Vol. 7, Number 11
November 2015
cheryl riley, James Freire,
Dr. David Bearman,
Gradi Jordan, Ed Glick,
Paul Armentano, Keith Stroup
Sunil K Aggarwal,
Al Byrne, Amanda Reiman,
Jim Greig, Chip Whitley,
Sandee Burbank, Joan Bello
Dr. Ethan Russo,
Arthur Livermore
Who's Who
What's New
Contact Us Click here to donate to the American Alliance For Medical Cannabis! Bookmark and Share
AAMC California
AAMC El Dorado County CA
AAMC Idaho
AAMC Kansas
AAMC Oregon
AAMC Rhode Island
AAMC Washington

Current Status and Future of Cannabis Research - Ethan Russo, et.al.

Although cannabis is primarily viewed by the public as a recreational drug or agent of abuse, its medical application spans recorded history. Evolution has yielded a cannabis plant that produces a family of some 100 chemicals called phytocannabinoids (“plant cannabinoids”), many of which have distinct and valuable therapeutic effects.

Cannabis is a versatile herb that can produce a variety of medicinal preparations with distinct pharmacologic properties, depending on the content of cannabinoids and other phytochemicals, many of which possess synergistic effects. The best known plant cannabinoid is tetrahydrocannabinol (THC), the primary psychoactive agent in cannabis, responsible for the preponderance of the cannabis “high”; however, it is also a powerful analgesic, muscle relaxant, and antinausea agent, among myriad other effects. Coming to greater recognition is its analogue sister, cannabidiol (CBD), which distinguishes itself by its lack of intoxication and its ability to complement the pain relief, antiemetic, anticonvulsant, and other benefits of THC, while modulating and attenuating its associated side effects (anxiety, tachycardia, et al.).

To gain regulatory approval of a cannabis-based product, pursuing the dietary supplement/botanical path—as opposed to the pharmaceutical one—may be an option for certain preparations. Dietary supplements rarely contain substances with abuse potential, and manufacturers and vendors of such products can make only “structure and function” claims (e.g., “promotes heart health”), rather than medical claims. Therefore, it is probably unlikely that cannabis preparations with a notable amount of THC could be treated as dietary supplements. However, nonpsychoactive cannabinoids, such as CBD could be descheduled (i.e., removed from the federal Controlled Substances Act [CSA]) and developed and marketed as botanical supplements.

Cannabis exerts its effects through a variety of receptor and nonreceptor mechanisms. All vertebrates tested to date harbor an endogenous cannabinoid system (ECS), a regulator of physiological homeostasis whose function has been summarized as “relax, eat, sleep, forget, and protect.” The ECS has three components: endocannabinoids, biosynthetic and catabolic enzymes, and two cannabinoid receptors—CB1, the “psychoactive” neuromodulator that is the most abundant G-protein coupled receptor in the brain, and CB2, a nonpsychoactive immunomodulatory and anti-inflammatory receptor most abundant in the periphery.

Although various surveys support the idea that the American public already accepts the medical utility of cannabis and is acting upon that belief in ever higher numbers, the U.S. Food and Drug Administration (FDA) requires more rigorous proof. Additionally, a survey of Colorado family physicians found that; “Despite a high prevalence of use in Colorado, most family physicians are not convinced of marijuana’s health benefits and believe its use carries risks. Nearly all agreed on the need for further medical education about medical marijuana.”

If cannabis-based medicines are to overcome prejudice and gain greater trust from physicians, their production must be standardized and their contents proven safe and efficacious in randomized clinical trials (RCTs) that follow accepted scientific method and are the sine qua non of regulatory bodies such as the FDA. However, botanical cannabis is highly inconsistent and variable in its chemical composition.

Procedures for standardization of plant-based medicines have been formally presented in the U.S., providing an FDA blueprint for their regulatory approval in the “Guidance for Industry: Botanical Drug Products.” Meanwhile, although cannabis smoking may not be epidemiologically linked to lung cancer, it is responsible for chronic cough, sputum, and cytological changes, which render smoked cannabis an impossible candidate for approval as a prescription product in most jurisdictions.

