Cannabis: State of the Science

Cannabis Xray webX-ray image of a Cannabis sativa plant (Ted Kinsman/Science Source)These days, cannabis and cannabis-derived compounds are ubiquitous.

Millions use these products with the hope of preventing or mitigating a wide variety of disorders—everything from chronic pain and insomnia to diabetes and some forms of cancer. Odds are good that some of your patients are among them.

So, it is reasonable to ask: Is there any solid science to support the use of phytocannabinoids in clinical practice?

The answer is yes….and no.

It depends on how you define “cannabis” and “cannabinoids;” whether you’re talking about inhaled (ie, smoked or vaped), ingested, or sublingual delivery; and of course, which diseases you’re considering. The quantity and quality of evidence varies widely.

“Cannabinoid science is still in a very early stage,” said Richard Carlton, MD, in a webinar hosted by Holistic Primary Care, and sponsored by the Helix Institute of Health. “In truth, most of the phytocannabinoids have barely been characterized.”

Carlton is a New York City psychiatrist who has used cannabis clinically for decades. He also worked closely with New York State legislators in developing that state’s medical cannabis program.

The first thing to understand is that cannabis is complex, says Carlton. “The plant contains literally thousands of bioactive compounds, and at least 80 known cannabinoid compounds.” THC and CBD are the headline-grabbers. But there are others, including cannabivarin (CBV), and cannabigerol (CBG), that may have anti-inflammatory and anti-oxidant effects, and possibly neuro-reparative effects.

The ECS Circuit-Breaker

The endocannabinoid system (ECS) is, essentially a set of biochemical circuit breakers that helps the nervous system self-regulate, he explained.

“When a presynaptic neuron is firing excessively, and thereby inducing excessive activation at the post-synaptic cleft--as would be the case from glutamatergic excitoxicity in seizures, stroke, and traumatic brain injury--the post-synaptic neuron can “sense” this excessive activity, and reacts to it by synthesizing and releasing an endocannabinoid, like anandamide or 2-AG, that down-regulate that excessive firing.”

In essence, phytocannabinoids from C. sativa (and, to be fair, some other plants also) give similar effects. Cannabinoids may also interact with other physiological systems, including the gut microbiome. But researchers attribute most of the reported benefits to the effects of cannabinoids on the ECS.

And yes, says Carlton, there are controlled studies showing that inhaled or ingested cannabis—or extracts from it—have some degree of efficacy in: multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s, dementia, migraines, chronic pain, migraines, seizure disorders, gastroesophageal reflux, Crohn’s and ulcerative colitis, diabetes, premenstrual symptoms, and some types of cancer (as palliative and directly anti-neoplastic). But there are also plenty of negative studies showing little or no effect.

Hazekamp and Grotenherman at Leiden University summarized many of these trials. They note, “cannabinoids present an interesting therapeutic potential mainly as analgesics in chronic neuropathic pain, appetite stimulants in debilitating diseases (cancer and AIDS), as well as in the treatment of multiple sclerosis (Hazekamp A, Grotenhermen F. Cannabinoids. 2010: 5: 1-21).

A new review of CBD research by CM White, a University of Connecticut pharmacist, concludes that the evidence is strong for purified CBD as a treatment for refractory seizures, and promising for schizophrenia and certain forms of anxiety. But the data are far less convincing for other conditions (White CM. J Clin Pharmacol. 2019)

In reading a cannabinoid study, keep in mind the specific substance being tested: Is it cannabis plant material smoked, vaporized, or ingested? Purified cannabinoid extracts (ie CBD, THC)? Synthetic cannabinoids? Equally important is the dose level and cannabinoid concentration.

Many of the best studies were done either with inhaled cannabis containing a wide spectrum of compounds, or with highly purified, concentrated CBD or CBD/THC Richard CarltonRichard Carlton, MD, Integrative Psychiatrist, New York, NYcombined. The outcomes from a given trial are specific to the particular form(s) and dose(s) tested, and for the particular patient type with the specific condition described in the paper.

One of the biggest challenges in this field is that marketers often cite data on one form, dose level, or patient group to support claims about very different forms or patient types. They may imply an equivalence that has not yet been proven.

When it comes to cannabis claims, balance open-mindedness with good critical thinking.  Following is a brief review—by no means comprehensive—of important cannabinoid science.

