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. 2022 Jul 18;5(8):642–651. doi: 10.1021/acsptsci.2c00077

Quantification of Cannabis in Infused Consumer Products and Their Residues on Skin

Rosalynn Quiñones †,*, Sara Moreno †,‡, Amanda L Smythers §, Carrie Sullins †, Haley Pijor †,‡, Glenna Brown ‡, Ashley Trouten ∥, Lauren L Richards-Waugh ‡, Aladin Siddig ⊥
PMCID: PMC9380210  PMID: 35983282

Abstract

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Cannabis consumer products are a $4.6 billion industry in the U.S. that is projected to exceed $14 billion by 2025. Despite an absence of U.S. Food and Drug Administration (FDA) regulation or clinical data, thousands of nutraceuticals, topical consumer products, and beauty products claim benefits of hemp or cannabidiol. However, a lack of required quality control measures prevents consumers from knowing the true concentration or purities of cannabis-labeled products. Thirteen over-the-counter consumer products were examined for the presence of cannabidiol (CBD), cannabinol (CBN), Δ9-tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), and Δ9-tetrahydrocannabinolic acid A (THCA). Additionally, the efficacy of topical applications was investigated using a porcine skin model, in which particle size and zeta potential relate to skin permeability. Skin permeation was correlated to particle size and relative stability in skin-like conditions but not directly related to the CBD content, suggesting that topical products can be designed to enhance overall skin permeation. Of the products analyzed, all products have some traceable amount of cannabinoids, while seven products had multiple cannabinoids with quantifiable amounts. Overall, the need for further regulation is clear, as most products have apparent distinctions between their true and labeled contents.

Keywords: topicals, chromatography, Franz cell, cannabis, skin permeation, hemp

The international impact of cannabis has increased over recent years with the legalization of industrial hemp and approximately 2.5% of the population using products with cannabis components.1−4 Cannabis is divided into three species: Cannabis sativa (C. sativa), Cannabis indica, and Cannabis ruderalis.5−7C. sativa is preferred by most consumers because of its high Δ9-tetrahydrocannabinol (THC) content, which has widely been used to treat different medical diseases/symptoms, such as AIDS/HIV, chronic pain, and inflammation.7−9 Cultivars of C. sativa, such as industrial hemp, are grown to take advantage of the benefits of other cannabinoids found in C. sativa without the psychoactive effects induced by THC. Industrial hemp, commonly used in consumer products, has a high cannabidiol (CBD) concentration.10 As defined by the U.S. Food and Drug Administration (FDA), industrial hemp has no more than 0.3% THC on a dry weight basis.11

CBD is marketed in commercial products with various formulations, the most common being CBD oil. However, other formulations, such as creams, lip balms, lotions, and edibles, are also commonly available.8,9 Despite the interchangeable usage on product labels, CBD and hemp are not the same. This can be misleading to customers purchasing certain products with the expectation of CBD content. Ingredients, such as Cannabis sativa seed oil, hemp seed extract, hemp seed oil, hemp extract blend, and hydrolyzed hemp seed protein can be found in the list of said products. Customers will often see the words “CBD” or “hemp” without an understanding of how these products were prepared. Consumers are often not aware of which part of the plant was used or how much CBD, THC, and other cannabinoids, such as cannabidiolic acid (CBDA), Δ9-tetrahydrocannabinolic acid A (THCA), or cannabinol (CBN), may be found in these products. In an attempt to increase CBD delivery, consumer products have been developed to permeate the skin.12−14 These topical applications are marketed as medicinal products relying on CBD’s proposed antiaging, antiseborrheic, antioxidant, and skin-protective properties to treat a variety of conditions.12,15−20 While research has demonstrated positive effects of some topical CBD products, they are not yet regulated by the FDA. Additionally, the therapeutic effects of these commercial products cannot be judged solely on their cannabinoid content because they contain other anti-inflammatory or analgesic components.13,14,17

