphoria: suppresses

psychoactive effects of

THC

Causes: drowsiness,

lethargy

Cannabinoids in Pain (some examples)

Research available on opioid sparing effects of

cannabinoids (primarily delta-9-THC +/- CBD)

Nielsen et al effective opioid dose 3.6 times lower

in animals subjects with concomitant THC.

Mondello et al THC/CBD remarkable analgesic

capabilities as adjuvants to spinal cord stimulation for

refractory failed back surgery syndrome (FBSS)

refractory pain

Cannabinoids – Nausea and Vomiting

Effectiveness of cannabinoids reducing nausea and

vomiting in chemotherapy patients is widely known

Hypothesis: surgical patients at high risk for PONV

may also benefit

Only limited research available for cannabinoids in

PONV; no demonstrated efficacy for THC, nabilone

(synthetic cannabinoid)

No research available for CBD in PONV

Key: PONV – post-op nausea and vomiting

CBD Dietary Supplements

FDA warning letters sent to several CBD

supplement manufacturers

Misbranded products – false claims,

ingredients not what’s on the label

Website claims are for drugs

Foods may not contain approved drugs

FDA excluding CBD products as dietary

supplements

Ongoing CBD research and approval of

Epidiolex® indicated new drug application

Cannabidiol (Epidiolex®) Highly purified pharmaceutical grade CBD

FDA approval (June 25, 2018) for Lenox-Gastaut

Syndrome (LGS) and Dravet syndrome

Orphan Drug designation: autoimmune hepatitis,

prevention of ischemia/reperfusion injury from solid

organ transplantation

Schedule V controlled substance (verses Schedule I

for THC)

Cannabidiol (Epidiolex®) MOA

Does NOT bind to CB receptors

Antagonizes CB1 and CB2 receptor agonists (i.e. THC)

Also, non-competitive negative allosteric modulator of

CB1 and CB2

Agonist of vanilloid / capsaicin receptor TRPV1 body

temperature, heat sensation, pain nociception

Facilitate neurotransmission by serotonin receptor 5-

HT1a mood, anxiety, aggression

Activates peroxisome proliferator-activated receptor Y

(PPARy) anti-inflammatory, glucose and lipid storage

Cannabidiol (Epidiolex®) MOA (cont.)

Antagonizes G-protein-coupled receptor GPR55, GPR2,

GPR6, GPR12 Parkinson’s, Huntington’s

Increases mitochondrial complexes (rodents)

neuroprotection, Parkinson’s

Decreases pro-inflammatory cytokines IL-1β, TNF-α, IFN-β,

IFN-γ, IL-17, and IL-6

Increases anti-inflammatory cytokines IL-4 and IL-10

Inhibits COX2 anti-inflammatory

Antioxidant / free radical scavenging properties

Anticonvulsant effect – MOA unknown

Cannabidiol (Epidiolex®) ADRs > 5%

Somnolence (23-25%)

Fatigue/malaise (12%)

Sedation (3-6%)

Sleep quality / insomnia

(4-11%)

Lethargy (4-8%)

Irritability (5-9%)

Reduced Appetite

(16-22%)

Diarrhea (9-20%)

Rash (7-13%)

ALT and/or AST

elevations (8-16%)

Cannabidiol (Epidiolex®) Precautions

Pregnancy – birth defects

and miscarriage risk

unknown. Enroll all PG

mothers in North American

Antiepileptic Drug (NAAED)

Pregnancy Registry

Breastfeeding – infant risk

cannot be ruled out

Providers should evaluate

risk/benefit

• Monitor for changes in

behavior or mood,

aggression, suicidal

thoughts / behaviors

• Do not abruptly

withdrawal

Cannabidiol (Epidiolex®) Warnings

Potential for positive result on cannabis drug

screen. Random drug testing concerns

Monitor for hepatocellular injury at 1, 3, and 6

months post-initiation. More frequent if taking

valproate or elevated LFTs at baseline

Dose-related elevations in AST, ALT, total Bili:

Increase risk: valproate, clobazam, or medications

known to increase LFTs.

