Stress is often an inevitable part of everyday life and can affect the skin in many different ways, from accelerated the visible signs of ageing, to dehydration, to irritation, to dullness and uneven skin tone and texture. Cannabis Sativa Seed Oil tackles the signs of stressed skin, calming, soothing and reducing the appearance of redness . Like every other organ in the body, the skin has its essential needs for optimal health and beauty. The most important two ingredients that a skincare product can contain are essential fatty acids and vitamin E. In nature Cannabis Sativa Seed Oil contains a balanced concentration of omega 3 and omega 6.
What is hemp?
Alongside a balanced ratio of essential fatty acids, one of the omega-6 fatty acids that hemp oil contains is gamma-linolenic acid (GLA), which simultaneously encourages skin growth and cell renewal. This can help to calm irritation on the skin, while keeping the skin intensively nourished, plumped and moisturised.
Understanding the differences between cannabis, hemp, and marijuana can be confusing because marijuana and hemp come from the same plant, Cannabis Sativa. The distinction is the variety of the plant. In the case of cannabis, the varieties differ in the amount of tetrahydrocannabinol (THC) that they contain. THC is the psychoactive constituent responsible for the high that cannabis gives. Hemp generally contains very little THC, so it has absolutely no psychoactive effects.
A natural antioxidant
Δ 9 -THC primarily undergoes liver metabolism through CYP3A4 and CYP2C9. 16 Due to the polymorphic nature of P450 enzymes, 17,18 people consuming hemp seeds may gradually accumulate Δ 9 -THC due to its slow metabolism or relatively long half-life in the body, leading to potentially higher concentrations. In the report by Chinello et al., Δ 9 -THC concentration in the prescribed hemp seed oil was 0.06%, that is, 0.6 mg of total Δ 9 -THC in 1 g of hemp seed oil, and the child was administered two teaspoons (∼10 mL or 9.2 g) a day for 3 weeks before the incidence of neurological symptoms. 19 This amounts to 5.52 mg total Δ 9 -THC per day, when one consumes 10 mL above hemp seed oil. If one were to compare these total Δ 9 -THC levels, a similar quantity of total Δ 9 -THC (5.52 mg) is contained in ∼44.2 g of hemp seeds (brand# 1, total Δ 9 -THC estimate based on SFE extraction), and this is certainly a normal quantity that consumers may consume as part of their daily food consumption. In people with liver impairment or patients consuming other drugs such as ketoconazole (an inhibitor of CYP3A4) or sulfaphenazole (an inhibitor of CYP2C9), one would expect the metabolism of Δ 9 -THC to be slower, and would be at risk for adverse effects upon the consumption of hemp seeds with higher concentrations of total Δ 9 -THC. 16,20,21 However, we note that the bioavailability of Δ 9 -THC is only 10−20% and could vary if consumed along with fatty food, and such factors would influence the plasma levels of Δ 9 -THC. 22–24
The other major phytocannabinoid in hemp, CBD, is an antagonist of CB1 and CB2 with relatively weak binding affinities. 12 While CBD is not known to exhibit psychoactive properties, CBD can be cyclized into Δ 9 -THC when incubated with artificial gastric juice at 37°C. 25 Given that CBD was present in generally higher amounts than Δ 9 -THC, the conversion of CBD into Δ 9 -THC in the stomach after consumption may further contribute to the psychoactivity of hemp seeds.
Cannabis spp. of plants produce a unique class of compounds called cannabinoids. Hemp is a variety of the Cannabis sativa plant species that is grown specifically for the industrial uses of its derived products. 1–3 This plant can be refined into a variety of commercial items, including food, and animal feed. C. sativa species leads to both medical cannabis and industrial hemp, and this species contains the psychoactive component Δ 9 -tetrahydrocannabinol (Δ 9 -THC); these two plants are two distinct strains with unique phytochemical signatures. 1 Hemp has lower concentrations of Δ 9 -THC, thus limiting its psychoactive effects, and its concentration is regulated in the consumer products where hemp is legal. 4,5 The seeds of hemp are rich in unsaturated fats and protein, while containing little to no cholesterol. In fact, a 100 g serving of seeds meets up to 63% of the recommended daily value for protein. 6 Whether in the raw seed form or as a derived product such as cold-pressed seed oil, hemp seeds have become increasingly popular as both food and health supplements; in 2011, the United States alone spent more than $11 million on hemp imports for consumption. In most nutritional food stores and grocery stores, hemp seeds are a staple nowadays, in countries where it is legal.