Apart from the Hemp Production Program and the 2018 Farm Bill in the United States setting a legal threshold of THC, hemp is not regulated in consumer products.21 Therefore, consumers have no guarantee the cannabis products purchased contain the labeled content.21,22 The lack of regulation on cannabinoid concentration in these products is concerning and research has shown some labeling inaccuracies in cannabis products.8,23,24 Assessment of CBD edibles demonstrates this issue where a study determined 23% of products were under labeled with 60% over labeled regarding CBD content, increasing the overdose risk.8,24 Likewise, no regulations on product handling and storage conditions currently exist, increasing the chance of cannabinoid degradation during processing and shipping.25,26 The European Union (EU), which has more regulations in place than the U.S., has shown inadequate product labeling, poor product quality, and inconsistent cannabinoid content are common.25 A study conducted in Switzerland found only 7 out of 20 e-liquid products contained the label amount of CBD.27 While independent testing in Czechia showed one-third of products tested had label discrepancies.25 Limited regulation means consumers have no guarantee products are labeled with the correct components or concentrations, potentially leading to accidental intoxication.25,28 While CBD is not known to have psychoactive effects, studies have shown it can be converted to THC in acidic or high temperature conditions.28−30 However, other studies have not supported the conversion between CBD and THC in vivo despite CBD degrading under acidic conditions like the stomach.31,32

In this study, the cannabinoid content of various consumer products was quantified and compared to the content stated on the packaging (structures shown in Figure 1). High-performance liquid chromatography (HPLC), Franz diffusion cell, dynamic light scattering (DLS) with zeta potential measurements, ultraviolet - visible spectroscopy (UV–vis), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to characterize ten water-based and three oil-based cannabis products intended for topical use. Consumer products included lotions, creams, shampoo, conditioner, salve, and lip balms, all chosen for their topical application and array of listed cannabis components (see Table 1 and Supporting Information for more details). Using a Franz cell to replicate skin physiology, a further understanding of products’ permeation abilities through the particle size and environmental influence on particle direction in an electric field was assessed.12,33 Products claiming to contain specific cannabis components had various cannabinoids present, despite not being labeled for them. Additionally, not all products with quantifiable amounts of CBD were permeable to the skin.

Figure 1.

Figure 1

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Cannabinoids of interest (A) CBD, (B) THC, (C) CBN, (D) THCA, and (E) CBDA.

Table 1. List of the Consumer Cannabis Products Intended for Topical Use Analyzed.

product categorization product cannabis component
water based Hempz Lotion Cannabis sativa seed oil
Hempz CBD pure CBD isolate (cannabidiol) from hemp
Shikai CBD Body Lotion Cannabis sativa seed oil, cannabidiol
Zen Renu Cream hemp seed extract and 100 mg hemp seed oil
Neu Hemp 1000 mg hemp extract blend, hemp oil
Greenford Hemp Cream 1000 mg hemp extract blend
Trueganic Hemp Cream hemp oil, “30× power”
Hemp Genius Cream 8500 mg hemp oil, “20× power”
Hemp Shampoo hydrolyzed hemp seed protein
hydroxypropyltrimonium chloride
Cannabis sativa seed extract
Cannabis sativa seed oil
Hemp Conditioner hydrolyzed hemp seed protein
hydroxypropyltrimonium chloride
Cannabis sativa seed extract
Cannabis sativa seed oil
oil based Pure Ratios Salve hemp oil (CBD)
Cannasmack Lip Balm Cannabis sativa hemp
Hempz Lip Balm Cannabis sativa seed oil
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Methods

Cannabinoid Sample Preparation for Quantitative Analysis

There were ten water-based, over-the-counter consumer products purchased from various companies (Tables S1 and S2). Product labels claimed to contain “hemp”, “hemp oil”, “Cannabis sativa seed oil”, “pure CBD isolate”, or “hemp seed extract”. To prepare water-based samples for analysis, 0.5000 g of each product was centrifuged for 15 min in 25 mL of methanol before sonicating for 15 min. The samples were then diluted to 50.00 mL with methanol using a volumetric flask.