Cannabidiol Interactions – Moderate Risk

CNS depressants

CYP3A4 and

CYP2B6

CYP1A2 and

CYP1A9

CYP2B6CYP2C9

and CYP2C19

UGT1A9 and

UGT2B7

Cannabidiol Interaction Examples

CYP3A4 Moderate Inhibitors: amiodarone,

erythromycin, fluconazole, miconaole, diltiazem,

verapamil, delavirdine, amprenavir, fosamprenavir,

conivaptan

CYP3A4 Strong Inhibitors: clarithromycin,

telithromycin, nefazodone, itraconazole, grapefruit

juice, ketoconazole, atazanavir, darunavir, indinavir,

ritonavir, saquinavir, tipranivir

Cannabidiol Interaction Examples

CYP 2C19 Moderate Inhibitors: esmeprazole,

fluoxetine, moclobemide, omeprazole, voriconazole

CYP2C19 Strong Inhibitor: Amitriptyline,

clomipramine, fluconazole, fluvoxamine,

imipramine, ticlopidine

For complete list of medications affecting CYP see:

FDA list

Cannabidiol – Surgical Considerations

Bleeding risk – theoretically may interfere with

warfarin metabolism at CYP1A2 and CYP3A4

Pain control – adjunctive role perhaps, more research

is needed

Enhanced sedation – combination with CNS

depressants including opioids.

Safety – large margin of safety, well tolerated, drug

interaction concerns

Supplements vs Rx – quality issues

Essential OilsImage Source: WebMD

About Essential Oils• A mixture of saturated and unsaturated hydrocarbons,

alcohols, aldehydes, esters, ethers, oxides, phenols, and

terpenes that produce characteristic odors

• Used by ancient civilizations over 6,000 years ago

• Florence Nightingale used lavender oil on soldiers and

proclaimed that nursing care should put the patient in the

best condition for nature’s reparative processes to work

• Administered by: inhalation, massage, or topically (at

pulse points to enhance absorption or via Vita Flex)

EOs Pharmacophysiological MOA

EO inhaled

through the nose

Nasal receptors integrate

into biological signal

Signal transmitted to limbic

system via olfactory bulb

Endorphins, serotonin, and

norepinephrine released

Eos Pschophysioloical MOA• Pleasant aroma altered

psychological state

emotional distraction-like

response

• Psychological or emotional

alteration may be indirectly

related to limbic system via the

amygdala, thalamus, and

hypothalamus responsible for

emotional reactivity

Image Source: https://www.news-

medical.net/health/Limbic-System-and-Behavior.aspx

Essential Oils Vita Flex Technique

• Vita Flex – vitality through the reflexes

• Applying EOs topically using specialized form of hand

and foot massage

• EOs applied on reflexology points on hands and feet

or on affective area

• Technique – apply oil to area or on finger pads;

roll/rotate finger pads over until finger nail is touching

the skin, move to next position and repeat.

Essential Oils Aromatherapy

• Applied topically or through inhalation

• Inhalation is fastest onset

• Low cost, minimal side effects, generally safe (FDA)

• Many claims but most research focuses on depression,

anxiety, muscle tension, sleep disturbance, nausea,

and pain.

• More effective at treating nociceptive and acute pain

inflammatory and chronic pain

EOs for PainEucalyptus

Image sources:

organic facts.net

Lavender Lemon Clary Sage

Marjoram Peppermint Rose

Ginger Spearmint Cardamom

Lavender EOs for PONV

Aromatotherapy with ginger; combination of

ginger, spearmint, peppermint, and cardamom;

QueaseEase® (lavender, peppermint, ginger,

spearmint) all found effective for PONV.

EOs Adverse Effects• Hypersensitivity

• Rash, contact dermatitis, and skin

irritations (burns, hives, blistering)

• Photosensitivity

• Respiratory reactivity

• Mucous membrane irritation

• Nausea, vomiting

• Seizures (oral eucalyptus)

• Gynecomastia in prepubescent boys

(lavender and tea tree oil)

Image Source: WebMD

Consumer overuse is

a major concern.