Anecdotal claims for efficacy of crude cannabis hold no sway for the FDA. There is a relative paucity of published RCT data for inhaled cannabis: the existing trials for pain total only three patient-years of data, whereas the corresponding figure for nabiximols (Sativex®, GW Pharmaceuticals), a standardized oromucosal extract spray combining THC, CBD, and other cannabis components, exceeds 6,000 patient-years of data in published studies of pain, or a two thousand-fold difference. The latter is also approved in 26 countries for treatment of spasticity in multiple sclerosis, and is currently completing clinical trials for opioid-resistant cancer pain in the U.S. and elsewhere. This agent has fulfilled criteria of safety and consistency, and has not been abused or diverted to any degree in more than 30,000 patient-years of recorded usage.

Regulatory Challenges and Solutions

The FDA has responsibility for assessing human research and evaluating data from clinical studies. Such research is initiated by an individual researcher in an investigator-initiated trial (IIT) or by a pharmaceutical company. In both situations, an Investigational New Drug (IND) application containing one or more protocols must be presented to, and allowed by, the FDA.

For industry-sponsored programs, the FDA requires a range of nonclinical/preclinical studies and then clinical trials to demonstrate that the product meets the FDA’s exacting standards of quality, safety, and efficacy in a particular patient population.

The FDA has clarified that it will allow both IITs and RCT development programs with cannabis or cannabis-derived products. Examples of such IITs have been completed and published. An industry-sponsored development program is also progressing with a cannabis-derived product. Finally, FDA has promulgated “expanded access” regulations in the Code of Federal Regulations in 21 CFR sections 312.310, 312.315, and 312.320, allowing seriously ill patients who lack conventional treatment options and clinical trial opportunities to be treated with an investigational product on a compassionate access basis. More than 300 children with various types of medication-resistant epilep- sies have been allowed by FDA to receive treatment with a cannabis-derived (but purified) CBD product under such expanded access programs.

Studies involving herbal cannabis must obtain the material from the National Institute on Drug Abuse (NIDA), which is the sole federally lawful source of research-grade cannabis. NIDA has contracted with the University of Mississippi to grow cannabis (of various cannabinoid ratios and potencies) for research.

FDA has approved at least two products based on botanical extracts; however, FDA has not previously approved any raw botanical/herbal material as a prescription medicine. Such material would face regulatory challenges, such as achieving adequate purity, displaying batch-to-batch standardization, and identifying an appropriate method of delivery (i.e., one that would supply a precise and reproducible dose without the production of toxic by-products).

Cannabis, THC, and products containing botanically or synthetically derived cannabinoids found in the cannabis plant are classified under Schedule I of the federal CSA. The CSA contains five schedules corresponding to a substance’s abuse potential and medical usefulness.

Schedule I and II substances are subject to strict security, recordkeeping, and other measures. Substances in Schedule I have “no currently accepted medical use in the U.S.” and a high potential for abuse. Substances in Schedule II also have a high potential for abuse, but have an “accepted medical use,” a phrase given specific meaning by the federal Drug Enforcement Administration (DEA) and upheld by federal courts:

1. The drug’s chemistry must be known and reproducible;
2. There must be adequate safety studies;
3. There must be adequate and well-controlled studies proving efficacy;
4. The drug must be accepted by qualified experts; and
5. The scientific evidence must be widely available.

If FDA approves a cannabis-derived product, such approval constitutes “accepted medical use,” and that product will then be moved to a less stringent schedule. Although a substance and a product containing that substance are in the same schedule, “differential” scheduling is possible. For example, Marinol, a product comprising synthetic THC in sesame oil, is classified in Schedule III, whereas other forms of THC remain in Schedule I. This may serve as precedent if a cannabis-derived product is FDA approved and rescheduled, although cannabis may remain in Schedule I.

Cannabis’s (and THC’s) Schedule I status means there are additional hurdles to overcome to conduct research in the U.S. As provided in 21 CFR section 1301, a physician who holds a DEA registration (license) to prescribe controlled substances in Schedules II–V may conduct research within those schedules as a “coincident activity” to his or her existing registration, with no further approval from the DEA.

However, to conduct research with a Schedule I substance, an investigator must secure a Schedule I research registration from DEA (which is substance- and protocol-specific), and (often) a Schedule I research license from the state-controlled drugs agency. These additional steps can add three to six months to the time required before an investigator can begin the research project.

