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A Review of CBD Clinical Trials on Human Subjects

Over recent years, a dizzying amount of news and anecdotal (unscientific) claims about CBD and its potential therapeutic actions has flooded the media landscape. Our team of scientists and advisors are corresponding with universities and medical institutions to assess results and claims for CBD and other cannabinoid compounds. So far, the vast majority of published CBD research has been preclinical (prior to human testing) using either cell cultures or animal models. Furthermore, many studies were conducted with a small number of subjects and lack standardization making it difficult to claim definitive results.

To provide clarity focused on human studies, below we briefly review CBD legality, quality control, and peer-reviewed scientific results from CBD clinical trials on human subjects.

As regulations lift, more clinical research will begin to definitively confirm therapeutic trends arising from CBD usage. The need for more research also stems from the confusing CBD market where not all CBD is made the same and other companies try to market non-CBD products as CBD. We hope the below provides some clarity on your CBD journey!

Is hemp legal? Yes, if it is produced in accordance with Farm Bill regulations.

The 2018 Farm Bill drastically reformed hemp policy nationwide, but because hemp and marijuana are both Cannabis, confusion and grey areas still exist. In the legislation, hemp and marijuana are both defined as cannabis with hemp being different from marijuana through one key definition: hemp cannot contain more than 0.3% THC (the compound in the plant most commonly associated with getting a person high). In other words, hemp cannot get you high from THC. For decades, federal law did not differentiate hemp from other cannabis plants (i.e. marijuana) until now. 

The 2018 Farm Bill broadly allows hemp cultivation as well as the transport, sale, and possession of hemp-derived products across state lines, so long as those items are produced in a manner consistent with the law. More information for regulated hemp cultivation can be found here.

Section12619 of the Farm Bill removed hemp-derived products from its Schedule I status under the Controlled Substances Act, but this alone does not federally legalize all CBD products. This is in part because CBD can be extracted from both hemp and marijuana plants. The 2018 Farm Bill ensures that any cannabinoid, including CBD, derived from hemp will be legal if and only if that hemp is produced in a manner consistent with the Farm Bill, associated federal regulations, associated state regulations, and by a licensed grower [1]. All other non-FDA approved cannabinoids produced in any other setting will remain a Schedule 1 substance under federal law and are thus illegal.

1) https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/

CBD Quality Control

Since the 2018 Farm Bill, the CBD market has exploded. However, little regulatory enforcement by the FDA has resulted in a vast spectrum of ineffective products and bad actors flooding the market. In a report from the Journal of The American Medical Association [2, 3], 69% of CBD products tested on the market have ingredients misrepresented on the label, with 25% of those containing less CBD than advertised. Even more alarmingly, 21% of labels understated the amount of THC in the product, which can lead to users accidentally failing drug tests – yikes. Please see our other blog outlining our guide on how to best choose your CBD products. 

2) Bonn-Miller, M. O., Loflin, M. J., Thomas, B. F., Marcu, J. P., Hyke, T., & Vandrey, R. (2017). Labeling accuracy of cannabidiol extracts sold online. Jama, 318(17), 1708-1709.

3) White, C. M. (2019). A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. The Journal of Clinical Pharmacology, 59(7), 923–934. http://doi.org/10.1002/jcph.1387

Mechanism

CBD is metabolized in the liver and affects cytochrome (CYP) and uridine 5′ -diphosphoglucuronosyltransferase (UGT) enzyme activity among others. CBD can inactivate some CYP enzymes in the short-term but can then activate them through chronic (i.e. long-term) dosing similar to other anticonvulsants [3]. CBD interacts with cannabinoid receptors that are part of the Endocannabinoid System (ECS): one of the most widespread biological systems throughout the body composed of naturally occurring endocannabinoids (internally made neurotransmitters in the human body) that bind to cannabinoid receptors (CBRs). For a deep dive on how the ECS maintains body homeostasis and overall health, check out our ECS Blog: Welcome to Your Endocannabinoid System: The heart of balance. Two of the most relevant and ubiquitous cannabinoid receptors are CB1 and CB2 found in the brain and immune system, which bind naturally occurring endocannabinoids [4].

