1. Cannabis and Neuropathy
Dr. Nick Salamie PharmD, RPh
PDI Medical

2. Condition that affects normal activity of the nerves
25% to 30% will be affected
At risk populations
Hereditary or acquired neuropathy
What is Neuropathy?
So what is neuropathy? Neuropathy, also called peripheral neuropathy, refers to any condition that affects the normal activity of the nerves in the peripheral nervous system.
It is so common that it is estimated that about 25% to 30% of Americans will be affected by neuropathy.
Neuropathy affects people of all ages, but older people are at an increased risk. Also, it is more common in men and Caucasians.
The cause of neuropathy can either be hereditary or acquired. However, acquired neuropathy is much more common.

3. Acquired Neuropathy Causes
Trauma
Infections and Autoimmune Disease
HIV
Herpes
Lyme Disease
Lupus
Rheumatoid arthritis
Systemic Diseases
Diabetes
Cancer
Medications and Poisons
Chemotherapy
Heavy Metals
Industrial Chemicals
Vascular Disorders
Vitamin Imbalances
Alcoholism
Acquired neuropathy can have many causes.
Various types of trauma can cause neuropathy.
Many infections and autoimmune disorders can damage the nerves including: HIV, Herpes, Lyme Disease, Lupus and Rheumatoid arthritis can cause neuropathy.
Diseases that affect the entire body can cause neuropathy. These include kidney disorders, certain cancers, hormonal imbalances and diabetes. With diabetes being one of the most common causes of neuropathy.
Certain medications and Poisons can damage the nerves. Strong medications such as chemotherapy can induce neuropathy. Also poisonous substances like heavy metals such as lead and mercury and industrial chemicals like solvents can affect nerve function.
Neuropathy may occur when blood flow to the extremities is disrupted by inflammation, blood clots, and other blood vessel disorders.
Healthy nerves require adequate levels of vitamins E, B1, B6, B9, B12 and niacin, so an imbalance with any of these vitamins may cause neuropathy issues.
Alcoholism can deplete the body of thiamine and other essential nutrients which in turn can lead to neuropathy in the arms and legs.

4. Symptoms/Subtypes Sensory Neuropathy Motor Neuropathy
Tingling
Numbness
Changes in sensation
Loss of coordination and/or reflexes
Burning sensation
Feeling that you are wearing socks or gloves when you are not
Motor Neuropathy
Muscle weakness, Muscle twitching
Difficulty walking or moving your arms or legs
Cramps, Spasms
Loss of muscle control, Loss of muscle tone, Loss of dexterity
Falling
Autonomic neuropathy
Abnormal blood pressure or heart rate
Decreased sweating
Problems with urination, sexual dysfunction
Diarrhea, Unintentional weight loss
Dizziness when standing up or fainting.
Nausea/Vomiting, Problems with digestion
-Symptoms of neuropathy will really depend on the type of nerve affected.
-Sensory nerves are nerves that receive sensation, such as temperature, pain, vibration or touch, from the skin. Some common symptoms of sensory neuropathy include: tingling, numbness, especially in the hands and feet. Changes in sensation – Some people feel severe pain, especially at night, and some are unable to feel pain, pressure, temperature, or touch. A Loss coordination or reflexes and a burning sensation can also occur. A feeling that you are wearing socks or gloves when you are not is also possible.
-Motor nerves are nerves that control muscle movement. Some possible symptoms of motor neuropathy include muscle weakness, muscle twitching. Difficulty walking or moving your arms or legs are just to name a few.
-Autonomic nerves are nerves that control functions such as blood pressure, heart rate, digestion and bladder. Symptoms of autonomic neuropathy include abnormal blood pressure or heart rate, decreased sweating, problems with urination and sexual dysfunction, weight loss, dizziness and nausea and vomiting.

