While consuming CBD isolate might sound like a great approach, keep in mind that there is also a key disadvantage of isolating CBD from other cannabis compounds. Research has shown that the combination of cannabinoids and terpenes generates an entourage effect, a synergistic interaction that boosts the individual effects of each compound involved. Stripping away all the other cannabinoids prevents you from experiencing the potential benefits of the entourage effect.
While you might not know what to do with a pile of odorless CBD isolate powder at first, there are a number of different ways to consume CBD isolate. Here are some of the most common delivery routes:
How to use CBD isolate
It’s incredibly easy to measure CBD isolate dosages, as there’s nothing else to account for aside from the pure CBD. With other CBD-based products, such as broad-spectrum and full-spectrum CBD oil, the cannabinoid is mixed with other cannabinoids, making it more difficult at times to quantify the exact amount of CBD that is being consumed.
For starters, true CBD isolates consist of nothing but pure CBD, so there’s no need to worry about THC possibly entering your system and showing up on a potential drug test. Although it’s highly unlikely, trace amounts of THC found in hemp-derived CBD oil can theoretically cause a positive drug screening result.
Once all of the impurities and solvents are stripped away, you’re left with 99% pure CBD crystalline.
The effect of LCT on intestinal processing of lipophilic cannabinoids was assessed using an in vitro lipolysis model. This model simulates physiological lipid digestion processes in the small intestine, and is commonly used in the design and development of oral lipid-based drug delivery systems [22-26].
In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients may substantially increase the systemic exposure to orally administered cannabis or cannabis-based medicines. Our data suggest that the primary mechanism of the increased absorption of cannabinoids in the presence of lipids is intestinal lymphatic transport. The amount of lipids present in cannabis-containing foods, or following a high-fat meal, is sufficient to activate intestinal lymphatic transport and lead to increased systemic exposure to cannabinoids. The increase in systemic exposure to cannabinoids in humans is of potentially high clinical importance as it could turn a barely effective dose of orally administered cannabis into a highly effective one, or indeed a therapeutic dose into a toxic one. Therefore, it is important for cannabis-prescribing clinicians and those who self-medicate with cannabis to carefully consider the effect of the co-administration of lipids on the therapeutic outcomes of orally administered cannabis or cannabis-based medicines.
The intestinal lymphatic transport potential of THC and CBD was assessed using incubation studies with artificial lipid emulsion and with natural rat and human CM [27,29]. The results of the uptake are shown in Figure 4 . The association values of both cannabinoids with artificial lipid particles and natural CM were in the range of 70-80%. No significant differences were seen between the uptake of cannabinoids by artificial lipid particles, rat CM or human CM ( Figure 4 ).
The right external jugular vein was cannulated with a two-part catheter consisting of polyethylene (PE-50) connected to silastic tubing. Following an average recovery period of 36 hours, animals were divided into the following 6 treatment groups: IV bolus of THC or CBD at a dose of 4 mg/kg (8 mg/mL solution in propylene glycol-ethanol-sterile water (80:10:10, v/v/v)), oral gavage of THC or CBD at a dose of 12 mg/kg in lipid-free formulation (12 mg/mL solution in propylene glycol-ethanol-sterile water (80:10:10, v/v/v)), and oral gavage of THC or CBD in lipid (LCT)-based formulation at a dose of 12 mg/kg (12 mg/mL solution in sesame oil). Blood samples (0.25 mL) were then withdrawn from the cannulae at 5, 15, 30, 60, 120, 240, 360, 480, and 720 minutes after IV injections or 30, 60, 120, 180, 240, 300, 360, 480, and 720 minutes after oral administrations. Plasma was separated by centrifugation (3,000 g, 10 minutes, 15°C) and stored at -80°C until analysis. Phoenix WinNonlin 6.3 (Pharsight, Mountain View, CA, USA) software was used for pharmacokinetic analysis of the data using a non-compartmental approach.
To assess post-luminal (inside the enterocytes) effects of lipids on the absorption of THC and CBD, we evaluated the role of the intestinal lymphatic transport in the absorption process of cannabinoids. The absorption of dietary lipids (in the form LCT) involves the formation of CM in enterocytes ( Figure 5 ). The association of lipophilic compounds with CM in the enterocyte is a pre-requisite for their intestinal lymphatic transport. The affinity of compounds for CM ex vivo has previously been shown to be predictive for the intestinal lymphatic absorption of drugs . In this study, the lymphatic transport potential was initially investigated by assessing the uptake of THC and CBD by artificial CM-like lipid particles. Both compounds showed remarkable association with lipid particles (> 76%). However, lipid particles lack the surface apoproteins found in natural CM which might affect the process of association . Association experiments were also performed with natural CM isolated from rats and showed association values of 72.5 ± 3.6% and 73.7 ± 3.6% for THC ( Figure 4A ) and CBD ( Figure 4B ), respectively. Therefore, the data suggest that CM serve as carriers to transfer THC and CBD to the systemic circulation via the intestinal lymphatic system following oral administration with lipids. Drugs that are transported via the intestinal lymphatic system avoid hepatic first-pass metabolism and therefore achieve significantly higher bioavailability than after administration in lipid-free formulation ( Figure 5 ). It has previously been suggested that THC and CBD exhibit substantial first-pass metabolism [40,41]. Indeed, higher bioavailabilites were reported after administration by routes that avoid first-pass metabolism such as inhalation of THC [37,42] and CBD , or rectal administration of THC . Comparable results were reported previously for the synthetic lipophilic cannabinoid PRS-211,220, which had 66% association with rat CM, and showed 3-fold increase in oral bioavailability following oral administration with LCT compared to lipid-free formulation . In addition, it was found in that study that about two-thirds of the absolute bioavailability of PRS-211,220 was solely due to a contribution of the intestinal lymphatic transport. These observations support our proposed mechanism of intestinal lymphatic transport as a primary mechanism underlying the enhanced exposure to THC and CBD when co-administered with LCT in rats. In order to assess if intestinal lymphatic transport might affect bioavailability of cannabinoids in humans, the uptake of THC and CBD by CM isolated from human volunteers was also assessed in our study. Association values observed in these experiments were similar to the uptake profile seen in rat CM ( Figure 4 ). Therefore, it is reasonable to assume that similar effects of increased systemic exposure to orally administered cannabinoids when co-administered with lipids would occur in humans.