A specific medical product cannot be prescribed by physicians and dispensed by pharmacists unless the FDA has approved that product (the “compounding pharmacy” exception is very limited). Therefore, even if cannabis were moved to Schedule II, physicians could not automatically prescribe it directly to patients. Although the NIDA single-source supply is the only domestic source, cannabis-derived products may be manufactured in Europe or elsewhere, and the finished product may be imported into the U.S. for research or ultimately for commercial distribution following FDA approval.

Current Status of Clinical Cannabinoid Medicine

Due to the obstacles involved in human clinical research using cannabis, widespread use in the clinical setting has preceded well-established data on dosage, delivery systems, safety, and efficacy. In states that have legalized medical cannabis, about 0.77% of the population use cannabis with the recommendation of a medical provider.

Cannabinoids are considered nonlethal and have a wide range of effective and tolerated dosages. Many patients use medical cannabis in a harm-reduction paradigm to decrease or discontinue the use of prescribed and illicit substances. Also, the growing number of medical providers accepting cannabis as a viable treatment option may attest to observed or suspected clinical efficacy. Meanwhile, observational studies can inform the emerging clinical practice of cannabinoid medicine, while guiding the development of clinical experimental design.

One of this article’s authors has observed clinical responses in his patient population in oral doses beginning as low as 0.1 mg cannabinoids/kg body weight/day, whereas some find optimal benefits at doses as high as 25 mg/kg/day. This wide dosing range is complicated by a biphasic dose-response curve, where lower doses may exhibit greater efficacy and tolerability than higher doses, as seen in a clinical trial of nabiximols for poorly controlled chronic pain in opioid-treated cancer patients.

Another clinical trial of inhaled cannabis for neuropathic pain found low-potency (3.5% THC) and high-potency (7% THC) cannabis to have equivalent analgesic properties. Biphasic dose-response effects may be due to subjects’ sensitization to cannabinoids at lower doses and tolerance building at higher doses. This hypothesis is supported by preclinical studies in which administration of exogenous cannabinoids both upregulate endocannabinoid system function at acute and lower doses via increased endocannabinoid production, cannabinoid receptor expression, and cannabinoid receptor affinity, and downregulate endocannabinoid system function upon persistent agonism via membrane receptor endosome internalization.

Bidirectional effects are often related to dosage, with high doses of cannabinoids potentially causing symptoms usually ameliorated by lower dosages. The mindset of the cannabis user and setting in which the cannabis use takes place also influence bidirectional effects; anxious subjects tend to become less anxious and more euphoric, nonanxious individuals tend to become somewhat more anxious, and stressful environments can precipitate adverse emotional responses.

Polymorphisms have been associated with variable responses to cannabis, including protective effects on development of cannabis dependence in adolescents, intensity of withdrawal and craving during cannabis abstinence, and white matter volume deficits and cognitive impairments in schizophrenic heavy cannabis users.

Cannabis use history also complicates clinical response, with cannabis-naïve patients demonstrating more frequent adverse effects and regular users demonstrating less psychotomimetic, perceptual altering, amnestic, and endocrine effects.

Another factor to note is that physicians often lack training in using botanical medicines, and endocannabinoid physiology is still absent from most medical school curricula. Many legal cannabis patients receive permission to use cannabis from their physician, but must rely on formula selection and dosing instructions provided by cannabis growers or dispensary staff with little training or experience.

Properly interpreting observational data on medical cannabis patients requires an understanding of the chemical composition and potency of the cannabis preparations used, and of the pharmacokinetics of the delivery system employed. Laboratories offering third-party chemical analysis of herbal cannabis preparations under industry-published standards can be found in most states that allow the use of medical cannabis.


The endocannabinoid system regulates physiologic homeostasis and is an exciting target for disease management and health promotion. Cannabis-based preparations are poised to become an accepted option in mainstream medicine, with broad support from preclinical models, patient testimonials, and more recently, human clinical trials.

However, numerous regulatory, botanical, and pharmacologic factors challenge the collection and interpretation of clinical data on the efficacy of cannabinoid therapies. The understanding of an individual’s optimal dosing and delivery method of cannabinoids for various ailments is still emerging, and must be guided by both observational and experimental data.