Seizure Disorders

The case for CBD as a treatment of refractory seizures is strong, thanks largely to a series of trials sponsored by GW Pharmaceuticals in support of Epidiolex, its 99% pure plant-derived CBD. Those, and other trials were thoroughly reviewed in articles by Perucca and Stockings et al, and they laid the basis for the FDA’s approval of Epidiolex for Dravet and Lennox-Gastaut Syndromes.

A new review by University of Colorado researchers confirms Epidiolex’ status as a “new hope” for patients with severe seizure disorders (Chen JW et al. Ann Pharmacother. 2019). Similarly, University of Alabama neurologists note that open-label expanded access programs show that purified CBD gives, “significant improvement in seizure frequency in large numbers of patients with various types of treatment-refractory epilepsy,” while randomized controlled trials show “significant seizure reduction compared to placebo” in patients with Dravet or Lennox-Gastaut (Gaston TE, Szaflarski JP. Curr Neurol Neurosci Rep. 2018.)

In a new open-label extension trial involving 264 refractory seizure patients, New York University researchers report that at a median dose of 21 mg/kg per day for 9 months or more, CBD produced “sustained, clinically meaningful reductions in seizure frequency.” (Devinsky O, et al. Epilepsia. 2019).

While the evidence is impressive, bear in mind that all of these trials tested highly purified CBD as an adjunct in patients already taking one or, in many cases, several anti-seizure medications. As Zaheer and colleagues point out in their recent review, “it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications.”

Also in question is whether non-Rx products with lower CBD levels can modulate seizures. There are plenty of testimonies and anecdotes, but so far, no one has tested that hypothesis.

Chronic Pain

In 2007, Abrams and colleagues at San Francisco General Hospital reported that smoked cannabis containing 3.56% THC could markedly reduce HIV-associated neuropathy. The study involved 50 patients. It was placebo controlled in the sense that the control group was given cannabis cigarettes with the cannabinoids extracted.

Patients using active cannabis (thrice daily) had a 34% reduction in mean pain intensity, versus 17% in the placebo group. In the active cannabinoids group, 52% of patients had a 30% or greater reduction in pain versus 24% in the control arm (Abrams DI, et al. Neurology, 2007).

Several years later, Abrams’ group also showed that vaping THC-rich cannabis thrice daily reduced pain scores by an average of 10 to 11 points  in 21 patients suffering chronic pain despite use of sustained-release morphine or oxycodone. THC appeared synergistic with opioids in terms of analgesia, but did not alter opioid blood levels (Abrams DI, et al. Clin Pharm Therapeut. 2011).

Prior to Epidiolex, GW Pharma had filed an investigational new drug (IND) application for its Sativex CBD/THC combination as a pain treatment. Investigator Ethan Russo notes that “numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis, and cancer pain.” (Russo EB, Ther Clin Risk Manag. 2008). Though approved in the UK, Europe, and parts of Asia, it has not yet been approved in the US.

While these studies do suggest that cannabis can attenuate certain types of intractable pain, they need to be interpreted cautiously.

Last year, the Cochrane Collaboration published a systematic review of 16 placebo-controlled pain studies using various forms of cannabis (10 of oral THC/CBD sprays; 2 of inhaled cannabis; 2 of naturally-occurring THC extract; one of nabilone, a synthetic THC-like compound).

Cochrane’s conclusion?  While cannabis‐based meds in aggregate performed better than placebo for pain relief, global symptom improvement, sleep and psychological distress, the quality of evidence is moderate at best, and the benefits may be outweighed by the high prevalence of non-serious but significant side effects like sleepiness, dizziness and cognitive problems such as confusion (Mucke M, et al. Cochrane Database Systematic Reviews. 2018).

In the cancer care context, recent randomized studies of Sativex in patients with refractory cancer-related pain have shown no significant benefits. That runs counter to earlier observational studies suggesting that cancer patients experience pain relief when using medical cannabis. This is a subject ripe for further exploration (Steele G, et al. Curr Oncol Rep. 2019)

Psychosis & Schizophrenia

A double-blind, randomized study comparing CBD versus the antipsychotic drug, amisulpride, in 39 patients with acute schizophrenia showed that at 800 mg, both treatments were safe and led to significant clinical improvements. But CBD had a better side-effect profile. Patients taking amisulpride were more prone to drug-associated weight gain and movement disorders; these adverse effects were not seen in CBD patients (Leweke FM, et al. Transl Psychiatry. 2012: 2(3): e94).

