CBD OIL –THE ALL NATURAL WONDER

DRUG?Stacy Peterson, MD

Objectives

◦ Look at use of CBD in the United States

◦ Review differences between THC & CBD

◦ Evaluate available evidence & case studies for use in pediatrics (&adults)

◦ Evaluate available evidence for adverse effects including drug interactions

◦ Review legal status of cannabinoids

Just some of the Proposed Benefits of Cannabinoids◦ Analgesic

◦ Antispasmodic

◦ Antiemetic

◦ Neuroprotectant

◦ Anti-cancer

◦ Antioxidant

◦ Antibacterial

◦ Antifungal

◦ Anti-inflammatory

◦ Immunosuppressive

◦ Dermatologic uses

◦ Bronchodilator

◦ Anti-glaucoma

◦ Anti-diabetic

◦ Anxiolytic

◦ Antipsychotic

◦ Anticonvulsant

CBD and pregnant and nursing mothers◦ Pregnant and nursing mothers are using CBD

◦ Possible transfer to infants via breast milk following maternal consumption

◦ Reports of positive THC in newborns following material use of CBD only products

Non-Prescription use of CBD in Children

◦ Likely increasing

◦ No available statistics

◦ In my patient population – often tried upon questioning, less frequently reported without specifically questioned.

Endocannabinoid System

In all Vertebrate animals

eCB has roles in:• Hunger, feeding, energy• Neural Plasticity• Neuroprotection• Nociception, pain• Autonomic tone• Immune response• Connective Tissue repair

Cannabinoids

Endogenous Cannabinoids

• Anandamide & 2-arachidonylglycerol

• Synthesized at or near site of action

• Rapidly broken down at site of action

Phytocannabinoids Cannabinoids

• C. Sativa – more than 80 cannabinoids

• Most notable Plant derived: THC and CBD

• Large Volume of distribution

• Sustained and global effect

Synthesized:

• Marinol• Nabilone (THC)• Sativex (CBD: THC)

Marijuana vs Hemp◦ 2 strains of same plant – Cannabis Sativa

◦ Marijuana – Any cannabis plant that contains > 0.3% THC◦ THC isolated from Marijuana

◦ Hemp: cannot contain more than 0.3% THC◦ CBD isolated from hemp

THC

Partial CB1 agonism – reason for psychoactive actions of cannabis

CB2 agonism in immune system

Positive allosteric modulator of the mu and delta opioid receptors

Produces mild antioxidant activity – may protect neurons against oxidative stress

Adapted from Dept of Health, District of columbia

CBD

Inhibition of endocannabinoid reuptake

Transient receptor vanilloid 1 receptor activation

Augmentation of serotonin 5-HT1A receptors

Minimal CB1 agonism à minimal psychoactivity ?Adapted from Dept of Health, District of columbia

Route of administration◦ Oral : Prescription cannabinoids, edibles◦ Onset: 30-60 minutes, Duration of effect: 8-12

hours◦ Dronabinol: Onset: 30-60 minutes◦ GI absorption can be erratic

◦ Sublingual: lozenges, lollipops◦ Onset: 15-40 min, duration 4-6 hours

◦ Topical: chemically-extracted concentrates –oils, creams)◦ Likely to have systemic absorption◦ Pharmacology poorly understood

◦ Inhalation: Herbal cannabis◦ Onset: 5 min, Duration of effect: 2-4 hours◦ Approximately30% enters systemic circulation

Adapted from Cannabionid therapies in oncology- Curr oncology 23: 398-406

MEDICATIONS

Approved Medications◦ Epidiolex: purified CBD oral solution

◦ approved in US for treatment of Lennox-Gasteaut and Dravet syndrome◦ Age 2 yo old and older

◦ Sativex: oral spray 1:1 THC to CBD ◦ Approved in Europe for neuropathic pain associated with MS

◦ Dronabinol: synthetic cannabinoid ◦ US -treatment of Chemotherapy induced Nausea and Vomiting◦ US – appetite stimulation in AIDS

◦ Nabilone◦ US for chemotherapy N/V◦ Canada/other: fibromyalgia/ MS

Drug Interaction

Studies

Warfarin• THC & CBD increased warfarin levels

Alcohol• Alcohol can increase THC levels

Theophylline• Smoked cannibis can decrease Theophylline levels

Indinavir/ Nelfinavir• No effect

Docetaxel/ Irontecan• No effect

Clobezam• CBD increased clobazam active metabolites

Valproate• No effects

CNS depressants• Additive CNS depressant effect with alcohol, barbiturates &

benzodiazepines

Epidiolex◦ Contains purified drug (CBD oil) from cannabis

plant

◦ Approved Indications: Lennox-Gastautsyndrome and Dravet syndrome◦ 10mg/kg daily◦ 20 mg/kg max daily