1 Center for Molecular Design and Preformulations, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
The concentrations of Δ 9 -THC, Δ 9 -THCA, CBD, and CBDA, along with total Δ 9 -THC (i.e., Δ 9 -THC + Δ 9 -THCA) and total CBD (CBDA + CBD) from each brand of hemp seeds, using each of the four extraction procedures, are shown in Table 1 , and are plotted in Figure 2 . The discussion and interpretations henceforth are in the context of total Δ 9 -THC and total CBD.
Discussion: We discovered that Δ 9 -THC concentrations in these hemp seeds could be as high as 1250% of the legal limit, and the amount of phytocannabinoids depended on the extraction procedure employed, Soxhlet extraction being the most efficient across all three brands of seeds. Δ 9 -THC and CBD exhibited significant variations in their estimated concentrations even from the same brand, reflecting the inhomogeneous nature of seeds and variability due to the extraction method, but almost in all cases, Δ 9 -THC concentrations were higher than the legal limit. These quantities of total Δ 9 -THC may reach as high as 3.8 mg per gram of hemp seeds, if one were consuming a 30-g daily recommended amount of hemp seeds, and is a cause for concern for potential toxicity. It is not clear if these high quantities of Δ 9 -THC are due to contamination of the seeds, or any other reason.
5 The Pain Research Unit, Department of Anesthesia and Pain Management, Toronto General Hospital, University Health Network, Toronto, Canada.
Results and Discussion
Commercial hemp seeds are marketed for their high nutritional values, but due to their relationship to Cannabis spp. of plants, there is a potential for the presence of phytocannabinoids in these seeds. By regulation, total amount of Δ 9 -THC (whether in its acid form, Δ 9 -THCA, or as neutral Δ 9 -THC) must be less than 10 μg/g of hemp seeds (10 ppm) in Canada, and similar regulations exist in other countries where hemp seeds are legal. Hemp seeds from three brands in local supermarkets were purchased and brought to the laboratory. Each brand of hemp seeds was subjected to four different extraction protocols, and each protocol was repeated thrice to account for any variability due to the extraction procedures and associated errors. In total, 36 extracts were obtained from the three brands and analyzed using UPLC-mass spectrometry to quantify the two major phytocannabinoids, Δ 9 -THC and CBD. We expected the quantity of Δ 9 -THC to be within the regulation limits and CBD to be in relatively higher quantities, as one would expect in hemp seeds. As it is common in the Cannabis spp. plants, majority of phytocannabinoids such as Δ 9 -THC and CBD exist in their carboxylic acid precursor forms, Δ 9 -THCA and CBDA ( Fig. 1 ). Subjecting the extract or resin to high degree of temperature converts these acid precursors into decarboxylated forms, Δ 9 -THC and CBD. However, we calculated the total Δ 9 -THC equivalency (including Δ 9 -THCA and Δ 9 -THC found in each extract) to assess the total concentrations; similar procedure was used for the total concentration of CBD.
Extractions of brand# 2 hemp seeds exhibited more variance, where total Δ 9 -THC amounts were estimated to be 68±101, 54±13, and 75±12 μg/g of hemp seeds using sonication, Soxhlet, and SFE extractions respectively, all of which are fivefold to sevenfold higher than the permitted limit ( Fig. 2B ), whereas microwave extraction estimated the total Δ 9 -THC content to be 17±14 μg/g only. Variations on the CBD estimates are even more significant, where the variation ranged from 3±4 μg/g (using microwave technology) to 172±31 μg/g (SFE) of hemp seeds. It is interesting to note that a different brand led to a completely different profile in the phytocannabinoid variations (brand# 1 vs. 2), and the results based on the extraction method employed are different as well.
