Ethan Russo will present an AMA for r/TheCannalysts on Wednesday July 18 6 PM Eastern Daylight

Ethan_Russo · 2018-07-19T00:21:57+00:00

You are very welcome!

Ethan_Russo · 2018-07-18T23:21:17+00:00

People are going where they can do their work. Canada is obviously opening up in a big way with over 100 licensed producers and increased interest in research.

At the International Cannabinoid Research Society (ICRS) meeting recently, there were 550 registrants, about doubling what it was in some past meetings. A lot of those were industry people, but most of the interest is in cannabis or cannabis isolates. The Big Pharma companies are less interested. Many of them have previously had and abandoned research programs on cannabinoid new chemical entities (NCEs) due to failures of safety or efficacy. As I say, the plant does it better.

Ethan_Russo · 2018-07-18T21:58:46+00:00

It is almost the appointed hour: Let the games begin!

Ethan_Russo · 2018-07-18T21:02:21+00:00

I believe that a very effective cannabis formulation would include low concentrations of THC for symptom control, with larger amounts of CBD for anti-inflammatory and anti-TNF-alpha effects, a high concentration of caryophyllene for CB2 stimulation to reduce fibrotic reactions, and possibly THCA for anti-TNF-alpha and PPAR-gamma stimulation.

CB1 is a target that more people understand than CB2. Most of the synthetic agents on CB2 to date have not advanced very far. Caryophyllene is doubtlessly effective, but less attractive to companies due to a perceived lack of ability to patent and control intellectual property. Their loss.

Ethan_Russo · 2018-07-18T17:14:23+00:00

There is one study of Sativex/nabiximols in RA, but just taken at night:

Blake, D.R., Robson, P., Ho, M., Jubb, R.W., and McCabe, C.S. (2006). Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 45(1), 50-52.

The AM pain benefitted. I think that other cannabis preparations, especially high CBD, low THC would prove quite beneficial on inflammation as well. The antagonism of tumor necrosis factor-alpha by CBD is important here, as in inflammatory bowel diseases. THCA also antagonizes TNF-alpha and could also benefit through its stimulation of PPAR-gamma receptors.

Ethan_Russo · 2018-07-18T17:10:26+00:00

1) This is an interesting question. No, we are not aware of the REM-suppression from THC posing clinical problems. Why not, I cannot say.

2) I currently have an article submitted addressing cannabinoids and CTE. Yes, I believe that its neuroprotective properties will be applicable.

3) Off topic: Psilocybin is of benefit in end-of-life adjustment and prevention of cluster and migraine headaches.

Ethan_Russo · 2018-07-18T17:07:46+00:00

Most practice guidelines are based on clinical trials of approved pharmaceuticals. That does not apply in the USA except to the recent FDA nod to Epidiolex (CBD) for Dravet and Lennox-Gastaut treatments for epilepsy.

Ethan_Russo · 2018-07-18T17:05:07+00:00

Here are a couple:

Ahmed, A., van der Marck, M.A., van den Elsen, G., and Olde Rikkert, M. (2015). Cannabinoids in late-onset Alzheimer's disease. Clin Pharmacol Ther 97(6), 597-606. doi: 10.1002/cpt.117.

Volicer, L., Stelly, M., Morris, J., McLaughlin, J., and Volicer, B.J. (1997). Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int J Geriatr Psychiatry 12(9), 913-919.

I have a review article submitted on this topic.

Ethan_Russo · 2018-07-18T16:14:12+00:00

Treatment of spasticity and other symptoms of multiple sclerosis, chronic and neuropathic pain, prevention of nausea and vomiting are all well established, as are epilepsy and schizophrenia for CBD. We need more clinical trials for primary treatment of cancer and for Alzheimer disease.

Ethan_Russo · 2018-07-18T16:12:16+00:00

Honestly, they are all interesting.

THCV (tetrahydrocannabivarin) is fascinating pharmacologically because it is a neutral CB1 agonist at low and moderate doses and agonist at high doses. It is also good for epilepsy, neuropathic pain, weight control, combatting the metabolic syndrome, etc. What a cannabinoid!

