Hemp (Cannabis sativa L.) is an annual herbaceous plant from the Cannabaceae family [1]. Its use by humans is widely documented for textile and food purposes [2]. Although archaeobotanical findings show that C. sativa was indigenous to Europe [3], the first evidence of its cultivation and domestication suggests that it was introduced to Europe from Asia more than 4000 years ago during the Bronze Age [4].

Hemp is one of the oldest crops that has been domesticated by humans [5]. While the stems have been widely used for the production of ropes and fabrics, the seeds have been used as a food, thanks to their remarkable nutritional properties. However, this intended use seems to be more relevant in recent times, while in ancient times hemp was mainly used for textile purposes and only marginally in medicine and as traditional food ^[6][7][6,7].

As regards their nutritional use, hemp seeds, and, therefore, the fruits of C. sativa, are the part of the plant used most for human consumption. From a botanical point of view, hemp seed is an achene, i.e., a dried fruit whose hardened pericarp does not adhere to the internal seed, as for quinoa, amaranth, buckwheat and strawberry achenes ^[8][27].

There are nearly 50 hemp cultivars grown for nutritional interest with a varying macronutrient composition. The protein content does not exceed 30%, with the dietary fiber content ranging between 30 and 40% and a lipid content of approximately 25–30% ^[9][30]. Dietary fibers are concentrated in the external integuments of the seed, and hulling allows the elimination of most of them ^[10][31]. Hulled seeds show fat and protein contents over 46% and 35%, respectively [11]. On the other hand, the amount of available carbohydrates is usually very low and negligible since its polysaccharide component is almost exclusively composed of dietary fiber (refer to the specific section below). However, the interesting nutritional aspects of hemp also include the presence of bioactive peptides with an antioxidant effect, and other phytochemicals such as polyphenols and sterols ^[12][32]. Hemp seeds are very versatile and promising and the nutritional profile of hemp-based products can meet the market’s needs ^[13][33]. They can be consumed as a whole, hulled or in the form of oil, flour, or isolated proteins. Seed germination contributes to further modifying the nutritional profile by increasing the bioavailability of the phytochemicals present ^[14][34]. This could increase the beneficial effects of the seeds due to the increased anti-inflammatory and antioxidant power. The USDA database is currently the widest archive about food composition ^[15][35].

2. Hemp as a Functional Food in Vegetarian Nutrition

Generally, hemp seeds are processed as a first step for the extraction of the oil, thus obtaining the defatted meal or seed cake, whose macronutrient composition shows a high protein content. Hemp seeds are a promising source of protein that deserves more attention, as found in recent proteomic characterizations ^[16][36]. In an evaluation of the nutritional characteristics of hemp seeds of the Futura 75 cultivar grown in Caserta (South Italy), it was highlighted that the seed flour or the oil meal (the byproduct obtained through the mechanical cold-pressing extraction of the oil), contains more than 30% of protein ^[17][37].

The hemp protein is composed of three main fractions: globulins, albumins and minority peptide chains rich in sulfur ^[18][38]. Among its notable characteristics, hemp protein exhibits high levels of glutamic acid and arginine, which have sparked interest in this protein source. Arginine accounts for 12% of hemp protein, a markedly higher fraction than other high-protein animal-derived or plant sources such as wheat, soy, egg white and whey, showing up to 7% content ^[19][8]. While the effect of arginine on blood pressure via the nitric oxide regulatory pathway is well known ^[20][39], it may have a positive effect on athletic performance ^[21][40]. Furthermore, hemp has a higher sulfur amino acid content than soy and casein ^[10][31]. A high ratio of Arg/Lys in the globulin fraction compared to albumin (4.37 vs. 1.74) may suggest its use for various health purposes ^[22][41]. This ratio is also higher than those found in soy or casein [11]. Among the globulins, edestin is a legumin that represents up to 75% of the protein fraction of hemp, followed by a 37% fraction represented by albumin ^[16][36]. A third protein fraction is characterized by the presence of a vicilin-like protein: a beta-conglycinin protein that represents about 5% ^[23][42]. The highest protein concentration was found in the cotyledons, and to a lesser extent in the hull fraction ^[23][42]. The removal of both the hull and oil leads to an increase in the relative protein content to 50% and over ^[10][31].

Hemp proteins may exert beneficial effects on human health. A clinical trial is currently underway to evaluate the effects on blood pressure of various protein sources, including hemp protein, and also hydrolysates and derived biopeptides ^[24][43]. The results are expected to be available in 2024. Some of these mechanisms will be discussed later.