Concerning the functional effect, most of the phenolic compounds isolated from hempseed have been shown to have high radical scavenging activity compared to quercetin, and, in addition, the phenolic amide N-trans-feryoryltyramine and especially, the lignanamides 3,3′-demethyl-grossamide and 3,3′-demethylheliotropamide were also able to in vitro inhibit the acetylcholinesterase (AChE) enzyme at a concentration of 100 µg/mL, thus exhibiting properties similar to the medicines used for the treatment of mild to moderate Alzheimer’s disease (AD) such as galanthamine . Bourjot and co-workers  found that, among the phenolic amides they have extracted from hempseed flour, N-trans-caffeoyltyramine had the highest antioxidant and arginase inhibitor activities. In this regard, the inhibition of arginase could raise NO bioavailability that ameliorates endothelial functionality and it can also reduce oxidative stress which plays a central role in the onset and progression of endothelial dysfunction involved in various diseases, including cardiovascular ones. However, the most important biological effects attributable to hempseed phenylpropionamides are the anti-inflammatory and neuroprotective activities. In this context, Zhu and co-workers  had recently isolated and characterized the chemical and functional features of two unique hempseed bioactive compounds named sativamides A and B. According to the authors, from a chemical point of view, they are non-lignanamide compounds characterized by a benzo-angular triquinane core (i.e., a core consisting of fused five-membered hydrocarbon rings and arranged in an angular position), derived from N-trans-caffeoyltyramine. Interestingly, it has been shown that pre-treating of the SH-SY5Y human neuroblastoma cell line with 50 µM of sativamides A or B, reduced the cell death caused by endoplasmic reticulum stress that has been shown to play an important role in neurodegenerative diseases, such as Parkinson’s disease and AD. The same cell line was also used by Maiolo and colleagues  to create a cellular model of Parkinson’s disease, on which the neuroprotective effect of various natural compounds, among which is N-trans-caffeoyltyramine extracted from hempseed, was tested. The obtained results highlighted that 150 µM of the hempseed’s phenolic amide was able to prevent the cell death induced by up to 150 µM of H2O2 treatment and due to oxidative stress and mitochondrial dysfunction caused by this toxic compound. Oxidative stress and mitochondrial dysfunction are thought to contribute to cell death in Parkinson’s disease; therefore, the resulting effect of 150 µM N-trans-caffeoyltyramine can be considered as potentially neuroprotective.
Other works employed the hempseed oil as a dietary treatment/supplementation to explore its potential cardiovascular benefits on humans. In this regard, Schwab and colleagues  observed that 4-week daily supplementation of 30 mL of hempseed oil was able to reduce the total TGs plasma level and to induce significant changes in the composition of serum cholesteryl-esters (CEs) and TGs of healthy volunteers. Particularly, the content of LA, ALA, and GLA increased whilst the OA concentration significantly decreased after the hempseed oil treatment. In contrast, the proportion of AA and DHA in both TGs and CEs did not change after hempseed oil intake as well as the plasma glucose, insulin, and haemostatic factors, including fibrinogen, coagulation factor VIIa (FVIIa), and plasminogen activator inhibitor-1 (PAI-1). Interestingly, the hempseed oil treatment led to reduction of the TC/HDL-cholesterol ratio which is considered an important index to predict the risk of coronary heart disease. Contrarily, Kaul and colleagues  found that the daily assumption of 2 capsules, each containing 1 g of hempseed oil, in healthy volunteers for 12 weeks neither significantly affected any blood lipid parameters (i.e., the TGs, TC, LDL, and HDL plasma levels), nor induced any changes in the LA and ALA plasma concentrations as well as in the inflammatory and platelet aggregation markers, namely TNF-α and C-Reactive Protein (CRP), and collagen and thrombin-induced platelet aggregation, respectively. The authors hypothesized that these findings could be due to a limited and low gastrointestinal absorption of hempseed oil’s LA and ALA, or to the fact that a larger dosage and a longer experimental period may be necessary to obtain significant changes in the evaluated parameters. It is also important to note that these studies have been performed on healthy subjects, and therefore, they do not exclude potential beneficial actions in a specific pathological status. Furthermore, this evidence also introduces