Located in the cerebellum, hippocampus, neocortex, amygdala, and striatum, CB1 and its splice variant CB1A mediate a wide range of behavioral functions related to emotion, memory, sensory perception, hunger, and motor responsiveness. CB1 is the predominant cannabinoid receptor in the Central Nervous System (CNS). CB2, however, can be found in the spleen and hematopoietic cells indicating its role in modulating the immune system. CB receptors are involved in just about every reaction in the body, from the immune system to decision-making and behavior to the dampening of excitatory transmission. A dysfunctioning ECS can have widespread consequences since it may be involved in regulating various components of the immune system, appetite, pain-sensation, mood and memory. 

4) Pertwee RG (January 2008). “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin”. British Journal of Pharmacology. 153 (2): 199–215.

Seizure Disorders

Numerous clinical trials including double blinded and placebo controlled studies have been conducted to assess CBD efficacy on seizures [5]. Outcomes included 50%+ seizure reduction, complete seizure freedom, and improved quality of life (QoL) in patients with refractory, drug-resistant seizures including Dravet and Lennox-Gastaut syndrome. Although some statistical analysis was hampered by the low number of patients tested, results and trends were generally consistent across independent studies. As more clinical studies are conducted, more in-depth analyses will likely strengthen these therapeutic findings.  

5) Stockings E, Zagic D, Campbell G, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89:741-753.

Anxiety

A large amount of anecdotal evidence exists for CBD’s ability to curb anxiety. There have been multiple clinical studies assessing the effects of CBD on feelings of anxiety, but many of these studies have very small sample sizes (i.e. human subjects) [3], which could influence results. Additionally, all studies employ single-dose CBD as opposed to a weight-based dosing strategy (doses based on body weight) like those carried out in the seizure disorder studies above. Hence, only generalizations about acute use of CBD before/after an anxiety-provoking event can be made. Finally, in most trials, subjects were normal volunteers, so the extent of their anxiety and their responses may be less severe and ultimately different than those patients with anxiety disorders.

The first category of studies examined the impact of single-dose CBD on lessening the anxiety-promoting effects of single-dose delta-9-THC, the psychoactive cannabinoid from marijuana [6-9]. Results suggest that CBD does indeed reduce THC-induced anxiety. This seems intuitive as CBD can interact allosterically (e.g., indirectly) with the endocannabinoid CB1 receptor, thereby weakening CB1’s ability to directly bind THC.  

A second category of studies examined human subjects taking a single dose (i.e. acute) of CBD before/after anxiety-provoking events (reviewed in [3]). While there was general evidence that an acute dose of CBD provides some relief, results were hard to compare due to differences across studies including variable CBD doses, manufacturers, routes of administration, durations between CBD doses and stressor, total evaluation times, anxiety rating scales, and specific stressors themselves. More research is needed to tease apart exactly how CBD influences anxiety reduction.

6) Zuardi AW, Shirakawa I, Finkelfarb E, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9- THC in normal subjects. Psychopharmacology. 1982;76:245-250

7) Karniol IG, Shirakawa I, Kasinski N, et al. Cannabidiol interferes with the effects of delta 9-tetrahydrocannabidiol in man. Eur J Pharmacol. 1974;28:172-177.

8) Zuardi AW, Cosme RA, Graeff FG, et al. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychophar- macol. 1993;7:82-88.

9) Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d-9-tetrahydrocannabidiol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Design. 2012;18:4966-4979.

Schizophrenia and Psychosis

Of the randomized clinical trials assessing the impact of moderate-length CBD on patients with schizophrenia, they all demonstrate evidence for a reduction in schizophrenia symptomatology over time for at least some measures [10-12]. However, they differ in terms of their impact on the disease itself. The trials were relatively small, which can compromise the ability to detect significant results in the studies. Many more rigorous studies are needed to make definitive conclusions on the effects of CBD on schizophrenia.

10) McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175:225-231

11) Boggs DL, Surti T, Gupta A, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology. 2018;235:1923-1932.

12) Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2, e94.

Pain and Spasticity

Human studies assessing CBD alone for pain relief remain relatively sparse, although relief and pain reduction were indeed observed across different patients (reviewed in [3]). In 1 randomized double-blind, multigroup crossover trial assessing pain and spasticity [13], the CBD group exhibited significantly better pain control as well as a reduction in spasm severity but not frequency. Taken together, CBD shows some positive improvements for pain and spasticity but much more research is needed to paint a comprehensive picture of its effects.

13) Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17:21-29.