Three oil-based, over the counter consumer products were purchased with listed ingredients of “hemp oil”, “Cannabis sativa”, or “C. sativa seed oil” (Tables S1 and S2). Oil-based samples were more challenging to disperse in solution, requiring optimization of a previously published extraction procedure.34 Samples were prepared by centrifuging 0.1250 g of each product for 15 min in 10 mL hexane and before sonicating for 15 min. The samples were dried under a vent hood using pressurized air and then reconstituted using 10 mL methanol and sonicated for 15 min. Lastly, samples were centrifuged for 15 min and diluted to 25.00 mL in a volumetric flask with methanol. More details describing HPLC, UV–vis, and LC-MS/MS analysis can be found in Supporting Information.

Standard Preparation

Calibration curves were generated using CAN, (a reference standard containing CBD, CBN, and THC), along with THCA and CBDA standards. Calibrators were prepared by adding sample matrix to subsequent cannabinoid concentrations following the same procedure as sample preparation. Matrices were chosen for each product with the closest ingredient agreement apart from C. sativa, to analyze the matrix effect of unidentified components in the chromatogram (Table S2 for the matrices list). Each matrix solution was made according to its corresponding product’s preparation: water based, or oil based. An aliquot of the matrix solution was transferred to a new volumetric flask along with the corresponding calibrator and diluted to the mark with methanol. The concentration range utilized for the CAN standard was 1–120 mg/L while the range utilized for CBDA and THCA standards was 1–10 mg/L.

Franz Diffusion Cell Analysis

Pig skin was used as a proxy for human skin, as previously published.12,35 The hide from a Hampshire pig (Nelson’s Meat Processing LLC, Milton, WV) was shaved and stored in small sections at −30 ± 2 °C prior to preparation. After the skin had thawed, the epidermal layer was removed from the remaining fat and cut into circles with a diameter of 2.5 cm to fit the chambers of the Franz Cell apparatus. The top part of the pig’s skin was used for the skin permeation analysis.

The products with quantifiable amounts of CBD (Table 2) were spread onto the pig skin disks with a glass stirring rod at 3 mg/cm2.35 Skin samples were then placed on the 25 mm circles of the Franz cell apparatus before 4 mL of buffer was extracted and replaced with 4 mL of phosphate buffer at 1, 3, 5, 7, 9, 12, and 24 h. The samples were then analyzed using the previously described HPLC analysis parameters. The HPLC run time was changed to 10 min to only analyze for the presence of CBD.

Table 2. Quantitative and Qualitative Analysis of the Cannabinoids Analyzed for Product.

      quantitative cannabinoid presence
product CBD declared(mg/g) qualitative cannabinoid presence cannabinoid mg/g μg/g % wt. % RSDa
Hempz Lotion   CBD          
Shikai CBD Lotion 4.41   CBD 5.90   0.590 7.33
Hempz CBD Lotion 1.25   CBD 1.33   0.133 5.89
Zen Renu Cream     CBD 2.22   0.221 6.78
CBN   3.77 3.77 × 10–4 7.82
THC   261 0.0261 28.4b
CBDA   1.51 1.51 × 10–4 14.2b
Neu Hemp Cream     CBD 9.46   0.946 4.79
CBN   8.96 8.96 × 10–4 14.0b
CBDA   4.47 4.47 × 10–4 13.6b
Greenford Hemp Cream   CBD, CBDA          
Trueganic Hemp Cream   CBD, CBDA          
Hemp Genius Cream     CBD   67.7 6.77 × 10–3 12.6b
Hemp Shampoo   CBD, CBN          
Hemp Conditioner   CBD          
Pure Ratios Salve 6.22 CBDA CBD 6.04   0.604 6.95
CBN   27.2 2.72 × 10–3 13.2b
Cannasmack Lip Balm   CBDA CBD   38.8 3.8 × 10–4 9.65
Hempz Lip Balm   CBD          
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a

Relative standard deviation (RSD) was calculated by dividing the standard deviation by the average of all trials per sample.

b

Because of the nature of topical product, matrix effects caused more interferences at small quantities.

An in vitro study was also conducted by performing extractions on each of the skin samples at the end of the 24 h, as previously published.12 After the 24 h period, the pig skin samples were removed from the Franz cell apparatus and placed in 15 mL of methanol for 30 min. The samples were then rinsed with an extra 5 mL of methanol and sonicated for 1 h. These extractions were analyzed using HPLC as well as GC-MS to identify and quantify the CBD retained on skin. More details about the Franz cell and GC-MS analysis can be found in the Supporting Information.