5. Mainstream Treatments
Pain Relievers
OTC medications
Opioids
Anti-seizure medications
gabapentin (Neurotin)
pregabalin (Lyrica)
Topical Treatments
Capsaicin
Lidocaine
Antidepressants
Tricyclic antidepressants
duloxetine (Cymbalta)
venlafaxine (Effexor)
These are some of the mainstream treatments used to treat the signs and symptoms of neuropathy in patients.
Pain relievers are commonly used in neuropathy patients. Over the counter medications, such as Tylenol or advil may help mild symptoms. Opioids such as tramadol, norco or oxycontin are generally reserved for more severe symptoms. Doctors are really trying to get away from opioid based medications given the dependence issues and the current opioid epidemic, which I will discuss more during next months talk.
Medications developed for epilepsy such as gabapentin and pregabalin are very prevalent in patients receiving pharmaceutical treatment for neuropathy as they have been proven useful in some patients.
Topical treatments, such as capsaicin may be useful in patients, but I don’t see this used a whole lot amongst neuropathy patients as capsaicin can cause burning and irritation where the topical is applied. Lidocaine patches are probably the most common topical treatments I come across in neuropathy patients.
Tricyclic antidepressants like amitriptyline, doxepin and nortriptyline have been found to help relieve pain by interfering with the chemical processes in your brain and spinal cord that cause you to feel pain. Cymbalta and Effexor are sometimes used to treat symptoms of neuropathy especially those caused by diabetes.
When ever you see an ad for drugs, like the one for Lyrica on the slide, the person or people are always overly joyous and look to be in a state of extreme peace. I think a more accurate of picture of what some patients experience is on the next slide.

6. Mainstream Treatments: Side Effects
Tramadol
Constipation (24-46%)
Nausea (24-40%)
Headache (18-32%)
Gabapentin
Dizziness (16-20%)
Fatigue (11-15%)
Somnolence (16-20%)
Duloxetine (Cymbalta)
Nausea (23-25%)
Fatigue (10-11%)
Somnolence (10-12%)
Pharmaceutical treatments for neuropathy do work for some patients, but they may experience debilitating side effects. The real kicker is for the patients that are prescribed these medications and don’t experience any relief, but still experience the side effects.
Lets take a look at some of the adverse effects caused by some of the more popular mainstream treatments from the previous slide. The percentages shown will refer to the incidence of the side effects amongst patients in clinical trials.
As you can see a good chunk of patients experience constipation, nausea and headaches from tramadol. You also have to take dependence into consideration with tramadol.
With gabapentin we see a lot of dizziness, fatigue and somnolence which is just excessive sleeping or sleepiness.
With Cymbalta we see nausea, fatigue and somnolence. Also, this isn’t talked about much with Cymbalta, but coming off of this drug can be rough for patients as withdrawal symptoms can be experienced.
This point I am trying to make here is that we don’t see a high incidence of debilitating side effects in patients using cannabis as medicine. Most side effects of cannabis in low to moderate doses are fairly benign with no physical dependence.

7. Endocannabinoid System
Found in all animals
CB1 and CB2 receptors
Located all over body
Anandamide and 2-AG
Balance In the body
Pain Modulation
Phytocannabinoids as treatment
THC
CBD
- When it comes to cannabis and neuropathy we first need to talk about the endocannabinoid system. If you ask most healthcare professionals about the endocannabinoid system they will probably look at you with a blank stare and have no idea what you are talking about. Most health care professionals will not learn a single thing about the endocannabinoid system during their time in school.
- The endocannabinoid system is a complex regulatory system found in all mammals. It regulates functions such as memory, digestion, motor function, immune response and inflammation, appetite, pain, blood pressure, and bone growth, just to name a few.
- The CB1 and CB2 receptors are the primary endocannabinoid receptors involved. These receptors are located all over the body as you can see in the graphic. However, there are other receptors involved and mechanisms that still need to researched.
- Our body produces our own cannabinoids. These 2 endocannabinoids are called anandamide and 2-AG.
- Endocannabinoids seem to be connected to the concept of homeostasis, meaning they play a major role in maintaining a balance throughout the body.
-Communication of pain throughout the body is mediated by endocannabinoids interacting with cannabinoid and other receptor-based signaling systems. Background pain levels appear to be modulated by the endocannabinoid system.
-Phytocannabinoids like THC and CBD work by activating or blocking the signaling through CB1 and CB2 receptors – both of which are important in modulating persistent neuropathic pain.