the importance and the necessity of identifying the appropriate dosage and vehicle/matrix that will have benefits in healthy people too as a preventive tool. In the context of the usage of hempseeds or their products for a specific pathological target groups, a recent report of Del Bo’ and colleagues  explored the effects of hempseed oil supplementation in the modulation of hyperlipidaemia and CVDs risk in children and adolescents (6–16 years old) with primary hyperlipidaemia. In more detailed, the test group was daily supplemented with one hempseed oil soft capsule containing 3 g of oil, which provided 700 mg of ALA, 1400 mg of LA, 30 mg of SDA, and 100 mg of GLA, with 2.3 g total PUFAs and a PUFAs/SFAs ratio of 7.7:1. As a consequence of this treatment, it has been shown that, although the hempseed oil supplementation after 8 weeks did not significantly change the plasma lipid profile of the volunteers, it was able to improve the red blood cell (RBC) FAs composition, significantly increasing the total n-3 PUFAs, including the LC-n-3 PUFAs EPA, DPA, and DHA and decreasing the n-6/n-3 PUFAs ratio, as well as the total amount of SFAs and MUFAs. Considering that an altered FAs composition in RBCs has been shown to be positively related with coronary heart disease, atherosclerosis-related diseases, arterial hypertension, and dyslipidaemia, and that SFAs have been reported to have hypercholesterolemic activity in adults, the observed effect of hempseed oil supplementation could have a contribution in counteracting the negative consequences of hyperlipidaemia on the cardiovascular system. Interestingly, in this work was also noted that the dietary intake of higher ALA amounts led to an increase in the RBCs’ LC-n-3 PUFAs derived by the ALA conversion (EPA, DPA, and DHA) in comparison to the control group, and this evidence could indicate that hempseed oil supplementation may stimulate the endogenous conversion of ALA into its biologically active derivatives. According to the authors and in agreement with Kaul and colleagues , the lack of differences between the control and the test group on the serum lipid markers, may be dependent on the food matrix/vehicle used and/or the length of the intervention. This evidence has highlighted again the importance to understand the molecular mechanisms through which hempseed components can exert their beneficial effect on human health, the level of each functional component needed in order to obtained an effective and clinically detectable action, and the more suitable matrix able to maximize the gastrointestinal bioavailability and structurally preservation of these components in the human body.
The high intrinsic genetic variability rate of C. sativa L. has been further accentuated by the long history of its domestication. Indeed, the different intended uses of the C. sativa L. cultivation’s products have led over the years, to an artificial phenotypic selection of specific features of the domesticated plants, useful for increasing the yield and/or the quality of the commercial interest’s cultivation products . The direct consequence of this selection was the unaware artificial creation of the C. sativa L. varieties, each with specific genotypic and phenotypic features, which at first, induced the taxonomists and botanists to erroneously recognize two or three different species of C. sativa L., embracing a polytypic concept of the Cannabis genus . To further complicate the taxonomic classification of the Cannabis genus, there has been also the fact that C. sativa L. is a crop which tends to exist in “crop-weed complexes”, that is complexes of domesticated forms in cultivation and related ruderal (weedy) forms growing outside of cultivation, developing morphological characteristics also very different from those of the domestic progenitor, as a consequence of adaptation to the wild environment . However, it must be considered that, despite the high genetic variability of C. sativa L., the varieties that genotypically and phenotypically differ, are interfertile. Therefore, taking into account the Darwinian definition of biological species, “a group of organisms that can reproduce with one another in nature and produce fertile offspring”, C. sativa L. varieties cannot be consider as different species of the Cannabis genus. For this reason, to date, the polytypic concept has been definitely given up and replaced by the monotypic one. According to this, a single species of Cannabis genus exists, namely C. sativa L., which includes several varieties or cultivars (cvs) that genotypically and phenotypically differ, but they all are interfertile and therefore, they belong to the same species [29,30].