Pharmacokinetics/Drug Interactions

In one study, 13 subjects (age range, 4-19 years) with refractory epilepsy took both the anticonvulsant drug, clobazam, and the FDA-approved CBD drug, Epidiolex. Since CBD inhibits the same enzyme (CYP2C19) that is required to process clobazam, researchers saw a significant increase in clobazam levels in the body. Therefore, when coadministered with CBD, it is suggested that clinicians consider a reduction in dosage of sensitive CYP2C19 substrates (e.g., clobazam) as clinically appropriate [14]. Another small, pharmacokinetic study examining the interaction of the synthetic opioid fentanyl and CBD yielded no conclusive results [15]. Hence, the pharmacokinetic impact of CBD on opioid drug interaction remains largely unknown. In general, there is a significant probability of drug interactions between CBD and drugs that affect CYP and UGT enzymes [16]. More research is needed to assess patient management, especially those taking multiple drugs that impact the CYP enzyme system. It is hypothesized that these drug interactions may have the potential for adverse effects through high dosages (reviewed in [3]).

14) Iffland K, Grotenherman F. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis and Cannabinoid Res. 2017;2:139-154.

15) Epidiolex (Cannabidiol) prescribing information. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018.

16) Manini AF, Yiannoulos G, Bergamaschi MM, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015;9:204-210.

Effects of CBD Hemp Extract on Opioid Use in Chronic Pain Patients

In a recent study, chronic pain patients consumed full hemp extract cannabidiol (CBD) to determine its impact on opioid use and quality of life (QoL) indicators. According to the National Academies of Science, Engineering, and Medicine, extensive evidence has been shown for cannabinoid efficacy for pain relief with good tolerability, along with its potential to reduce addiction risk and physiological dependence on opioid use while managing pain [17].

Preclinical studies demonstrate the ability of CBD to reduce opioid seeking behavior, thereby decreasing relapse risk [18],  and in early human trials, CBD was shown to reduce opioid withdrawal symptoms [19]. In a recent survey study, 44% of hemp CBD users reported reduced use of their opioid pain medication [19]. More specifically, CBD was found to alleviate previous opioid dependency through the reduction of the craving, anxiety, and psychological manifestations in drug-abstinent individuals [20, 21]. 

Although scientific literature provides evidence for CBD in pain relief and opioid reduction, more research is needed that evaluates the effects of readily available hemp CBD in chronic pain and opioid use in a single cohort. One study aimed to close this gap by “…investigating the impact of hemp CBD use on opioid use in chronic pain, disability, physical and psychosocial symptoms, sleep, and motivation to taper opioids.” [22]

After participants were educated on safe CBD use, they ultimately elected whether or not to use CBD and self-titrate (personally adjust based on their perceptive effects) their CBD dosage. Of the total subjects (97 participants) who completed the study, 97% chose to consume CBD softgels, and almost all participants (94%) used two soft gels (~30 mg total) daily (equal to about 1 Asha Softgel). 

The results of this study concluded that consuming CBD for chronic pain in patients using opioids significantly reduced opioid intake leading to reduced pain and improved quality of life (QoL). Over the course of 8 weeks, over half of the participants reduced or eliminated opioids, and almost all CBD users reported improvements in QoL [22].

17) Khan SP, Pickens TA, Berlau DJ. Perspectives on cannabis as a substitute for opioid analgesics. Pain Manag. 2019 Jan 25;9(2):191-203.

18) Ren Y, Whittard J, Higuera-Matas A, et al. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009 Nov 25;29(47):14764-14769.

19) Moeller-Bertram T, Schilling J, Hughes C, et al. (360) Can CBD reduce the use of pain medication? Lessons from a survey in a pain clinic environment. J Pain. 2019 Apr 1;20(4):S64.

20) Hurd YL, Yoon M, Manini AF, et al. Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage. Neurotherapeutics. 2015 Oct 1;12(4):807-815.

21) Hurt YL, Spriggs S, Alishayev J, et al. Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial. Am J Psychiatry. 2019 May 21.

22) Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgraduate Medicine. 2019 DOI: 10.1080/00325481.2019.1685298.

Conclusion

We know that nothing good comes easy! That’s why we are dedicated to pushing the scientific field forward to transparently translate its progress into Asha’s products for optimal efficacy and purity. It’s a bit of a wild west out there, and so it is our mission to be your trusted partner and help steward the full potential of the hemp plant-forward for both people and planet. We will continue to release updates from the scientific frontlines as they roll out. Onward! 

-Dr. Nathan Walworth, PhD
Chief Scientific Officer

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