8. THC One of the major therapeutic cannabinoids
Beyond the psychoactivity
Anti-inflammatory
Analgesic
Neuroprotective
Increased Potency via Gastrointestinal absorption
Side Effects
Anxiety
Dizziness
Rapid Heartbeat
-More than 700 chemical contituents are produced in cannabis. The most interesting are the phytocannabinoids and terpenoids, and in this presentation I only will briefly cover a few.
-So THC, which is short for delta-9-tetrahydrocannabinol is one of the major therapeutic cannabinoids. This particular cannabinoid is the one most people are familiar with due to the psychoactivity or “euphoric” effects.
- Looking beyond the THC “high.” THC has many therapeutic effects including potent anti-inflammatory and analgesic activity. THC has 20 times the anti-inflammatory power of aspirin. It is neuroprotective and also reduces intraocular pressure, spasticity, and muscle tension.
- When THC gets absorbed in the gut the liver metabolizes it and turns it into 11-hydroxy-tetrahydrocannabinol which is about 4-6x more potent than inhaled THC.
-Although THC is non toxic, it does have side effects. Too high of doses in a patient can produce anxiety, dizziness, which can be dangerous in elderly and aging populations, and possibly rapid heartbeat.

9. CBD Second most prevalent therapeutic cannabinoid
No prevalent psychoactivity
Eliminates some of THC’s adverse effects
Sedation
Hunger
Therapeutic value
Anti-inflammatory
Anti-convulsant
Anxiolytic
Side effects
Headache
Diarrhea
Agitation
CBD more effective with THC: “Power Couple”
Hemp vs. Whole Plant CBD
CBD, short for cannabidiol, is the other major therapeutic cannabinoid found in the cannabis plant.
CBD by itself has no significant psychoactivity.
CBD reduces some of THCs adverse effects by modulating its psychoactivity, reducing some of the THC-induced sedation, hunger, anxiety, and rapid heartbeat.
Therapeutically CBD has a very long list of potential effects to the point where it almost sounds like snake oil. For neuropathy we interested in the anti inflammatory and neuroprotective properties of CBD.
CBD is generally very safe but some possible side effects are a headache, diarrhea, agitation and possibly sedation which tend to happen at higher doses.
CBD and THC work synergistically together. They are seen as the power couple in the cannabis world.
A lot of patients who come into PDI say that they have tried hemp CBD. Theres a big difference between between Hemp based CBD and Whole plant CBD. The Hemp based CBD with little to no THC that’s found legally in all 50 states is not as effective therapeutically as the whole plant based CBD you find in dispensaries. The whole plant CBD medicines offer the full entourage effect where all the components work syngerstically compared to the CBD working by itself in Hemp based CBD.

10. Cannabis Treatment Approaches
Find the “Sweet Spot” aka minimum effective dose
RCT trial by Mark A. Ware
Initial Dosing Strategies
No or Little Cannabis Experience
Intermediate Cannabis Experience
Advanced Cannabis Experience
There are no cookie cutter guidelines for the correct amount of THC and/or CBD to use in a patient. We always shoot for the sweet spot also known as the minimum effective dose. We want the dose where the patient is getting sufficient symptom relief without any unwanted side effects like excessive levels of psychoactivity, sedation, or dizziness. Also, sometimes too much THC can actually make the pain worse.
In a randomized controlled trial led by Mark Ware patients took a single inhalation of smoked cannabis and experienced a decrease in post-traumatic or post-surgery-induced neuropathic pain, measured by a numeric rating scale. The very interesting aspect of the study is that patients used a 9.4 THC percentage flower which translates to a dose of less than 2mg of THC. This is a very low dose and just goes to show you don’t need obscene amounts of THC for symptom relief.
Initial Dosing Strategies with neuropathy patients are typically based off the patients experience and comfort with cannabis.
Patients with no or little cannabis experience I will take a way different approach than someone with Advanced Cannabis Experience. Patients with no or little cannabis experience I typically recommend starting out with CBD Rich cannabis products or microdosing of a THC rich product. This conservative approach reduces the chances of any unwanted side effects and allows patients to find their sweet spot in a comfortable fashion.
A patient with intermediate cannabis experience can be defined as someone who is familiar with the effects of THC on their body and have somewhat of an idea how well they tolerate cannabis. Typically they are also able to share some of their previous cannabis experiences with clarity. I typically will recommend either a 1:1 cbd to thc product and/or thc rich products at low to moderate doses for these types of patients.
A patient with advanced cannabis experience can be defined as someone who has been self medicating for quite some time and knows exactly how well and the amount of cannabis they can tolerate. These patients are the easiest to dose since you don’t have to worry as much about adverse effects.