Clinical researchers can overcome the challenges inherent in cannabinoid therapeutics and help elucidate solutions for a wide variety of prevalent health challenges.


The authors would like to express sincere thanks to Tyler Strause, Brendon Strause, and Linda Strause, PhD, for their excellent support and review in preparing this article.

For more information see: http://www.letfreedomgrow.com/cmu/Russo-et-al-Current-status-and-future-of-cannabis-research-Clin-Researcher-2015.pdf

How to avoid cannabis-fueled anxiety. - Chip Whitley
Anxiety and paranoia can be extremely unpleasant side effects of marijuana. Some people even experience full-blown panic attacks whenever they give cannabis a try.

Not fun.

This can be a tremendous obstacle for people looking to medicate with cannabis, and many avoid the herb altogether because of it. I should know because I was one of these people for the longest time.

After all, how could it be that some people use this plant to treat anxiety and for others it causes anxiety?

The confusion and the repeated frustration was enough to get me digging into some serious research. I wanted to know what caused the anxiety and how or even if I could avoid those unpleasant feelings.

Here’s what I found.

How cannabis treats anxiety.

Cannabinoid receptors can be found throughout the body and in several parts of the brain – including the amygdala. Near the center of our brains we have a twin set of neuron bundles called the amygdalae, responsible for importing cognitive processes, including fear and are fight or flight response.

The discovery that these amygdalae contain cannabinoid receptors – as verified by researchers at Vanderbilt University in 2014 – is a major step in understanding how cannabis can actually treat anxiety.

The idea is that these receptors depend on cannabinoids to do their job, to regulate all of those important emotional processes – as well as a ton of other processes in the body.

But sometimes the body doesn’t produce enough of its own cannabinoids – what we call endocannabinoids. In the case of anxiety, for example, research indicates that traumatic experiences can actually hinder the production of these endocannabinoids.

This would explain how people have reported success in treating various anxiety disorders, such as anorexia or PTSD, with cannabis.

But this still doesn’t explain why cannabis causes anxiety and paranoia for certain people. And although more research is needed, there are a few key factors we can examine now.

The Chemical Composition of Cannabis

Cannabinoids work best together. For example, CBD can actually help mitigate the effects of THC thus reducing the odds of a panic attack. As most of you already know, cannabis comes in a variety of chemical makeups. There are sativas and indicas, each with their own differing levels of CBD and THC. Because of these chemical variations, people tend to use different types to achieve a desired effect.

But when you look at the chemical makeups between the two, generally we see that indica strains are higher in THC than CBD (creating a ‘heavier’ high), and sativas are higher in CBD.

Not that THC is a bad thing, but it has been linked to feelings of paranoia and anxiety. So, using an indica strain, or indica-derived product, may cause anxiety more frequently than a sativa.

Depending on what type of product you’re using, and what specific strains (and chemical compositions) are present, you may be more apt to experience anxiety.

Your Physical Make-Up

We all have different bodies, different metabolism rates, and different reactions to marijuana. This is why figuring out the perfect cannabis regimen often takes a bit of trial and error. Everyone is affected by chemicals differently. This is why you may eat just a few bites of a medicated brownie and find yourself on another planet, yet your buddy can eat the whole brownie and not feel a thing.

You’re both handling the chemicals differently, and there are seemingly a million factors that play into that.

Body size, age, gender and many other chemical processes in the body can all play a role in how you metabolize that brownie.

Also, the method in which cannabis is ingested plays a part. If you’re smoking dry flower, you may notice that you get a faster, or more impactful result. Edibles on the other hand can take up to two hours before you notice anything.

So, How Can I Actually Avoid Anxiety?

Understanding how cannabis actually works is a huge step in learning how to reduce the potential for anxiety or paranoia. You can try a number of things to alleviate yourself of cannabis-induced anxiety.
  • Consume smaller doses of cannabis.
  • Experiment with different strains.
  • Try alternative methods.
  • Mind your set and setting.
These are extremely valuable tips, so let’s dive a little deeper into each one.

#1) Smaller doses

For many people, consuming too much pot leads to anxiety and other unwanted side effects. Whether you’re new to cannabis or not, taking in smaller doses can help you steer clear of anxiety and other unwanted side effects while achieving greater medical benefits over a longer period of time.