DLS with Zeta Potential Sample Preparation

Water-based samples were prepared by combining 50.0 mg of product with 10 mL of solvent (NaCl solution or artificial eccrine perspiration solution) and sonicating in an ultrasonic bath for 30 min. A 500 μL aliquot was diluted to 10 mL of the same solvent that had been previously triple filtered using nylon 0.20 μm filters before being analyzed by DLS and zeta potential. The oil-based products were analyzed in the same manner, but the analysis used 25.0 mg of product. More details about instrumentation and analysis can be found in the Supporting Information.

Results and Discussion

Cannabinoid Qualitative and Quantitative Analysis

While many consumer products claim to contain CBD and other cannabinoids, little regulation or required quality control studies exist to validate these claims. Therefore, liquid chromatography was implemented to quantify and identify cannabinoids in 13 C. sativa infused commercial products (Tables 2, S1, and S2). All products were stored at room temperature (24 °C) to match typical consumer use and were analyzed within one year of being opened. Cannabinoid standards were first analyzed using UV–vis spectroscopy to determine the optimal wavelength for HPLC analysis. The United Nations recommends HPLC-UV analysis of cannabinoids at a wavelength of 220 nm, while the manufacturer recommendation for standard analysis was 228 nm, in which one wavelength was provided for optimal analysis of multiple cannabinoids simultaneously.36,37 However, CBD and THC were found to absorb at the maximum wavelengths at 207 and 210 nm, respectfully. Therefore, the HPLC analysis was performed at 210 nm for the CBD, CBN, and THC analytes contained with the CAN standard to optimize the potential instrument response of THC. This optimized technique permits adequate separation while yielding the greatest signal over that produced by the suggested wavelengths.36 THCA and CBDA, however, were analyzed per manufacturer’s recommendation. The THCA compound analyzed was the isomeric form THCA-A, which is more abundant in the cannabis plant.38 Hemp-free products (Tables S1 and S2) were chosen as a chemical matrix to represent the elution and retention of the nonanalyte sample components. Using a more appropriate blank matrix permits the identification of nontarget components coeluting with the target cannabinoids. Linear calibration curves were validated through the addition of high and low validation points, yielding a bias within ±7% (Table S3). The coefficient of determination (R2) was calculated for each calibration curve with relative values of 0.99 and above (Table S4). For HPLC-UV detector, the limit of detection (LOD) and limit of quantification (LOQ) for each matrix type was calculated based on the cannabinoid signal after at least five different standards with a concentration of 1 mg/L were both analyzed and quantified (Table S4). LOD was based on the lowest response compound yielding the most conservative value and standard deviations of that signal were calculated and divided by each slope for each product and each calibration curve. Then, the LOD was determined when the peak achieved a signal-to-noise ratio of 3 and LOQ when the peak achieved a signal-to-noise ratio of 10.39 LC-MS/MS was then used to qualitatively confirm cannabinoid identification and to quantify cannabinoids below the detection limit of the HPLC-UV-(Table S5). The method was validated for bias, calibration model, limit of detection, limit of quantification, and precision (Table S3), following the ANSI/ASB standard and more details can be found in the Supporting Information.39

While CBD was detected in all 13 products, only 7 of those products had quantifiable amounts of CBD (Table 2). Considering hemp is known to contain CBD, detection of CBD was expected (Table S2). Of the products with detectable quantities of cannabinoids, six contained CBDA, four with CBN, and one contained THC. THCA was not detected in any of the analyzed products. Interestingly, one product (Zen Renu Cream) contained quantifiable amounts of CBD, CBDA, CBN, and THC as observed in the multiple reaction monitoring (MRM) transitions achieved with LC-MS/MS analysisFigure 2). Although the product lists both hemp seed extract and hemp seed oil among its ingredients, the ingredients list on the package does not list any cannabinoids. Similarly, Neu Hemp Cream contained every analyzed cannabinoid except THC and THCA. This contradicts the manufacturer’s claim that only hemp extract blend and hemp oil are included in the ingredients, allowing them to cover any missing components with ambiguous terms. Hemp Shampoo, Hemp Conditioner, and Hempz Lip Balm only contained cannabinoids that were below the LOQ.

