By Peter Grinspoon, MD, Contributor Harvard Medical School
Medical cannabis is currently legal in 37 states and, with 94% of Americans in favor of legal access to medical marijuana, it seems as if this treatment option is returning to the mainstream. Many people aren’t aware that cannabis was a popular treatment in this country in the late 1800s and early 1900s — commonly dispensed by doctors — and that the American Medical Association was one of the strongest voices testifying against prohibiting it in 1937.
I’ve been aware of the ability of medical cannabis to alleviate suffering since I watched my brother Danny use it during his unsuccessful battle with leukemia. Cannabis was the only thing that allowed him to keep down food during chemotherapy. Now, decades later, I am a physician who certifies patients that qualify for medical cannabis in Massachusetts. People often have questions about its safety and its proper use, and these are often the same considerations I have before certifying patients.
Is it safe?
As with nearly everything else about cannabis, how safe or dangerous it is remains hotly debated. As a primary care doctor, I have to ask myself: is cannabis safer than the alternatives I would be prescribing? For example, if I’m treating a patient for chronic pain, is cannabis safer than opiates? Medication risks must be balanced against the safety concerns of cannabis; the main ones are as follows:
- Its safety during pregnancy and breastfeeding has not been established.
- It can worsen, and even potentially cause, psychotic disorders.
- It can temporarily worsen short-term memory and cognitive functioning.
- It can have cardiac and lung effects, such as rapid heart rate and bronchitis.
- You can get addicted.
- There can be drug interactions, especially with CBD.
- It can cause or worsen anxiety at high dosages, even leading to panic attacks.
- Driving and the operation of heavy machinery is impaired.
- It can be especially dangerous for teenagers to use, as there is evidence that they are particularly susceptible to cognitive effects and addiction.
Cannabis should be used with extreme caution — if not avoided altogether — in patients with a history (or potentially a family history) of the problems listed above, such as psychosis, substance misuse, or cardiac arrythmias.
As I frequently tell patients, if you read the warning labels of any medications that are commonly prescribed, each and every one has potential side effects, some serious. There is truly no free lunch with medication, including medical cannabis; however, with good education and with legal regulation (which leads to a safer product), many of the above harms can be avoided or minimized. For example, many of the harms are dosage-related, so I always remind patients to "start low and go slow," meaning keep the doses as low as possible for the desired effect.
How can I consume cannabis?
Cannabis can be consumed in a variety of ways: by inhalation, with a tincture under the tongue, as an edible, or as a topical lotion. The advantages of consuming cannabis by inhalation, either by smoking or by vaporizing dried flower with a machine that heats it up, are rapid onset and easier titration of dosage. The disadvantages are that it can irritate the lungs, causing chronic bronchitis, and the therapeutic effect only lasts a few hours, so one has to redose frequently.
In many places cannabis combustion is simply not allowed, such as in public housing. The pros of using an edible are that you don’t have to inhale anything, and the therapeutic benefit can last for up to eight hours, but finding the correct dose is much trickier: it usually takes an hour or two for an edible to start working after consumption, so you truly have to start low and go slow to avoid taking too much!
A tincture is a liquid formulation that can be put under the tongue for quicker absorption; its mode of action and duration are in between inhalation and edibles: perhaps 30 minutes to take effect, with a duration of about four hours.
Topicals are just what they sound like: creams and lotions to rub on painful, inflamed, or itchy areas. There are very few safety concerns with topical preparations.
Will I get high?
In many cases, the answer to this is: only if you want to, unless the dosage you need is quite high. The doses needed for medical purposes are often significantly lower than what is used recreationally. Today, with a regulated cannabis market, there is much more choice about different strains or ‘chemovars’ of cannabis — it used to be that medical patients only had access to whatever the dealer happened to have.
These days, people can avoid highly sedating strains, as well as strains that are extremely high in the main intoxicant, THC. Also, patients develop a tolerance to the psychoactive effects of cannabis, so a medical patient using a small dose of cannabis twice a day would be markedly less impaired than a more recreational cannabis user who uses a high dose, say, once a month. They still shouldn’t drive when using this medicine, but they do report being quite functional.
Is it legal?
Cannabis is not legal if you are not living in a state where it has been legalized for medical usage, but it is now legal on the state level in the majority of states. Some states have gone partway and have legalized CBD only, or low-THC cannabis formulations. It is important to remember that cannabis is still illegal on the federal level, meaning that it is illegal to fly with it and to cross state borders with it — even if you are crossing between two states that have legalized it.
There can also be implications for your employment if your workplace does drug screens — a medical cannabis card won’t always protect you. Many hospitals, even in legal states, do not permit you to bring it into the building, as they receive federal funding that could be at risk if they are perceived as sanctioning medical cannabis use.
I am optimistic that, as a society, we will continue to make progress on the medical cannabis issue, so that the millions of patients who receive relief from medical cannabis can do so without stigma, judgment, and legal jeopardy, and so that medical research can be performed in a free and unrestricted way. In this way, our knowledge of both the benefits and the harms of cannabis can continue to progress.