CBD produced marked increases in serum anandamide which correlated with the observed clinical improvement. The data suggest CBD’s ability to block the deactivation of anandamide plays a big part in the antipsychotic effect. CBD inhibits degradation of anandamide in much the same way that monoamine oxidase inhibitors (MAOIs) prevent breakdown of dopamine.

This cannabinoid, the authors say, represents a potentially new approach to treatment of schizophrenia.

Reviewing the study, John Krystal, MD, Chairman of Psychiatry at Yale noted that, “CBD, in addition to having fewer side effects, also seemed to work better on schizophrenia’s negative symptoms, which are notoriously difficult to treat, including: social withdrawal, blunting of pleasure, and lack of motivation.”

In a recent review on CBD for psychosis, Dr. Britta Hahn, of the Maryland Psychiatric Research Center writes: “There is increasing evidence that (CBD) can reduce symptoms of psychosis and act as an anxiolytic, both of which are relevant in schizophrenia.” Further, she adds, “CBD seems to be very benign, much more so than the current standard-of-care antipsychotics and anxiolytics.”

Multiple Sclerosis

Sativex, the prescription THC/CBD product, has been approved in 15 countries for treatment of MS, though not in the US. There are several trials assessing other forms of cannabis in this disease.

The Cannabinoids in MS (CAMS) study, published in 2003, involved 630 MS patients randomized to oral cannabis extract (containing THC), dronabinol (a synthetic cannabinoid), or placebo. Both the plant-based cannabinoid extract and dronabinol reduced patient-reported measures of spasticity, pain, and sleep disturbances. However, there were no changes in overall MS assessment scores (Zajicek J, et al. Lancet, 2003).

In 2012, the same team compared oral cannabis extract (5-25 mg THC total) against placebo in 279 MS patients. They found 29% of those on active treatment experienced relief of muscle stiffness, compared to 16% in the placebo group. Cannabis patients had improvements in total body pain, spasticity, and sleep measures (Zajicek JP, et al. J Neurol Neurosurg Psychiatry. 2012).

In 2014, the American Academy of Neurology issued a position statement that certain forms of medical marijuana (pill or oral spray) have potential in the management of MS, based on a review of 33 studies of various forms of ingested cannabis.

Anxiety

In a study of 10 healthy male volunteers, single 400 mg doses of oral CBD produced significant reductions in anxiety and increased sedation. This was not just subjective; SPECT scans of subjects’ brains showed modulations in regional cerebral blood flow in areas of the brain associated with anxiety.

“These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas,” the authors report (Crippa J. et al. Neuropsychopharmacology (2004) 29, 417–426).

Anxiety is one of the most common conditions for which people seek medical marijuana and “OTC” cannabinoids like non-Rx CBD. But anxiety is also one of the most common adverse effects associated with high-THC cannabis.

There is a wealth of interesting animal work suggesting that CBD could reduce anxiety. Given what’s known about the endocannabinoid system, there are certainly plausible pathways (Lisboa SF, et al. Vitam Horm. 2017). So far, however, there are no large clinical studies supporting cannabis as a treatment for anxiety.

Opioid Addiction

For much of the last century, law enforcement and public health agencies claimed cannabis is a “gateway drug” for future addiction to opioids, cocaine, or other dangerous substances. Two years ago, epidemiological signals emerged to suggest that in fact, cannabis can be an “exit” off of addiction’s highway to hell.

Dr. Carlton cited a 2017 report showing that in states where marijuana had been legalized, there were major reductions (on the order of 23%) in opioid-related hospitalizations and an aggregate 13% reduction in opioid overdoses.

Several groups have independently reported that when given unobstructed access to medical cannabis, patients using prescription opioids for chronic pain decrease their opioid use by 40-60%, and generally prefer the former over the latter.

Addiction researchers are beginning to take cannabis seriously as a harm reduction modality and perhaps even as a treatment for opiate addiction. In their recent review, Weise and Wilson-Poe note that while there’s not yet a definitive clinical trial, the epidemiological signals combined with existing pre-clinical work make a compelling case for further investigation.