Figure 2.

Figure 2

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Identification and quantification of four cannabinoids for Zen Renu Cream by LC-MS/MS employing MRM transitions. Extra peaks can be due to other possible unknown ingredients or similar cannabinoids present.

Of the seven products with quantifiable amounts of CBD, Cannasmack Lip Balm claimed to contain Cannabis sativa hemp, and 38.8 ± 3.7 μg/g CBD was quantified with CBDA detected. Greenford Hemp Cream claimed to contain 1000 mg hemp extract blend but CBD and CBDA were present at concentrations below the LOQ. Along with its claim of “8500 mg hemp oil”, Hemp Genius Cream was found to have one of the lowest quantifiable amounts of CBD (67.7 ± 8.5 μg/g) while claiming “20× power”. Additionally, Trueganic Hemp cream listed no cannabinoid content while indicating “30× power” with hemp oil as the cannabis component, but CBD and CBDA were detected. Labeled claims, like “30× power” are likely to mislead consumers to associating this “power” with the amount of cannabinoids present. However, the “30× power” claim is likely to represent the product’s pain-reliving power derived from other ingredients in the extensive formulation rather than the CBD content (Table S2). Although these two products had claimed to include hemp, CBD and CBDA were present, but not at quantifiable concentrations (Table 2).

Neu Hemp Cream (9.46 ± 0.45 mg/g CBD, 8.96 ± 1.25 μg/g CBN, and 4.47 ± 0.61 μg/g CBDA) and Zen Renu Cream (2.22 ± 0.25 mg/g CBD, 261 ± 74 μg/g THC, 3.77 ± 0.29 μg/g CBN, and 1.51 ± 0.21 μg/g CBDA) had no direct labeling of cannabinoid content (i.e., no CBD and/or THC claims). However, the front label of Neu Hemp cream claimed to contain 500 mg (8.82 mg/g) of full spectrum hemp. Likewise, 1000 mg (17.6 mg/g) of hemp extract blend and hemp oil were among the listed ingredients for this cream. Zen Renu Cream had hemp seed extract and a listed amount of 100 mg (1.76 mg/g) hemp seed oil on the ingredient label. These two products were the only ones to list amounts of cannabis plant components.

The other three products with quantifiable amounts of CBD were Shikai CBD Body Lotion (5.90 ± 0.43 mg/g CBD), listed as having 100 mg (4.41 mg/g) or more per container, Hempz CBD Body Lotion (1.33 ± 0.08 mg/g CBD), claiming 80 mg (1.25 mg/g), and Pure Ratio Salve (6.04 ± 0.43 mg/g CBD and 27.2 ± 3.6 μg/g CBN, Figure 3), claimed to contain 150 mg (6.22 mg/g) CBD Hemp. The labeled ingredients of these three products all explicitly state CBD or cannabidiol, unlike their counterparts. These products were also clearly marketed for the use of CBD. Cannabinoids were also detected in Hempz Lotion, Hemp Shampoo, Hemp Conditioner, and Hempz Lip Balm (Table 2).

Figure 3.

Figure 3

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Chromatograms at 210 nm of (A) CAN standard in Hempz CBD Lotion matrix. CAN standard included the components of CBD, CBN, and THC that can be seen at the following retention times, respectively: 5.6, 7.4, and 8.9 min. (B) Chromatogram of Hempz CBD Lotion showing the retention of the CBD peak at 5.6 min.