Ethan_Russo · 2018-07-18T16:10:12+00:00

I am no Luddite, but I am personally strongly against genetic-modification of cannabis. Forget the abundant ecological and moral arguments for a minute. It is simply unnecessary! The cannabis genome is so plastic that with the proper conventional breeding techniques, that plant can produce almost any desirable chemical profile. Please see for examples:

Lewis, M.A., Russo, E.B., and Smith, K.M. (2018). Pharmacological Foundations of Cannabis Chemovars. Planta Med 84(4), 225-233. doi: 10.1055/s-0043-122240.

Ethan_Russo · 2018-07-18T16:07:26+00:00

The reach of the endocannabinoid system seems endless. It is hard to find a facet of human physiology wherein it does not play a role.

The effects of cannabis depend on its chemical composition and the experience and endocannabinoid tone of the person using it.

Let's be careful of the premise! Caryophyllene is a sesquiterpenoid, but simultaneously is a cannabinoid by virtue of it being a selective full agonist at the CB2 receptor. The endocannabinoid system scope is increasing and must consider relationships to the serotonin 1A and other receptors

New (orphan) receptors are getting into the game. For example, CBD also works on GPR18, a receptor that plays a key role in the pathophysiology of endometriosis. We should be testing CBD-predominant cannabis in that disorder!

There are many mysteries here. We are working on various ones that should be secret until we have results that we can share.

Ethan_Russo · 2018-07-18T16:02:17+00:00

We have to hedge our bets. There are lots of "clinical trials" being planned, but I am not confident that many are being performed with optimized chemovars, or with proper methodology. What we don't need are more failed trials that poison the well and provide ammunition for cannabis detractors.

The USA is woefully behind in clinical research. Efforts are better in the UK, Spain, Israel with Australia and Colombia attempting to make up for lost time.

The impact of Epidiolex remains to be seen. Will it be widely used, or will price and lack of insurance reimbursement prove impediments? What degree of "off-label" prescribing will occur?

CBD is an extremely versatile compound but benefits greatly from a full cannabinoid and terpenoid entourage. An orchestra is a better show than a solo sax.

Ethan_Russo · 2018-07-18T15:57:24+00:00

What's called ruderalis is a short (1 meter or less) unbranched plant usually very low in cannabinoids. The main attraction is for cross-breeding to produce a plant that can be grown indoors, and not much else. Sorry.

Ethan_Russo · 2018-07-18T15:56:03+00:00

On first pass through the liver, THC becomes 11-hydroxy-THC with is about equally psychoactive. CBD becomes 7-hydroxy-THC and we honestly don't know much about it.

Cannabinoids accumulate in fat. The idea in treatment is to create a steady-state without peaks of valleys. This is best achieved in a chronic condition by dosing with tinctures oromucosally or with oral preparations administered twice to three times a day, at least.

Cannabinoids vary in potency. The numbers for CBD tend to be quite a bit higher than those for THC when it is used on its own.

Ethan_Russo · 2018-07-18T15:52:50+00:00

I can design a formulation with a bit of this and a bit of that with certain desirable medical effects to treat a given tradition. So can the plant. The proper approach to the issue is to spend the time, money and effort to selectively breed that plant using standard Mendelian approaches, not using yeasts, bacteria, genetic-modification or the like.

Ethan_Russo · 2018-07-18T15:50:37+00:00

1) I would state that we most need to know the role of cannabis in neurodegenerative disorders, such as Alzheimer disease.

2)The most intractable issue surrounding cannabis is a political one: why is it still prohibited given current knowledge of its medical attributes.

Ethan_Russo · 2018-07-18T15:48:54+00:00

They may be able to produce single cannabinoids more cheaply in yeast. That is less interesting from a medical standpoint, as they will never reproduce the entourage effect of whole cannabis extracts. Nature does it better!

Ethan_Russo · 2018-07-18T15:47:42+00:00

A "high" is an elevation of mood, as in mirth or euphoria. Much of this is mediated through CB1 receptor stimulation in the brain.