A lot of people – including myself – swear by micro-dosing, which involves medicating with such a small amount of cannabis that you notice minimum to zero side effects.

If you’re curious to learn more about micro-dosing, check out this comprehensive article about how less may indeed be more.

#2) Different strains

Sativa versus Indica.

Some strains will make you more anxious than others, depending your body. It’s important that we are able to experiment and find the strains that we like best. All the more reason to fight for sensible marijuana regulation. If you live in a state or country where cannabis is still prohibited, you’re not going to have a lot of options here.

But if you do have access to a dispensary, you might want to experiment with a variety of CBD-dominant strains.

CBD actually works to modulate the effects of THC, so even an equal 1:1 ratio might be more to your liking.

#3) Alternative methods

If you live near a good dispensary, you’ll have access to all sorts of cannabis products and delivery systems. Smoking, vaping, edibles – all of these methods lead to different effects and experiences with cannabis.

With smoking and vaping, it’s much easier to self-titrate because the effects are almost immediate.

With edibles dosage can be much trickier, but if you can get it just right, this could be your ideal method of consumption.

If you are new to edibles, here is a detailed guide to get you started.

#4) Set and setting

Mindset and atmosphere are just as important as strains and dosage levels if you want to get the most out of cannabis. Being mindful about set and setting, which refers to your mindset and your immediate environment, before consuming cannabis will also help with anxiety.

For example, I am much less likely to experience anxious thoughts if I have a few puffs while relaxing with some chill music or hanging with a close friend.

But if I toke up before or during an occasion where cannabis would not add as much value, then anxiety could be inevitable.

These are important points to consider before each and every cannabis session. Why I am using cannabis now? What value will it add? Might it be better to wait until later?

#5) One more trick


There is actually a scientific explanation as to why pepper can reduce anxiety among cannabis users. If all else fails and you find yourself gripped in a miserable state of cannabis-induced anxiety, try chewing on a peppercorn or even just smelling fresh pepper.

I haven’t tried this myself yet, but apparently pepper has a phytocannabinoid-terpenoid effect that interacts in a synergistic way with cannabis to reduce anxiety and paranoia.

Worth a shot right?

What works best for you?

Establishing the perfect cannabis regimen is a very personal experience that takes a lot of trial and error, mindfulness, and a willingness to recognize what works and what doesn’t.

If you’re patient, you can find what works best for you and avoid those unwanted side effects of marijuana. For me, it’s all about taking smaller doses and consuming when my set and setting are just right.

What has your experience been with anxiety and paranoia when consuming cannabis? Have any of these suggestions worked for you? Have you tried the peppercorn trick?

Original article: greenflowermedia.com

Medical Cannabis
Educational Video Project

We are starting a campaign to support the Medical Cannabis educational video project. Please go to our donation page to support this campaign.

What's New

Alabama: Considering a medical marijuana law.
   HB642 - The Michael Phillips Compassionate Care Act of Alabama

Arkansas: Considering a medical marijuana law.

Florida: Medical marijuana did not pass with 58% support

Georgia: Medical marijuana is now partly legal in Georgia

Idaho: Considering a medical marijuana law.

Indiana: Considering a medical marijuana law.

Iowa: Considering a medical marijuana law.

Kansas: Medical marijuana petition drive underway.
   Marijuana Bill Reaches House
   Cannabis Compassion and Care Act

Missouri: Considering a medical marijuana law.
   HOUSE BILL NO. 1670 - An Act relating to the use of marijuana for medicinal purposes
   Cottleville Mayor Don Yarber hopes Missouri legislature passes medical marijuana law

North Carolina: Considering a medical marijuana law.
   North Carolina Medical Cannabis Act

Ohio: Medical marijuana law on November ballot.
   Ohio to vote on pot this year

Pennsylvania: Considering a medical marijuana law.
   HB 1393

South Carolina: Considering a medical marijuana law.

South Dakota: Medical marijuana petition drive underway.

Tennessee: Considering a medical marijuana law.

Texas: Considering a medical marijuana law.

Wisconsin: Considering a medical marijuana law.
   The Jacki Rickert Medical Marijuana Act

Featured Recipe - Mac Attack: A Canny Bus Treat by Jay R. Cavanaugh, Ph.D.