The cannabinoid synthetic pathway: cannabigerolic acid (CBGA) is the common precursor of all main cannabinoids. It is synthesized through an alkylation of the phenolic moiety of olivetolic acid with the terpenoid component of geranyl pyrophosphate (GPP). The reaction is catalysed by a geranylpyrophosphate:olivetolate geranyltransferase (GOT). Olivetolic acid is originated in the cytosolic polyketide pathway through an aldol condensation of hexanoyl-Coenzyme A (CoA) with three molecules of malonyl-CoA, that is catalysed by the polyketide synthase (PKS) enzyme in the presence of olivetolic acid cyclase (OAC). The GPP is synthesized by the plastidial methylerythritol phosphate (MEP) pathway. In the cytosol, CBGA is converted into the acidic form of the three main cannabinoids, tetrahydrocannabinol acid (THCA) that in the acidic form has no psychoactive activity, cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA). GPS: geranyl pyrophosphate synthase; IPP: isopentenyl diphosphate; OAC: olivetolic acid cyclase.
In addition to its nutritional value, hempseed is also rich in natural antioxidants and other bioactive components such as bioactive peptides, phenolic compounds, tocopherols, carotenoids, and phytosterols, the content of which appears to be mostly affected by the environmental and agronomic factors and, to a lesser extent, by genetic variability . Moreover, hempseed contains also some antinutritional compounds that could negatively influence its nutritional value. In the following subsections, these nutritional and antinutritional hempseed’s components are discussed in detail.
The beneficial effect of the short-term (20 days) hempseed feeding in Wistar rats on the prevention of hypercholesterolemia and coronary artery disease was observed also by Karimi and co-workers . Indeed, they found that the hempseed dietary treatment did not significantly affect the mean fasting triglyceride, total cholesterol and albumin levels, but it was able to improve the blood lipid and protein profiles, since it significantly decreased the mean fasting serum LDL level, and significantly increased the mean fasting serum HDL and total protein levels. These actions were attributed to the high and low contents of PUFAs and SFAs, respectively, in hempseeds, as well as to their relatively high amount of phytosterols, especially β-sitosterol. Actually, Seo and colleagues  showed that also hydrophilic components of hempseeds could exert an anti-atherosclerotic effect. In their study, the authors treated via intragastric inoculation Apo-E Knock Out (KO) mice atherosclerotic animal models, with a hempseed water extract for 14 weeks. The lack of Apo-E in these genetically modified mice led to increase in total plasma cholesterol and triglycerides and decrease of serum HDL-cholesterol level and, as consequence, generated atherosclerotic lesions similar to those found in humans. The treatment with hempseed water extract reduced the atherosclerotic plaque formation, as well as the serum level of total cholesterol and LDL-cholesterol and increased the serum HDL-cholesterol level. Moreover, a reduction in the serum level of the inflammatory cytokine TNF-α demonstrating a decrease in the inflammatory status related to atherosclerosis was found also. As previously said, all these findings have been generally attributed to the hempseed lipidic fraction, that is missing in the hempseed water extract used in this study, and therefore, the authors concluded that some hydrophilic compounds of hempseed, presumably phenolics, possessed the observed anti-atherosclerotic action, but the specific compounds and the molecular mechanisms by which they exerted this protective action have still to be elucidated.
Hence, in view of the above, it is clear that there are efforts by researchers to understand the structural, nutritional, and functional roles of the hempseeds and derivative utilization in the development of new heathier and nutritionally improved foods, also for specific intended groups of people such as coeliac ones. However, further investigations are needed for a better comprehension of the most appropriate hempseed product types, matrices, and dosages in order to develop a food product with a greater improvement of nutritional and functional properties, without negatively affecting the physical and sensorial properties of the food product. In-depth investigations are also necessary to identify the most functional hempseed’s compounds, their molecular mechanisms, and their targets in order to comprehend the most adequate concentration of the functional compounds and the vehicle/matrix most suitable to preserve their structure and functionality into the gastrointestinal tract to maximize their bioavailability in the human body and to allow the compounds to reach the target sites. Only in this way, the regular ingestion of the appropriate quantity of food product could actually exert a preventive and beneficial clinically detectable effect, as required in order to claim a food as a functional food.