◦ Age: 2 years of age or older

◦ Schedule 5

Reported Adverse effects – Epidiolex◦ GI◦ Diarrhea, Nausea, vomiting

◦ Central◦ sedation, somnolence, fatigue, convulsion

◦ Metabolic◦ Increases in serum aminotransferases, decreased appetite

Serious Adverse Effects◦ Elevated Transaminases, convulsions, sedation, lethargy and Upper Respiratory track infections

◦ Most known data is from Epidolex and may be related to co-use of other medications◦ Concomitant clobazam use: increased sedation, lethargy, and URI◦ Concomitant valproate use: increased risk of elevated transaminases

Adverse Events – Hepatic Injury

Transaminase elevation

Co medications implicated with hepatic injury reports

Acetaminophen, Antiepileptics, antipsychotics, abx, antifungals, verapamil

Caution recommended in people with pre-existing hepatic impairment

Recommend labs before starting therapy with Epidiolex, 1 month and 3 month after initiation of treatment

Adverse Events –

Infection Risk

Increased infection risk

Mechanism: via CB Receptors –thought to modulate immune system and decrease immune response, esp of T-cell lymphocytes

Caution in patients taking immunosuppressant medications

Adverse Effects-

Pulmonary Complications

Recent increase in vaping related injuries/deaths

Some deaths with nicotine use, some with Marijuana, some with both

Is this risk present if vaping CBD oil?

EVIDENCE FOR CBD USEAnimal Models

Mice Model for neuropathic pain◦ Mice 2-4 months of age

◦ Subjected to partial sciatic nerve ligation (pSNL)

◦ Baseline testing for hyperalgesia and allodynia were performed 3 days and immediately before pSNL

◦ After ligation, mice were tested for hyperalgesia and allodynia ◦ Days 5,7,12,15,18,22

◦ 4 groups control, THC, CBD or morphine gelatins for 7 days

Von Frey Test◦ Filaments used to determine allodynia

◦ Filaments buckle at a specific force and impart a consistent force

◦ Mechanical nociceptive test

◦ At what force is their pain

Other findings◦ Mice did not self increase THC, morphine or CBD doses◦ = there was no dose escalation

◦ Mice exposed to CBD and THC did gain weight

◦ Mice exposed to morphine did not exhibit the same hyperalgesia we see in human studies

◦ Mice who were pain-naïve do not have an analgesic effect from CBD

◦ Doses of THC used in these studies correspond to levels we have shown to observe significant cognitive and motor impairments in humans

Article Conclusions

◦“Finally, we have shown that the cannabinoids THC and CBD, in contrast to morphine, produce long-lasting relief of chronic neuropathic pain in a sciatic nerve injury model in mice.”◦ Specifically, CBD may represent a viable therapeutic option because of its low

psychoactive profile, lack of efficacy in a pain-free state, and long-lasting reduction in allodynia in chronic pain.

PEDIATRIC CASE REPORTS

Tx for Pediatric Anxiety and PTSD?◦ 2016 Case report

◦ 10 yo female with history of sexual abuse, hx of multiple treatments

◦ Started on CBD oil capsules 25mg at night, à improved sleep

◦ Changed to 12 mg (in 4 sublingual sprays) qhs + PRN for anxiety

◦ Results: reported improved sleep and ”mood at ease”

◦ Improved sleep scale score and SCARED scores

Transdermal Cannabidiol: pediatric fragile X

◦ 20 children with Fragile X ◦CBD gel administered 2x daily

for 12 weeks ◦ Starting dose 50 mg ◦ Increased up to 250 mg

◦ Improvement in behavioral and emotional symptoms

Epidermis Bullosa◦ 3 cases of children with CBD oil application

◦ Per parents -Improvement in EB lesions in all patients

◦ Per parents- Improvement in pain in all patient

◦ No set product, one a tincture, one also contained emu oil

Pediatric Dermatology – May 2018

Use in Autism◦ Several reports of use of both THC and Autism with benefits in outburst, attention, mood

◦ Majority of studies were not purse CBD, but contained a mixture of THC: CBD if varying ratio

◦ Crossover study in Israel showed promise but product was CBD and THC oil (20:1) ratio

Case report: THC intoxication ◦ 2yo given hemp seed oil extract as prescribed by their physician