Everyone loves macaroni and cheese. Nancy Wife and I sure do. Before we even start you better know that this recipe is a heart attack on a plate. I tried to measure the grams of saturated fat and just lost track. What's really different about our Canny version is that using Better Bud Butter actually lowers the saturated fat quite a bit but not nearly enough to call this healthy.

Please don't even try to follow this recipe too closely. Improvise. If you don't like white cheddar use yellow. If you don't like sharp cheese use Longhorn or mild. Heck you can even use a good Swiss cheese like Jarlsberg. It's OK. You won't go to jail for substitutions. Of course the cannabutter does make this overall recipe a Federal felony. Can you imagine getting 10 years in Leavenworth Prison for felony Mac? Yikes.

Once you've made your own home baked Mac you'll never do store bought again. The key to this recipe is using the freshest ingredients you have that meet your particular taste. If you're a vegetarian you'll love this recipe even without the ham (some vegetarians can consume dairy). If you'd prefer to use bacon or even ground beef instead of ham, go for it! You want it spicier? Kick it up with diced fresh chilies. This recipe comes with three guarantees:

  1. You'll love it
  2. You'll gain weight (lots of us patients need that J)
  3. You'll probably require anti-cholesterol meds if you eat this too often


8 tablespoons of Better Bud Butter
4 tablespoons of flour
2 cups of regular milk
1 cup of heavy cream
8 ounces of aged cheddar cheese grated (white or yellow)
12 oz of good macaroni noodles (you can use penne if you're snobby)
1 teaspoon salt
1 tablespoon cracked black pepper - to taste
1 tablespoon Jay's Essence or cayenne pepper - to taste
8 oz of fined diced smoked ham (real Black Forest if you can find it)

Optional: 2 medium sized Jalapeno chilies finely diced
Optional: ½ cup finely diced Maui onions
Optional: 1/3 cup of fresh bread crumbs


Cook the pasta of your choice in lightly salted boiling water. We use fresh pasta so 4 minutes is more than enough. If you use dry try 8 minutes. The key is Al Dente (that means "to the teeth"). Actually, I went to school with Al and have never forgotten him. A handy trick is to add a cap full of olive oil to the water to prevent sticking. Cook the pasta then drain and set aside.

Slowly melt the Better Bud Butter over a low heat. Gradually work in the flour with LOTS of stirring (yes you're making a rue). Whisk in the milk and bring to a slow boil then turn off the heat. Add the spices and mix in the finely grated cheese (yes, you're now making a Béchamel sauce). As the cheese melts (it will be very thick) slowly add just enough cream for the texture you like. Mix in the diced smoked ham and chilies and/or onions if you like.

Pour all of the ingredients into a large greased (we use Pam) baking dish and sprinkle with bread crumbs if you like (we leave them out for reasons explained below).

Bake in a preheated 350 degree oven for about 20-35 minutes or until brown and bubbly.

Hint Number One: Let the dish sit out for at least ten minutes before you try to plate it. This stuff is hot, hot, and hot.

Hint Number Two: Mac Attack Two (otherwise known as Maximum Mac)

Assuming you and your friends don't finish the entire casserole on the first evening, cover the leftovers and place in the refrigerator for 24 hours. The next night cut out rectangles of Mac Attack and dust with flour, roll in an egg wash, roll in fresh crumbs, and yes, oh my God, deep fry at 350 degrees. Yum! This dish is not for cardiac amateurs. Keep your nitro handy.

Recommended beverage: Any good Oregon Pinot Noir lightly chilled

Caution: Do not operate heavy machinery or attempt surgery after eating. Don't drive after two helpings.

Follow AAMC on:
9th National Clinical Conference on Cannabis Therapeutics
May 21-23, 2015
West Palm Beach, Florida USA

Contribute to the AAMC
Legal Fund here:
Click here to donate to the AAMC Legal Fund!

Medical Marijuana States

Alaska #
Arizona *
Colorado #
District of Columbia #
Maine *
Michigan *
Montana *
Nevada *
New Hampshire
New Jersey
New Mexico
New York
Oregon #
Rhode Island *
Washington #

* States with reciprocity law

# States with legal marijuana

Pacific One Distributors
Advertise on Facebook
Click here to join the American Alliance For Medical Cannabis!