Whilst access to cannabis-based medicinal products (CBMPs) has increased globally subject to relaxation of scheduling laws globally, one of the main barriers to appropriate patient access remains a paucity of high-quality evidence surrounding their clinical effects.
Whilst randomised controlled trials (RCTs) remain the gold-standard for clinical evaluation, there are notable barriers to their implementation. Development of CBMPs requires novel approaches of evidence collection to address these challenges. Real world evidence (RWE) presents a solution to not only both provide immediate impact on clinical care, but also inform well-conducted RCTs. RWE is defined as evidence derived from health data sourced from non-interventional studies, registries, electronic health records and insurance data. Currently it is used mostly to monitor post-approval safety requirements allowing for long-term pharmacovigilance. However, RWE has the potential to be used in conjunction or as an extension to RCTs to both broaden and streamline the process of evidence generation.
Novel approaches of data collection and analysis will be integral to improving clinical evidence on CBMPs. RWE can be used in conjunction or as an extension to RCTs to increase the speed of evidence generation, as well as reduce costs. Currently, there is an abundance of potential data however, whilst a number of platforms now exist to capture real world data it is important the right tools and analysis are utilised to unlock potential insights from these.
Cannabis-based medicinal products (CBMPs) are a collective term to describe a preparation or other product that contains cannabis or its derivatives for medicinal use in humans . There are significant barriers to the integration of CBMPs within treatment pathways including ongoing stigma, cost, education, complex pharmacology and a paucity of evidence to inform international and national guidelines [2, 3]. Limited evidence, does, however, support the role of CBMPs in conditions such as chronic pain, neurological disorders, and psychiatric disease . There is also growing evidence of side effects and how the severity and incidence of side effects may differ between patients . The quality of evidence, however, is often insufficient in the opinion of insurers, regulators, and guideline bodies .
The National Institute for Health and Care Excellence in the UK has only recommended licensed CBMPs for a limited range of indications . Changes to scheduling as recommended by the World Health Organisation, and within individual countries, recognises the potential medicinal value of cannabis and removes barriers for clinical and research use [1, 7]. However, widespread stigma, complex pharmacology, funding, and challenges in sustaining adequate supply of consistent products continue to act as barriers for clinical research.
Randomised controlled trials (RCTs) are necessary and should continue to be the standard against which medical evidence is upheld. However, they are expensive, time consuming and subject to their own limitations . Whilst these are awaited, there is a requirement to generate evidence of potential benefits and harms to inform policy and clinical practice.
Barriers to Controlled Clinical Trials for Medical Cannabis
RCTs are not infallible—they are expensive and time consuming. Globally $100 billion USD is spent on biomedical research . In the UK, the National Institute for Health Research (NIHR) provides £80 million GBP in funding for clinical trials . Yet, their narrow scope can lack ecological validity to real-world circumstances and therefore lack generalisability in more diverse populations. There are also specific barriers to conducting RCTs using CBMPs.
In addition to cannabidiol (CBD) and (−)-trans-Δ9-tetrahydrocannabinol (THC) there are over 140 cannabinoids, as well as flavonoids, terpenes, and other compounds within the flower of different cannabis plants . These can each potentially affect the clinical outcomes observed between CBMPs due to their individual and collective effects . The concentrations of each compound are influenced by the genetics and environment each plant is grown in producing a distinct chemical profile. The result of a clinical trial for one finished pharmaceutical product, therefore, cannot be extrapolated to all CBMPs, due to their heterogeneity. However, current evidence reviews often fail to account for this [12, 13].
The route of administration further affects the pharmacokinetics of CBMPs and the associated outcome of any trial. CBMPs can be administered sublingually, trans-dermally, via inhalation, or orally . This subsequently affects the distribution, biotransformation and elimination of active compounds. Heat exposure and vaporisation of dried flower or extracted oils changes the underlying phytocannabinoid composition compared to the original unprocessed dry flowers, increasing the proportion of decarboxylated cannabinoids [15, 16]. Assessment of efficacy using RCTs in isolation will therefore ultimately fail to identify the most appropriate CBMP for each clinical scenario .
An appropriately blinded assessment against placebo or active therapy is the optimal design for RCTs. It has been difficult to identify a placebo that cannot be distinguished against an active CBMP according to absence of both vasoactive and psychoactive effects, as well as the typical aroma associated with cannabis . This presents a challenge to adequate blinding.
Production methods and import costs mean that CBMPs are typically expensive, adding further to high research costs . Research has therefore focused on compounds under patent as opposed to generic CBMPs where research outcomes fail to provide a similar return on investment for licensed producers and pharmaceutical companies. Historically, clinical trials on CBMPs were funded privately, which may be associated with potential reporting biases .
RCTs are possible with CBMPs; however, the above issues present legitimate challenges. In many chronic diseases there is a need for novel therapeutics and CBMPs are therefore being utilised based on best available evidence. Due to the challenges in developing CBMPs through a traditional drug development pipeline, the exploration of its utility should not be limited to traditional methods. It is important that we capture a suite of real-world evidence (RWE) to inform prescribing guidelines, regulations, and clinical trials. By leaning on RWE there is an opportunity to improve the quality and design of RCTs and clinical evidence in general, via a top-down approach .