Some of the products tested had websites where the quantified cannabinoid content could be easily confirmed.40,41 A t-test comparing a mean to a fixed value was conducted at a 95% confidence interval to compare the quantification to the certified analysis by the manufacturers. When comparing the analysis of Pure Ratios salve, the quantified amount was considered statistically different than the certified analysis, with a quantified wt % CBD at 0.60 ± 0.04% compared to the certified analysis of 0.69% CBD.41 However, in this certified analysis, the lot number was not specified, and the most recently available analysis was in 2019.41 Shikai Body Lotion also had a certified analysis of their product on their website, with an available report for each batch.40 The batch used in this analysis was certified by the company to have a maximum weight percent of 0.48% CBD and no other cannabinoids above the limit of detection (0.36 mg/g) or limit of quantification (0.60 mg/g) reported.40 However, Shikai CBD Body Lotion was found to have 0.59% wt. CBD and detectable amounts of THC. For this product, the quantified and certified amounts were considered statistically different. Because of the lack or minimal quantities of CBN found in these two products, the discrepancies between the labeled CBD and the analyzed CBD cannot be equated to product degradation.

This statistical difference demonstrates even the certified analyses of available products can deviate from the listed cannabinoid amounts present in the consumer-purchased product. Throughout the examination of the products, discrepancies between labeled amounts, labeled cannabis components, and quantification can be seen, showing that the lack of regulatory standards for these products has given companies the freedom to label products with C. sativa components interchangeably. This use of the word 'hemp' acts as a catchall for the potential products as long as THC concentrations are low, leading consumers to believe the same cannabinoid outcome from two different products both labeled “hemp”. Marketing products with no true understanding of the cannabinoid content can be dangerous and misleading to the consumer.28,29

Cannabinoid Diffusion and Retention in Skin

There are few research studies empirically investigating the topical use of CBD, despite several consumer products’ claims of health benefits. In fact, the ability for CBD to permeate the skin has not yet been thoroughly investigated.12,42−44 To fill this gap, Franz cell analysis was performed using a porcine skin model to quantify the skin permeation of CBD in the acquired topical products with CBD contents above the LOQ of the HPLC-UV (Tables 2 and S4). HPLC-UV was employed to quantify the CBD permeated into solution for all time intervals as well as following the porcine skin extraction.

Following 24 h in the Franz cell, an average of 0.83 ± 0.06 mg/g CBD permeated through the skin for Neu Hemp Cream, Hempz CBD Lotion, and Shikai CBD Body Lotion (Figure 4). Neither Zen Renu cream nor Pure Ratios Salve showed detectable amounts of CBD present throughout the 24 h period. Previous research has shown that semisolid formulations, such as lotions and creams, have lower retention and permeation rates than other solutions, which could be a factor in the products’ lack of permeation.12 Studies also suggest sample composition plays a significant role regarding skin permeation, indicating that lipophilic mixtures may not be able to penetrate the first layers.12,44

Figure 4.

Figure 4

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(A) GC-MS spectra for Shikai CBD Body Lotion, Neu Hemp Cream, and CBD standards and (B) average amount of CBD present (mg/g) at 24 h for each product, as well as average amount of CBD present in the pig skin extractions and the maximum amount of CBD diffused per lotion sample at various time intervals.

Throughout the 24 h period, each product was monitored for the time at which maximum diffusion was reached (Figure 4B). The maximum amount of CBD in Neu Hemp Cream diffused between the 1–5 h range, with an average concentration of 8.7 ± 2.1 mg/g. Shikai CBD Body Lotion reached its maximum diffusion between 3 and 7 h, with an average diffusion of 2.1 ± 1.5 mg/g. Hempz CBD Lotion reached its maximum diffusion between 5 and 7 h, with an average diffusion of 2.3 ± 1.6 mg/g. Neu Hemp, which had the greatest amount of CBD (9.46 mg/g), had the quickest diffusion rate (Figure 4B). Both Neu Hemp Cream and Hempz CBD Lotion’s CBD quantitation, following HPLC analysis (Table 2), falls within the standard deviations of the quantified skin permeation.