EOs Research Limitations and Concerns

• Difficult to deceive patients with placebo oils; patient’s

aware of their assigned groups

• Duration of EO interventions varied across trials

• Lack of standardized treatment procedure in each study

• Multiple delivery methods, differing blends of EOs and

herbs, non-standardized doses poor reproducibility

• Many recent trials primarily from Iran - Possible

publication bias and lack of registration and retrospective

registration threaten validity

Dietary Supplements and Surgery

Discontinue 2 weeks prior to surgery

Coagulation/bleeding: Ginko, Ginger, Garlic, Ginseng,

Green Tea, Vitamin E, Gucosamine, Chondroitin, Devil’s

claw, Willow bark, Dong quai, Feverfew, Fish oil, DHEA, Co

Q-10, Fenugreek, Evening primrose oil,

Enhances anesthesia: Kava, St. John’s wort, Valerian,

Nelatonin, Lemon balm

CV risk (HR and/or BP): Ephedra (ma huang), Garlic

Reducing Reliance on Opioids

Psychotherapy

Acupuncture

Massage +/- EOs

Chiropractic

Exercise

PT/OT

Reflexology +/- EOs

Mindbody - mindfulness, yoga,

meditation, Tai Chi, Qigong

Biofeedback

Stress management

Psychotherapy

Antidepressants

Neuroleptics

Sleep Hygiene

Foot Reflexology

Image Source: Pacific College

of Oriental Medicine

Hand Reflexology

Image Source:

Ma’ati Spa

Acupuncture

Massage Therapy• Soft tissue manipulation has been practiced for thousands

of years.

• Common goal: help the body heal itself

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Mindfulness

“The awareness that emerges through paying attention on purpose, in the present moment, and non-judgmentally to the unfolding experience moment by moment.”- Jon Kabat-Zinn, Ph.D. 1994

Intension

AttentionAttitude

NOW

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Practice Foundations: 7 Core Attitudes

1. Non-judging

2. Beginner’s mind

3. Patience

4. Trust

5. Non-striving

6. Acceptance

7. Letting go/be; non-attachment

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Mindfulness Practices

FORMAL

Meditation (e.g. body scan,

sitting, walking, cultivating

kindness, embracing the

unwanted, awareness of

breath)

Mindful movement (e.g.

yoga, gentle stretches)

INFORMAL

Awareness of body

sensations, thoughts,

emotions in everyday life

Mindful activities of daily

living (e.g. eating,

showering, vacuuming,

brushing teeth)

The Guest House

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This being human is a guest house. Every morning a new

arrival.

A joy, a depression, a meanness, some momentary

awareness comes as an unexpected visitor.

Welcome and entertain them all! Even if they are a crowd of

sorrows, who violently sweep your house empty of its

furniture, still, treat each guest honorably. He may be

clearing you out for some new delight.

The dark thought, the shame, the malice, meet them at the

door laughing, and invite them in.

Be grateful for whoever comes, because each has been

sent as a guide from beyond.

- Jalal al-Din Rumi

Mindfulness Uses

Stress management

Depression

Anxiety disorders

PTSD

Insomnia

Chronic Pain

Substance abuse,

addictions

Personality disorders

Disordered eating

Parenting skills

Traumatic Brain Injury

ADHD and Autism

Parkinson’s Disease

….more to come

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Mindfulness Reduces Stress by:

• Enhances awareness of thoughts reduces

negative response styles (rumination,

pessimism)

• Reduces emotional reactivity – “wise mind”

• Present moment mindset

• Improves awareness and sensitivity to

mind/body

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Mindfulness Reduces Stress by:

• Increases awareness of emotions of others

creating empathy and reduced conflict

• Promotes self-care and self-compassion

• Reduces the fear response and threat

detection

• Enhances cognition and concentration

• Changes attitudes about stressors

positive thinking towards addressing

stress

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Benefits of Mindfulness Practices

• Improved attention

• Reduced ruminative thinking

• Diminished emotional reactivity

• Enhanced self-awareness, -expression, -acceptance

• Improved coping

• Reduced blood pressure

• Changes in pain perception and coping

• Possible improved immune function

• Possible reduced cortisol levels

• Possible enhanced cognition

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“Lost”

Stand still.. The trees ahead and bushes beside you

Are not lost. Wherever you are is called Here,

And you must treat it as a powerful stranger,

Must ask permission to know it and be known.