Real World Evidence
RWE is defined as evidence derived from health data sourced from non-interventional studies, registries, electronic health records and insurance data as opposed to the highly controlled setting of RCTs . There is an abundance of this unstructured data, however, the necessary frameworks and governance are needed for the application of this data . It is currently used extensively to monitor post-approval pharmacovigilence . There is clear evidence of benefit in using population-based data to detect safety events associated with specific medications to implement restrictions to reduce harm .
Consistent use of RWE to aid regulatory decision making is yet to be normalised, but the promise is apparent . Recently, regulator-supported initiatives have highlighted the desire to incorporate RWE into licensing and guidelines, developing a framework which can incorporate its insights into decisions regarding safety and effectiveness [21, 22]. It is important that studies standardise their methodology according to those set out by regulatory authorities to ensure research has the greatest impact [21, 22]. Moreover, they should seek to directly address questions set out by governing bodies as areas where there is insufficient research .
Types of Real-World Evidence for Medical Cannabis
NHS England and NHS improvement published a review on the barriers to accessing CBMPs in the UK . Their recommendations included the need for the collection of structured data, and the development of methods to further support the generation of new evidence, for patients who cannot enrol onto relevant RCTs.
RWE is already being incorporated into the scientific literature on cannabis (Table 1). Early examples utilised state-level records to examine the effects of cannabis laws on opioid misuse. Subsequently there have been examples of online and self-administered survey tools analysing national outcomes. More recently there has been a focus on collecting evidence from clinical registries and databases with evidence generated from patient-reported outcome measures and long-term pharmacovigilance.
Cannabidiol (CBD)-what we know and what we don't
By Peter Grinspoon, MD, Contributor Harvard Medical School
Cannabidiol (CBD) is often covered in the media, and you may see it touted as an add-in booster to your post-workout smoothie or morning coffee. You can even buy a CBD-infused sports bra. But what exactly is CBD? And why is it so popular?
How is cannabidiol different from marijuana, cannabis and hemp?
CBD, or cannabidiol, is the second most prevalent active ingredient in cannabis (marijuana). While CBD is an essential component of medical marijuana, it is derived directly from the hemp plant, a cousin of marijuana, or manufactured in a laboratory. One of hundreds of components in marijuana, CBD does not cause a "high" by itself. According to a report from the World Health Organization, "In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health related problems associated with the use of pure CBD."
Is cannabidiol legal?
CBD is readily obtainable in most parts of the United States, though its exact legal status has been in flux. All 50 states have laws legalizing CBD with varying degrees of restriction. In December 2015, the FDA eased the regulatory requirements to allow researchers to conduct CBD trials. In 2018, the Farm Bill made hemp legal in the United States, making it virtually impossible to keep CBD illegal – that would be like making oranges legal, but keeping orange juice illegal.
The evidence for cannabidiol health benefits
CBD has been touted for a wide variety of health issues, but the strongest scientific evidence is for its effectiveness in treating some of the cruelest childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications. In numerous studies, CBD was able to reduce the number of seizures, and, in some cases, stop them altogether. Epidiolex, which contains CBD, is the first cannabis-derived medicine approved by the FDA for these conditions.
Animal studies, and self-reports or research in humans, suggest CBD may also help with:
- Anxiety Studies and clinical trials are exploring the common report that CBD can reduce anxiety.
- Insomnia. Studies suggest that CBD may help with both falling asleep and staying asleep.
- Chronic pain. Further human studies are needed to substantiate claims that CBD helps control pain. One animal study from the European Journal of Pain suggests CBD could help lower pain and inflammation due to arthritis when applied to skin. Other research identifies how CBD may inhibit inflammatory and neuropathic pain, which are difficult treat.
- Addiction. CBD can help lower cravings for tobacco and heroin under certain conditions, according to some research in humans. Animal models of addiction suggest it may also help lessen cravings for alcohol, cannabis, opiates, and stimulants.
How can CBD be taken?
CBD comes in many forms, including oils, extracts, capsules, patches, vapes, and topical preparations for use on skin. If you’re hoping to reduce inflammation and relieve muscle and joint pain, a topical CBD-infused oil, lotion or cream – or even a bath bomb -- may be the best option. Alternatively, a CBC patch or a tincture or spray designed to be placed under the tongue allows CBD to directly enter the bloodstream.
Outside of the US, the prescription drug Sativex, which uses CBD as an active ingredient, is approved for muscle spasticity associated with multiple sclerosis and for cancer pain. Within the US, Epidiolex is approved for certain types of epilepsy and tuberous sclerosis.
The bottom line on cannabidiol
Some CBD manufacturers have come under government scrutiny for wild, indefensible claims, such that CBD is a cure-all for cancer or COVID-19, which it is not. We need more research but CBD may prove to be a helpful, relatively non-toxic option for managing anxiety, insomnia, and chronic pain. Without sufficient high-quality evidence in human studies, we can’t pinpoint effective doses, and because CBD currently is typically available as an unregulated supplement, it’s hard to know exactly what you are getting.
If you decide to try CBD, make sure you are getting it from a reputable source. And talk with your doctor to make sure that it won’t affect any other medicines you take.