In vitro skin retention studies were performed after 24 h to quantify the CBD remaining on the pig skin and confirm the presence of CBD within the skin extractions using HPLC-UV. Due to the high lipophilic nature of the skin extracts, GC-MS data was collected to confirm the presence of CBD in each extraction to preserve the LC-MS/MS column. The results can be observed in Figure 4A. For the three products with quantifiable CBD permeation, the relationship between the amount of CBD left on the skin and the average amount of CBD diffused was directly proportional. (Figure 4B) These results were consistent with a previous study that showed a correlation between the retained amount of CBD and the amount of CBD that permeated.12

Product Interactions with Skin Determining Diffusion

Topical pharmaceuticals are only effective if penetration of the outer layer of the epidermis is achieved, which acts as both a water transport barrier and an inlet for chemical diffusion.45 This outer layer of skin secretes eccrine perspiration, which includes metabolites, minerals, electrolytes, and amino acids.33,46,47 However, drug administration systems utilizing skin permeation have been limited to drugs with ideal physicochemical properties: a combination of molecular weight, lipophilicity, and charge that allow for optimal skin diffusion.48 Drug products with a negative charge on skin at neutral pH can cause the cationic compounds of the outer layer of skin to have increased skin permeation and skin binding.48

To assess the potential of permeation and skin binding, the products’ particle size and effective electric charge were characterized in a 29 mM solution of NaCl (based on the salt content of healthy human skin), as well as artificial eccrine perspiration (Table 3).33,47 Since pH and charge can affect the zeta potential measurements, the pH and voltages were obtained between 20.5 and 21.5 °C for NaCl solution and artificial eccrine perspiration, pH 7.4, −4.5 mV and pH 4.3, 165.2 mV, respectively. This was done to analyze media conditions that may cause changes to the sample’s interactions in solution. Of the products analyzed, only those with quantifiable amounts of CBD (Tables 2 and S4) were further analyzed for permeation.

Table 3. Particle Size and Zeta Potential Values of the Effects Skinlike Condition Have on the Hydrodynamic Diameter and Behavior of Cannabis Infused Products Using DLS.

  29 mM NaCl solution
 artificial eccrine sweat
product type particle size (nm) ± std deviation zeta potential (mV) ± std deviation particle size (nm) ± std deviation zeta potential (mV) ± std deviation
Shikai CBD Body Lotion 183 ± 11 –6 ± 3 198 ± 15 –1 ± 4
Hempz CBD Lotion 167 ± 25 –19 ± 4 226 ± 63 –4 ± 3
Zen Renu Cream 197 ± 5 –10 ± 5 388 ± 78 –3 ± 3
Neu Hemp Cream 231 ± 55 –16 ± 3 220 ± 23 –3 ± 2
Pure Ratios Salve 364 ± 103 –53 ± 7 1069 ± 279 –12 ± 6
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The listed ingredients of each product (Table S2) were compared to their apparent particle size in solution. All products analyzed contained a form of vitamin E, an amphiphilic lipid, which should allow them to partially dissolve in aqueous solutions regardless of permeation.49 However, in the artificial eccrine perspiration solution, the hydrophobic portion of these molecules most likely interacted with the solution’s components causing the product’s apparent particle size to enlarge in the more acidic and nonpolar conditions of the artificial eccrine perspiration. This interaction further decreases the solution’s conductivity because it is directly affecting the pH. Previous studies have correlated the ionic strength of the media to the hydrodynamic diameter.50,51 As the conductivity of the media decreases, the apparent particle size of the hydrodynamic diameter increases thereby reducing the diffusion.50,51 Yet this effect is not observed in Neu Hemp Cream, which showed a decreased apparent particle size in the artificial eccrine perspiration as seen in Table 3. This product contained the hydrophobic components emu oil and trideceth-6, which could contribute to the decrease in the overall conductivity of the sample, in turn increasing its apparent hydrodynamic diameter.

Pure Ratios Salve and Zen Renu Cream were the only products with quantifiable amounts of CBD that did not permeate through the skin using the Franz cell (Figure 4). These products had the largest particle sizes overall in artificial eccrine perspiration with particle sizes of 388 ± 78 and 1069 ± 279 nm, respectively. All other products demonstrated particle sizes less than 300 nm, including the standard deviations, with average particle size ranging from 198 to 226 nm. This suggests the particle size of the Pure Ratios Salve and Zen Renu Cream may be too large to penetrate through the epidermis as previously observed in the relationship of particle size and permeation.45,52−55 Lack of permeation may be due to other components the two products have in common: calendula, arnica flower extract, coconut derivatives, or turmeric. However, Neu Hemp cream, which was permeable to the skin, also contained arnica flower extract and coconut derivates. The observations from this study demonstrate not all purchased products will have the ability to effectively deliver the cannabinoids past the epidermis. Lack of permeation may be because of other components meant to aid the overall formula creating a hydrodynamic diameter on skin too large to effectively distribute the active components. Inadequate distribution of active components diminishes the likelihood of the health benefits consumers seek from the use of these cannabinoid products.