They point out, however, that despite the raging crisis of opioid addiction, the National Institutes of Health have shown little interest in funding research on cannabis as a solution. Nor have any pharmaceutical or supplement companies stepped up. 

“Barriers to research funding and access to “real world” cannabis for clinical research directly contribute to our inability to address the opioid epidemic with what appears to be a safe and efficacious tool,” they write (Weise B, Wilson-Poe AR. Cannabis Cannabinoid Res. 2018).

What about addiction to cannabis? There’s a longstanding debate about whether the herb is truly addictive in the classical sense. But there’s no doubt many people become dependent on smoking or vaping cannabis.

Dr. Carlton says there’s a simple inexpensive treatment for breaking the herbal habit: N-acetylcysteine (NAC).

In an 8-week placebo-controlled study of 116 cannabis dependent teens, researchers at the Medical University of South Carolina showed that compared with placebo, NAC at daily doses of 1,200 mg, doubled the odds that the kids would cease smoking weed (based on results of urine tests). “The findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence,” the authors write (Gray KM, et al. Am J Psychiatry. 2012).

Safety, Contraindications & Interactions

Given how widely it is used worldwide, and in how many forms, it is clear that cannabis is a fairly safe herb. There are few endocannabinoid receptors in the brain stem, and none in the parts that regulate respiration and heart function. Consequently, there’s little—if any—risk of lethal overdoses, says Carlton. In this sense, cannabis could not be more different from opioids or cocaine.

That said, cannabinoids can have downsides. Whether inhaled or taken orally, used in whole-plant form or as concentrated extracts, they need to be handled carefully.

THC can definitely induce anxiety in some people. For this reason, THC in any form is absolutely contraindicated for people with unstable heart disease, bipolar disorder, and schizophrenia, Dr. Carlton insisted.

In some people, THC-rich cannabis can induce hyperemesis—cyclic and uncontrollable vomiting. Though the true prevalence is not known, and is probably small, it is important to keep in mind. The good news is, the acute symptoms tend to improve with heat (hot showers) and generally stop with cannabis abstention (Sorensen CJ, et al. J Med Toxicol. 2017)

Both THC and CBD can induce or inhibit enzymes within the hepatic P450 system, and people on prescription drugs metabolized by P450 pathways need to be careful. As was pointed out in a recent ConsumerLab review, CBD is itself metabolized by p450 enzymes (CYP3A4 and CYP2C19). By competing for these enzymes, high-dose CBD can impair the clearance of other drugs broken down by those enzymes.

Likewise, prescription meds can alter the clearance of THC and CBD. Ketoconazole, for example, inhibits CYP3A4, and can therefore raise peak THC and CBD levels in people who use cannabis while taking the antifungal. Other drugs (clarithromycin, cyclosporine, verapamil among them) may do something similar (Horn JR, Pharmacy Times. 2014).

In their recent paper on cannabinoid treatments for epilepsy, Gaston and Szaflarski note that CBD “had a clear interaction with clobazam, significantly increasing levels of its active metabolite.” There may also be interactions with rufinamide, zonisamide, topiramate, eslicarbazepine, and possibly warfarin.

Dr. Carlton says it is also important to carefully consider modes of delivery, all of which have pros and cons. Though he acknowledged that many people enjoy smoking cannabis, he does not consider it an appropriate mode of therapy.

Vaping is often promoted as a healthier alternative, and it has an advantage of rapid effect onset—typically within 60 seconds. However, that positive is greatly outweighed by a big negative: “It’s dangerous to inhale propylene glycol (a common ingredient in vaping liquids), especially heated to ~200 degrees Fahrenheit.”

Oral ingestion has a very slow onset—in the range of 2 hours, and an even slower offset, often 8 hours or more. That’s not necessarily a problem for CBD, but for THC it can be highly problematic. The liver converts ingested Δ9-ΤHC into the far more psychoactive Δ11 form. This, plus the 8+ hour offset can be a nightmare for some.

Carlton says in general, he recommends oromucosal/sublingual delivery forms. They’re fairly quick to kick in—usually within 3 minutes, and exert effects typically for about 3 hours. The only downside is that the products need to be alcohol-based tinctures, which can be problematic for people who need to avoid alcohol.

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