11. Meeting the Patient Start Low, Go Slow Drug Interactions
Product selection and initial strategy
Minimum Effective Dose
Follow Up
- At PDI we are one of the only dispensaries in the state of Illinois who offers one on one consults to our patients with a licensed health care professional and we do this free of charge.
-When first meeting with a patient at PDI medical I assess their current cannabis usage and tolerance, if any. It is very important to start low, and go slow with cannabis in a patient who has limited or no previous experience with cannabis. Too high of a dose in a patient who is sensitive to cannabinoids may produce an unpleasant experience and may turn them off from trying cannabis as medicine again.
-The next step is to assess any drug interactions if the patient is taking any pharmaceuticals. THC and CBD are both metabolized in the liver when ingested and can interact with certain drugs that are also metabolized in the liver, like coumadin.
-Initial product selection and strategy is going to be based on the patients current cannabis use and any limitations, like if the patient cant inhale and so forth.
-The goal, as I mentioned before is to find the minimum effective dose where the patient is getting symptom relief without any significant adverse effects.
-Following up is important because it may take 3 or more visits before we find a sweet spot with cannabis as it can be some what of a dance to find out what will work best.

12. Dosage Forms Inhalation Ingestible Sublingual/Buccal/Oromucosal
Combustion
Vaporization
Ingestible
Edibles
Oils (RSO)
Tablets/Capsules
Sublingual/Buccal/Oromucosal
Topical
Transdermal
We have quite a few dosage forms to work with in the state of Illinois to achieve this “sweet spot.”
Starting with inhalation we have a couple of different methods we can use. We have the old tried and true combustion method with either a pipe, joint, bong, or steamroller just name a few different ways. We prefer patients to inhale using vaporization over combustion to avoid any possible harmful by products. Every cannabis patient should have some sort of inhalation product unless they have some of limitation that deters them from inhalation. The reasoning behind that is that inhalation is the fastest way to get the medicine into the body and is superior for acute neuropathic pain or flare ups. You can think of inhalation as your rapid or break through cannabis medicine.
The downside to inhalation is that it wears off very quickly with relief really lasting only 1 to 3 hours. That’s were other dosage forms come into play like ingestible products as these products can last anywhere from 4-8 hours. But the downside is that there is a high variability as far as the onset of effect goes, anywhere from 30 minutes to 2 hours. I am a big proponent of rick simpson oil when it comes to addressing any type of pain with cannabis. I recommend patients with chronic pain issues to take at least one to two doses of a CBD rich cannabis oil daily. RSOs are a good way to keep a constant baseline of cannabinoids in the body and I will discuss RSOs more on the next slide.
Sublingual forms like tinctures are excellent for new patients when we want to take a microdosing approach. Tinctures allow us to go drop by drop if need be in patients who are more comfortable with a conservative approach. RSOs can also be taking sublingually.
Topicals are a nice add on to any cannabis regimen when one part of the body is hurting more than another. We get localized action with topicals so patients don’t have to worry about any psychoactivity. I recommend patients who experience neuropathy in the hands or feet to try a topical.
Transdermal dosage forms such as a patch are very convenient, but are by far the most expensive dosage form per dose.

13. Cannabis Oils/RSOs Best medical dosage form
Whole Plant/Full Spectrum Extract/Herbal Shotgun
Varying Cannabinoid Profiles
Different CBD:THC ratios
Acidic Cannabinoids: THCa, CBDa, CBGa
“Varin” Cannabinoids: THCV, CBDV
Less abundant Cannabinoids: CBN, CBG, CBC
Terpenes Captured
Beta-Caryophyllene
Lets discuss Cannabis Oils also known as Rick Simpson Oils, RSO for short, even though Rick Simpson doesn’t like his name being used in commericialized cannabis products. And that’s Rick Simpson in the picture.
In my opinion Rick Simpson Oils are the best medical cannabis dosage form currently available.
The way the extract process works is that it literally extracts everything from the plant including the cholorphyll when ethanol is used as the main solvent.
Luckily medical cannabis patients in Illinois have access to a wide variety of RSOs ranging from all THC to nearly all CBD and everything in between. There are some with very unique cannabinoid profiles you can find offered from Shelby county. For instance when the traditional THC and CBD rich medicines don’t provide much relief we may look at using a RSO that’s rich in acidic cannabinoids since THCa shows promise in neurological problems. Or we can find one with a decent amount of the varin cannabinoids like CBDV. Typically the varin cannabinoids are found more in Oils that use Carbon dioxide as a solvent like Shelby uses. Also, you will find the less abundant cannabinoids listed here in some of these RSOs. RSOs are the best way to get as many cannabinoids and terpenes into the body as possible per dose size and we may be getting a better synergistic effect than just a typical thc dominant edible.
RSOs are typically rich in terpenes. The specific terpene profile or entourage will really be dependent on the strain. It best to look for Oils rich in Beta-Caryophyllene since this particular terpene also acts as an anti-inflammatory agent.