The zeta potential values of the products were also measured to examine the effect skin conditions have on the products’ electrical charges. In zeta potential measurements, the smaller the absolute value, the less electrically stable the sample.56,57 A large absolute value of zeta potential (greater than 30 mV) leads to a more stable and monodisperse sample but low absolute values of 5 mV or less indicate lower stability and more agglomeration.56,57 Overall, all products showed greater stability in the NaCl solution than in the artificial eccrine perspiration, with the highest stability observed in the Pure Ratios Salve samples. The samples analyzed in artificial eccrine perspiration possessed absolute zeta potential values lower than 5 mV, with 4 of the 5 products analyzed considered to have agglomeration and low stability. While Pure Ratio salve presented a low stability, the zeta potential did not fall within ±5 mV indicating more stability than all products showing skin permeation. Previous studies have shown that slight changes to zeta potential parameters, including pH, temperature, conductivity, and solvent viscosity, can have considerable effects on the zeta potential values.50 No direct correlation could be made between the zeta potentials and the cannabinoid content. Of the quantifiable products, the artificial sweat solution induced the least stability in all, becoming less negative in the low pH environment of the solution. This supports the idea that the cationic compounds on the outer layer of skin are interacting with the negative charge of the drug products, which should further support permeation.48

Conclusion

Of 13 consumer products with claims of various cannabis components and plant materials, cannabinoids were detected in all products. Further analysis identified seven of those products to have quantifiable CBD content and one product with quantifiable THC content. Cannabinoids compounds were detected in various products with several containing multiple compounds at concentrations above the LOQ. Additional analysis was performed on the quantifiable CBD products, showing detectable permeation of skin based on particle size and relative stability in skin-like conditions. From the permeation experiments, one product was found to have an approximate permeation directly correlated to the CBD content of the product, indicating topical products could be designed with awareness of skin permeation properties for optimal therapeutic formulations. However, these products are labeled with broad cannabis component terms failing to acknowledge the true cannabinoid content. This, in addition to a lack of quality control analysis misleads consumers, resulting in the purchase of products that do not yield the desired effects promoted on the packaging.

Acknowledgments

This work was funded by a National Science Foundation (NSF) Grant (Award CHE1828358, OIA1458952, and HRD 1826763, MRI 0821401), NASA West Virginia Space Grant Consortium (Training Grant NNX15AI01H and 80NSSC20M0055), West Virginia Higher Education Policy Commission under the Grant Numbers HEPC.dsr.18.7. and dsr.20.16 amend. 1.1, Marshall University Research Corporation (MURC) for the Undergraduate Creative Discovery and Research Scholar, and John Marshall University Scholars awards and by the Department of Chemistry at Marshall University. Authors would like to thank Duquesne University’s Agilent Center of Excellence in Mass Spectrometry for the support and Nelsons Meat Processing, LLC, in Milton, West Virginia for their donation of the pig hide. The authors would also like to thank Lena Salameh and Aakriti Damai for their participation in collecting preliminary data and Ryanne Brown for her forensic guidance.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.2c00077.

  • Reagents and standards, HPLC analysis, LCMS analysis, Franz diffusion cell analysis, DLS, and zeta potential analysis; infused cannabis products categorization and their corresponding matrixes; infused cannabis product content as claimed by the product label; validations of products with quantifiable amounts of cannabinoids; detection limits and resolution of HPLC instrumentation with UV detector; optimized conditions for the analysis of CBD, CBN, THC, CBDA, and THCA attained on a LC-MS/MS; and single-ion monitoring ensured low signal-to-noise during consumer product analysis (PDF)

The authors declare no competing financial interest.

Supplementary Material

pt2c00077_si_001.pdf (153KB, pdf)

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Supplementary Materials

pt2c00077_si_001.pdf (153KB, pdf)

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