◦ Presented to ED with decreased alertness, refusing to walk and talk

◦ Urine tested positive for THC

◦ Hemp seed oil tested - positive for THC

Pediatric Emergency care, May 2017

Vaping

NON-PEDIATRIC STUDIES

Chronic Pain◦ Affects between 40 -100 millions individuals in the US

◦ Annual economic burden of USD 600 billion dollars

◦ Recent increases in opioid medication prescriptions have contributed to the current opioid epidemic

◦ “Cannabinoids are promising candidates for the treatment of pain”

CBD studies◦ No great large RCTs for pain, depression anxiety, addiction or other potential

uses

◦ Some preclinic/pilot studies performed

◦ Little guidance for physicians trying CBD and/or hemp oils

◦ 2018, Donvito “an overwhelming body of convincing preclinical evidence indicates that cannabinoids produce antinociceptive effects in inflammatory and neuropathic rodent pain models"

Use in Chronic Pain (Not peds)◦ No good studies in humans◦ Many short duration (<6 months)

◦ 2018 article by Donvito◦ “Overwhelming body of convincing preclinical evidence that indicates that cannabinoids produce antinociceptive

effects in inflammatory and neuropathic rodent pain models”

JAMA 2015 review◦ Based on the GRADE approach

◦ moderate-quality evidence to suggest that cannabinoids may be beneficial for the treatment of ◦ chronic neuropathic or cancer pain (smoked THC and nabiximols) ◦ spasticity due to MS (nabiximols, nabilone, THC/CBD capsules, and dronabinol).

◦ low-quality evidence suggesting that cannabinoids◦ improvements in nausea and vomiting due to chemotherapy (dronabinol and nabiximols)◦ weight gain in HIV (dronabinol), sleep disorders (nabilone, nabiximols), and Tourette syndrome (THC capsules);

◦ very low-quality evidence for ◦ improvement in anxiety as assessed by a public speaking test (cannabidiol).

◦ low-quality evidence for◦ no effect on psychosis (cannabidiol) and ◦ no effect on depression (nabiximols)

Feb 2018

◦The best evidence is for increased risk of adverse events

Chronic Pain/opioid Studies

DO YOU REALLY KNOW

WHAT YOU ARE

GETTING?

2017 survey – Accuracy of Product labelling

◦ 84 online CBD and hemp oil products examined◦ 26 accurately labeled for correct CBD & THC content◦ CBD often overloaded, THC under labeled

Concerns with THC◦ THC◦ Linked to development of schizophrenia in adolescents ◦ Can lead to enduring neuropsychological impairment◦ Cannabis disorder that develops before age 18 more likely to become

persistent◦ Adolescents users have greater IQ decline compared to adult onset users

PNAS Oct 2012. Persistent Cannabis use.

LEGAL CONCERNS

History & Legality◦ Use dates back > 4000 years

◦ 1800’s: explored as a tx for mental ill

◦ 1937 : Marijuana Tax Act - Made illegal at state and federal level

◦ 1970 – Controlled Substances Act outlawed growing and selling of hemp and marijuana ◦ Still listed under schedule I US federal law for having “no accepted medical use” and “lack of accepted safety”

◦ 2014 Agricultural Act – distinguished between hemp and marijuana legality for the 1st time ◦ Industrial hemp: “Cannabis Sativa L. and any part of such plan, whether growing or not with a delta-9-THC

content of no more than 0.3% on a dry weight basis

CBD specific Legal

Considerations

◦ Wisconsin legalized CBD in 2013◦ 3 states Idaho, South Dakota, Nebraska –

no C sativa access laws ◦ CBD and hemp oils illegal to sell or

consume there ? ◦ South Dakota laws unclear◦ Idaho – what is the status there?

◦ Federal Govt and DEA - consider CBD and hemp oils to be schedule 1 substances

A note on “Medical Prescribing” ◦ THC/ Marijuana ◦ Recommended or certified by a physician◦ NOT prescribed – not approved by DEA/ FDA

◦ CBD◦ Do not require recommendation or certification – do not contain THC◦ Numerous companies have received warning letters for inconsistency in their

products or findings that their products contain THC at higher than allowed amount◦ Now that CBD has an investigation drug authorization (Epidiolex) – no longer

considered legal to use in dietary products and ”foodstuffs”

FDA – April 2019

“I believe these are egregious, over-the-line claims and we won’t tolerate this kind of deceptive marketing to vulnerable patients. The FDA continues to be concerned about the proliferation of egregious medical claims being made about products asserting to contain CBD that haven’t been approved by the FDA, such as the products and companies receiving warning letters today. CBD is marketed in a variety of product types, such as oil drops, capsules, syrups, teas and topical lotions and creams. Often such products are sold online and are therefore available throughout the country”

https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis

Q: Does the FDA have concerns about administering a cannabis product to children?