It would therefore appear that the clinical evidence collated to date is confounded by a number of factors, including studies with mixed patient populations, use of different cannabinoid preparations and in various formulations, and wide dosing ranges.
Poly-ε-caprolactone (PCL) is another polymer that is widely used in drug delivery systems. This is a biocompatible, biodegradable, FDA-approved, semi-crystalline aliphatic polyester that degrades slowly. Hernán Pérez de la Ossa has developed a formulation in which CBD is loaded into PCL particles. Spherical microparticles, with a size range of 20–50 μm and high entrapment efficiency (around 100%), were obtained. CBD was slowly released over within ten days when dissolved in the polymeric matrix of the microspheres in an in vitro test .
Furthermore, other improved oral-dosage formulations and therapeutic applications have been presented in a number of patents. Clinical considerations of the oral administration of a solid-dosage, CBD-containing form for the treatment of inflammatory bowel disease have been published in a patent by Robson (GW patent) . A small cohort of patients (8 patients) reported an improvement in Crohn’s disease. Furthermore, oral administration also led to another small cohort of patients being able to reduce steroid dose when treating inflammatory and autoimmune diseases . Based on this research, a CBD therapeutic formulation is being developed by Kalytera Therapeutics (Novato, CA, USA) for the prevention and treatment of graft-versus-host disease. Kalytera initiated a randomised, open-label, dose-response and comparator-controlled phase IIb trial in December 2017 to evaluate the pharmacokinetic profile, safety and efficacy of multiple doses of CBD for the prevention of graft-versus-host-disease following allergenic haematopoietic cell transplantation ( <"type":"clinical-trial","attrs":<"text":"NCT02478424","term_id":"NCT02478424">> NCT02478424).
Formulations that are based on self-(nano)emulsifying drug delivery technology (SEDDS) have been proposed as a means of improving the oral bioavailability of drugs that show poor aqueous solubility . The base formulation, which is an isotropic mixture of an active compound in combination with lipids, surfactants and a co-solvent, has been called a pro-nano-liposphere (PNL) pre-concentrate and is ingested as a soft gelatine capsule. When it reaches the aqueous phase of the gastrointestinal tract, the PNL spontaneously forms a drug-encapsulated oil/water micro-emulsion with a particle diameter of less than 60 nm. The clinical usefulness of SEDDS, which stems from their ability to increase the solubility and oral bioavailability of poorly soluble drugs, have led to them attracting considerable interest . Products, such as Sandimmune ® Neoral (cyclosporin A), Fortovase ® (saquinavir) and Norvir ® (ritonavir), have confirmed the value of this approach . PTL401 is the proprietary PNL-based formulation of THC and CBD. The PTL401 formulation is composed of THC-CBD (1:1) in a formulation with polysorbate 20, sorbitan monooleate 80, polyoxyethylene hydrogenated castor oil 40, glyceryl tridecanoate, lecithin and ethyl lactate [129,130]. The CBD-THC PNL formulation also allows absorption enhancers, such as curcumin, resveratrol and piperine, to be incorporated. PK evaluations in a rat model have indicated that only piperine enhanced the oral bioavailability of CBD in-vivo . Moreover, the enhanced oral bioavailability can be attributed to the inhibition of intestinal processes, rather than those of hepatic first-pass metabolism, while additional increases in the AUC of CBD prove that piperine-PNL also has an effect on phase II, and not on just phase I, metabolism. THC-CBD-piperine-PNL demonstrated higher absorption rates than Sativex ® in human volunteers, with peak values of 1 h for both THC and CBD, versus 3 h for THC and 2 h for CBD, respectively. Furthermore, the incidence and severity of reported adverse events were similar in both groups [131,132]. Nevertheless, regarding the role of piperine, it is important to remember that it is able to alter the metabolism of many drugs, being a cytochrome and glucuronyl transferase inhibitor. In addition, piperine demonstrates non-negligible toxicity (it is Generally Recognized as Safe only up to 10 mg/day).
The finding of the endocannabinoid-mediated retrograde synaptic signalling pathway has opened up a new era, for cannabinoid research, including evaluations of their therapeutic use . Selective CB2 agonists have shown considerable efficiency in a variety of neuropathic pain preclinical models, while increasing amounts of evidence, derived from clinical studies, have confirmed the potential of the cannabinoid system in affording benefits for patients with chronic pain and chronic inflammatory diseases (arthritis). Currently, patients with chronic arthritic and musculoskeletal pain are the most prevalent users of therapeutic cannabis products .
The authors are grateful to Franca Viola for fruitful discussions. Dale James Matthew Lawson is gratefully thanked for correcting English of the manuscript.
The endocannabinoid system’s contribution to the regulation of such a variety of processes makes phytocannabinoid pharmacological modulation a promising therapeutic strategy for many medical fields, including the studies of analgesic, neuroprotective, anti-inflammatory and antibacterial activity [13,14].