The forest breathes. Listen. It answers,

I have made this place around you.

If you leave it, you may come back again, saying Here.

No two trees are the same to Raven.

No two branches are the same to Wren.

If what a tree of a bush does is lost on you,

You are surely lost. Stand still. The forest knows

Where you are. You must let it find you.

-David Wagoner

Summary Highly purified form of CBD (C-V) is now available via Rx

approved for treatment of Lenox-Gastaut Syndrome (LGS)

and Dravet syndrome.

Recreational CBD supplements are not pharmaceutical

grade and may be misbanded.

CBD is highly metabolize by liver and subject to multiple

interactions.

THC +/- CBD demonstrated opioid sparing effects.

No research available for CBD in PONV.

Screen dietary supplements prior to surgery to avoid ADRs.

Summary• Multiple EOs found efficacious as adjuvants for the

treatment of pain and PONV.

• CAMs such as acupuncture, mindfulness, meditation,

chiropractic, massage, reflexology, and movement therapies

(e.g., yoga, Tai Chi, Gigong) may be useful in reducing

opioid demands.

• Consider alternative medications for chronic pain such as

antiepileptics and antidepressants.

• Psychotherapy for all chronic pain patients.

• Teach all patients proper sleep hygiene.

• Get patients involved in own self-care.

QUESTIONS

References

1. Mondello E, et al. Cannabinoids and spinal cord

stimulation for the treatment of failed back surgery

syndrome refractory pain. J Pain Res 2018;11:1761-7.

2. Nielsen S, et al. Opioid-sparing effect of cannabinoids:

A systematic review and meta-analysis.

Neuropscyhopharmacol 2017;42:1752-65.

3. Bakshi C, Barrett AM. Impact of recreational and

medicinal marijuana on surgical patients: a review. Am

J Surg 2018; in press.

4. Cannabidiol Drugdex evaluation. IBM Micromedex.

Last modified: November 27, 201849

References

5. Peres FF, et al. Cannabidiol as a promising strategy to

treat and prevent movement disorders. Front

Pharmacology. 2018 May 11:8:482. doi:

10.3389/fphar.2018.00482. eCollection 2018.

6. Kleine-Brueggency, et al. IV deta-9THC to prevent

postoperative nausea and vomiting: A randomized

controlled trial. Anesth Analg 2015;121(5):1157-64.

7. Leven DN, et al. A randomized-controlled trial of

nabilone for the prevention of acute postoperative

nausea and vomiting in elective surgery. Can J

Anesth/J Canadien Danesthesie 2017;64(4):385-95.50

References8. Cannabinoids and drug interactions. Drug Consult, IBM

Micromedex. Last modified: October 3, 2018.

9. Richtig G, et al. Cannabis consumption before surgery

may be associated with increased tolerance of anesthetic

drugs: a case report. Int J Case Rep Images

2015;6(7):436-9.

10.Welliver MD. Essential oils: an adjunct to holistic

nursing. Gasteroent Nurs 2018;41(3):250-4.

11.Marin GN. The effect of exposure to odor on the

perception of pain. Psychosom Med 2006;68:613-6

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References12.Lakhan SE, et al. The effectiveness of aromatherapy in

reducing pain: a systematic review and meta-analysis.

Pain Res Treatment 2016;

http://dx.doi.org/10.1155/2016/8158693

13.Lee MS, et al. Aromatherapy for managing pain in

primary dysmenorrhea: a systematic review of

randomized placebo-controlled trials. J Clin Med

2018;7:434.

14.Marshall L. Essential Oils: Natural doesn’t mean risk-

free. WebMD 2017. https://www.webmd.com/skin-

problems-and-treatments/news/20170809/essential-

oils-natural-doesnt-mean-risk-free52