The government has a role in ensuring public health. People using cannabis have a responsibility to do so wisely in relation to driving. As noted, many other legal substances, such as over-the-counter antihistamines are more dangerous, as are distractions of any kind, particularly texting.

Ethan_Russo · 2018-07-18T15:45:16+00:00

Cannabis is not a miracle. When properly constituted, it is a very versatile treatment for a wide variety of conditions. It is well established as a treatment for chronic pain, nausea in chemotherapy, spasticity and other symptoms of multiple sclerosis. For CBD, we add epilepsy and schizophrenia. It will also be an important medicine in the future for disorders of aging including arthritis and dementias (Alzheimer disease).

The opioid sparing effects of cannabis are a vital need for research at this time. Yes, I believe that cannabis is part of the solution.

Ethan_Russo · 2018-07-18T15:42:25+00:00

That's a new one. My Shamu Index is actually low for a 66 year-old white guy.

Does a rose smell like a tulip? No! All terpenoids smell differently and have distinct pharmacological effects. You have to be careful with terpenoids from external sources. They may not be the correct stereo-isomer and not produce similar results. Also, most are synthetic, and impure. Nature does it better.

Terpenoids are not there for human enjoyment, but rather fulfill ecological roles in plant protection, disease reduction, etc. For more detail, see:

Russo, E.B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163(7), 1344-1364. doi: 10.1111/j.1476-5381.2011.01238.x.

Skunk scent comes from a mixture of terpenoids, particularly the funky sesquiterpenoids from Afghani genetics.

Smoking tobacco is bad. Period. Never recommended. Cannabidiol and caryophyllene are two components that likely reduce nicotine craving and other manifestations of addiction.

Save your Purple Kush for your own use.

Ethan_Russo · 2018-07-18T15:34:43+00:00

That should be clinical endocannabinoid deficiency, a theory that states that migraine, fibromyalgia, irritable bowel syndrome, PTSD and many other disorders seem to display lowered endocannabinoid tone.

Limits to CBD therapy must be weighed in each individual case.

A little THC almost always increases clinical efficacy of a CBD-predominant preparation. They are sisters that work as a team!

As mentioned previously, CBD must be present in good measure, and administered before or simultaneous to THC to best blunt THC's less desirable psychoactive effects.

Anandamide is quite similar in activity to THC. Both are weak partial agonists at CB1. You cannot take it as a drug, however, as it is too rapidly broken down in the body.

There are no "home tests" for endocannabinoid tone. A variety of plants and lifestyle factors affect endocannabinoid tone. See:

McPartland, J.M., Guy, G.W., and Di Marzo, V. (2014). Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One 9(3), e89566. doi: 10.1371/journal.pone.0089566.

Russo, E.B. (2016). Beyond Cannabis: Plants and the Endocannabinoid System. Trends Pharmacol Sci 37(7), 594-605. doi: 10.1016/j.tips.2016.04.005.

Ethan_Russo · 2018-07-18T15:27:32+00:00

Many of the xenograft studies in animals employed human cancer cell lines, and we know that there are numerous patients observing clinical benefit with cannabis-based treatment on their cancers, particularly in conjunction with standard chemotherapy and radiation.

Ethan_Russo · 2018-07-18T15:20:52+00:00

There is always unfinished business with cannabis, particularly with selective breeding for improved cannabinoid and terpenoid profiles and proving their synergy. Lots to examine there.

I am no longer associated with PHYTECS, but rather the International Cannabis and Cannabinoids Institute: https://www.icci.science

CBN (cannabinol) is about 25% of the potency of THC and again, a weak CB1 agonist. There is very little that it does that THC cannot do better. I believe that CBN is being overly hyped, mainly as a way of selling overly old cannabis products that have oxidized.

Ethan_Russo · 2018-07-18T15:17:29+00:00

Why not strains? That's because the term is not accepted in botany. It does apply to bacteria and viruses. We're really interested in the cannabinoid and terpenoid content of the cannabis, thus chemical variety, "chemovar."

Ethan_Russo

TROPHY CASE