◦ A. We understand that parents are trying to find treatments for their children’s medical conditions.

◦ However, the use of untested drugs can have unpredictable and unintended consequences.

◦ Caregivers and patients can be confident that FDA-approved drugs have been carefully evaluated for safety, efficacy, and quality, and are monitored by the FDA once they are on the market.

◦ With the exception of Epidiolex, Marinol, and Syndros, no product containing cannabis or cannabis-derived compounds (either plant-based or synthetic) has been approved as safe and effective for use in any patient population, whether pediatric or adult.

FDA goals◦ The FDA is working to learn more about the safety of CBD and CBD products. More

specifically:◦ The effects CBD could cause in the body, such as toxicity to the liver, when someone

ingests CBD regularly over a long period of time. ◦ During its review of the marketing application for Epidiolex — a purified form of CBD

that the FDA approved in 2018 for use in the treatment of certain seizure disorders — the FDA identified certain safety risks, including the potential for liver injury. ◦ These are serious risks that can be managed when an FDA-approved CBD drug product is

taken under medical supervision, ◦ but it is less clear how these risks might be managed when CBD is used far more

widely,◦ without medical supervision ◦ and not in accordance with FDA-approved labeling.

FDA Goals Part II◦ The cumulative exposure to CBD if people access it across a broad range of

consumer products. For example, what happens if you eat food with CBD in it, use CBD-infused skin cream and take other CBD-based products on the same day? What if you use these products daily for a week or a month?

◦ The effects of CBD on special populations (e.g., the elderly, children, adolescents, pregnant and lactating women) or types of animals (e.g., species, breed, or class).

◦ The safety of CBD use in animals (e.g., species, breed, or class) including pets.

Summary Points◦ Endocannabinoids play a role in may physiologic responses including pain and inflammation

◦ The best evidence for use of cannabinoids is to treat neuropathic pain or nausea/vomiting

◦ There are no good studies with artisanal CBD (OTC CBD oil)

◦ There are very little long-term phase 3 clinic trials available◦ Many of these do not show benefit, or only low level evidence

◦ There are no long-term studies

◦ There are no good studies in children

◦ There are potential side effects with ingestion of CBD

◦ THC has known negative side effects, CBD products may be contaminated with THC

Making Recommendations –Mayo paper

◦ Does it meet the following quality standards?◦ Current Good Manufacturing Practices certification from

the US Food and Drug Administration◦ European Union (EU), Australian (AUS) or Canadian

(CFIA) organic certification◦ National Science Foundation (NSF) International

certification◦ Does the company have an independent adverse event

reporting program?◦ Is the product certified organic or ecofarmed?◦ Have their products been laboratory tested by batch to confirm

tetrahydrocannabionol levels <0.3% and no pesticides or heavy metals? ◦ Should you consider lab monitoring if you are making a

recommendation? ◦ Just because it doesn’t get you high doesn’t mean its not

psychoactive

Recommendations in Autism

◦ Physicians who treat individuals with ASD should educate themselves about CBD.

◦ Be open to discuss it with families with a non-judgmental approach

◦ Once rapport and trust are established, the physician can help families distinguish validated, evidence-based treatment approaches from treatments that have been proven ineffective from those that are unproven and potentially harmful.

◦ Clinicians should review the current state of evidence and safety with the parents and child.

◦ Most physicians have received requests from patients for clinical recommendations. ◦ Promote informed decision making

◦ Ultimately, a physician’s decision to utilize CBD in the management of children with ASD will be guided by the limited research findings, her or his clinical expertise and preference, as well as the parent’s values and wishes.

Other Miscellaneous CautionsContraindications

◦ Pregnant or breastfeeding

◦ Severe and unstable cardiopulmonary disease

◦ History of ETOH or substance abuse

◦ Acute psychosis or unstable psychiatric condition

Precautions

◦ Pediatric and Elderly patients

◦ Drug Interactions

◦ Family history of schizophrenia

◦ Personal history of psychiatric disorder

◦ Association with hypemesis syndrome

◦ History of arrhythmias

Handbook on Cannabis 2015

Potential ContaminantsFungal and Bacterial pathogensPesticidesHeavy Metals