14. Beyond THC and CBD for Neuropathy
CBG (cannabigerol)
Analgesic
CBC (cannabichromene)
THC potentiation
THCa (tetrahydrocannabinolic acid)
Anti-inflammatory
Neuroprotective
CBDV (cannabidivarin)
More studies needed
-A total in depth discussion about these less abdunant cannabinoids on the previous slide will have to be reserved for a later date, but the Main ones to look for when neuropathy isn't controlled by THC and CBD alone are:
-CBG also know as cannabigerol for its analgesic properties
CBC also known as cannabichromene for its ability to enhance the analgesic effects of THC
THCa which is THC in acidic or raw form is anti-inflammatory and neuroprotective.
- More studies are needed, but Im including CBDV on here also known as cannabidivarin. CBDv has been shown to have significant anticolvusant properties. Like I said more studies will be needed in regards to neuropathy, but the line of thinking here is that if other anticolvsuant drugs have helped neuropathic pain CBDV may prove to be very beneficial in a cannabis regimen for patients with neuropathy.

15. Getting Your Cannabis Card
Formal Diagnosis of 1 of the 41 qualifying conditions
Conditions that Cause Neuropathy
HIV/AIDS
Cancer
Fibromyalgia
Lupus RA
Completion of Physician Written Certification Form by Licensed Physician
Fingerprint/Background Check
Completion of Forms and Payment
Provisional Registration
-The actual process of getting a medical marijuana card in Illinois seems like an involved process, but its relatively simple especially with the help of PDI medicals staff.
The first step is to determine whether you have a formal diagnosis of 1 of the 41 qualifying conditions. Cancer, crohns disease, fibromyalgia and PTSD are just to name a few.
Some of the potential qualifying conditions that may cause neuropathy are HIV/AIDS, Cancer, Fibromyalgia, Lupus and Rheumatoid arthritis.
The next step and probably the most important step is to have a physician complete and sign a Physician written certification form. If your personal doctor wont sign, there is a list of Cannabis friendly doctors at pdimedical.com.
The next step is to call PDI Medical and schedule an application appointment, which we do free of charge. Fingerprints and background check is no longer required, but we will take your passport photo and we will also help you to make sure you have all your necessary paperwork completed correctly before you send everything down to springfield.
Provisional registration is something coming very soon. This will allow patients a temporary access card to the dispensary shortly after sending the required paperwork and registering online while they wait for the plastic hard card. This is being implemented in response to really long card processing times.

16. References
Backes, Michael, et al. Cannabis Pharmacy: the Practical Guide to Medical Marijuana. Black Dog & Leventhal Publishers, 2017.
Bersten, Melani PharmD, RPh. “Advanced Medical Cannabis: Dispensing and Dosing Considerations.” Powerpoint File.
Duloxetine. Adverse Effects. Medscape Mobile App. WebMD, LLC.
Gabapentin. Adverse Effects. Medscape Mobile App. WebMD, LLC.
Goldstrich, Joe D MD, FACC. “Unleashing the Full Potential of Cannabis’ Antineoplastic Benefits: Reimagining the Concept of Full Extract.” Powerpoing File.
“Neuropathy.” Cleveland Clinic, my.clevelandclinic.org/health/diseases/14737-neuropathy.
“Neuropathy Management and Treatment.” Cleveland Clinic, my.clevelandclinic.org/health/diseases/ neuropathy/management-and-treatment.
“Peripheral Neuropathy.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 9 Aug. 2017,
Russo, Ethan B., and Jahan Marcu. “Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.” Cannabinoid Pharmacology Advances in Pharmacology, 2017, pp. 67–134., doi: /bs.apha
Tramadol. Adverse Effects. Medscape Mobile App. WebMD, LLC.

17. Questions?