In a well-planned vegetarian diet, the protein requirement is achieved without great concern ^[25][26][27][17,44,45]. However, this requires a wide choice of vegetable protein sources every day to favor protein intake in general and all the essential amino acids in particular ^[28][46]. Hemp and derived products could help one to obtain an additional protein source with a high biological value. Hemp has been shown to have an amino acid score comparable to egg white protein ^[19][8]. The digestibility of hemp proteins increases if the extraction takes place from hulled seeds, with higher values compared to soy isolates ^[29][47]. A digestibility value of 97% of hulled hemp seeds was estimated, which was comparable to that of casein ^[10][31]. Although dehulling could presumably improve the Protein Digestibility Corrected Amino Acid Score (PDCAAS) value of hemp seeds, the literature is still scarce on this topic, especially regarding products derived from processed hemp seed. It has been shown that the in vitro digestion of isolated hemp proteins showed greater digestibility than isolated soy proteins ^[29][30][47,48].

The protein fraction with the highest biological value is represented by edestin, which has an amino acid composition rich in branched-chain amino acids, methionine, cysteine and aromatic amino acids, which are lowly represented in a vegetarian diet ^[31][32][49,50]. It is found in the aleurone layer of the seed and has a structure similar to soy glycinin ^[33][51]. The albumin fraction represents a smaller portion than that of edestin but contains fewer disulphide bonds with a consequently less-compact structure ^[31][49]. Furthermore, despite similar emulsifying capacities, hemp albumin shows a greater foaming capacity and solubility than globulin. This minority peptide fraction rich in cysteine does not show inhibiting effects on trypsin, an aspect that increases its digestibility ^[18][34][38,52].

Characteristics of hemp proteins such as solubility, foaming, emulsification, oil-binding, solubility, gelation and film formation are very important factors for the use of hemp in the food-grade industry and were extensively discussed by Wang and Xiong in a recent review [11]. Given the compact structure of hemp proteins, structural modifications through heat, pressure, filtration, enzymatic digestion, acylation, pH shift, irradiation, plasma technology, supercritical carbon dioxide, ultrasound, and electric fields can improve the characteristics that currently limit its industrial use. From a protein point of view, the composition of hemp seeds can be compared to soybean meal, which is often used for the production of plant-based meat alternatives due to its high biological value ^[10][35][31,53].

However, it should be considered that, like many other plant-based nutritional sources, hemp also contains some anti-nutrients that could interfere with the bioavailability of proteins such as phytic acid, tannins and protease inhibitors ^[36][54]. In defatted hemp seeds, 4–8 g/100 g of phytic acid, 11–28 U/mg of trypsin inhibitors ^[37][55], from 11 to 28 units per milligram of trypsin inhibitors ^[38][56] and from 47 to 70 mg per 100 g of saponins ^[38][56] may be found. Then again, the concentrations of these substances are comparable to those usually found in legumes and nuts ^[39][57]. Its digestibility is comparable to that of legumes but higher than grains ^[10][31]. The antinutrient content in hemp seeds is considered relatively low ^[38][56]. Furthermore, the removal of the hull allows an increase of almost 10% in the digestibility of hemp protein ^[10][31]. Lower amounts of antinutrients have been identified in dioecious varieties compared to monoecious ones ^[38][56]. The influence of these substances on human health is much debated and there are also clues to their possible beneficial effect on cancer and metabolic pathologies ^{[40][41][42][43]}[58,59,60,61]. The highest concentration of antinutrients appears to be in the external tissues of the seed, and for this reason, digestibility is higher in hulled seeds than whole seeds or from hemp seed cake, with higher PDCAAS values than wheat, lentils and beans but still lower compared to beef ^[10][31]. In a comparative study between two cultivars of industrial hemp, USO 21 and Futura 75, following extraction through cold pressing of the seeds, the hemp meal obtained showed a high amount of protein of about 30 g/100 g FW, with a negligible content of antinutrient factors ^[44][62]. This finding makes the byproducts of hemp oil a promising source for reuse as food and as a source of protein matter. The limiting amino acid in the case of raw hemp seeds appears to be lysine, as is generally observed for nuts and grains. This is reflected by a rather low lysine score of 0.5–0.62 ^[10][31]. Furthermore, it is well known that this amino acid is sensitive to Maillard reactions during cooking ^[45][63]. However, hemp can be still consider a high-quality protein source such as casein and soy ^[46][64].

As discussed, hemp is a good source of protein; however, bioactive peptides with various properties, including antioxidant activity, can be obtained from C. sativa polypeptides. The most active peptides are those with the lowest molecular weight because they readily interact with the molecular targets, reaching them even more easily by evading intestinal enzymatic hydrolysis. For example, Orio et al. obtained several peptides from the hydrolysis of hemp seed proteins, finding molecules with marked inhibitory properties on angiotensin-converting enzyme (ACE): a useful feature for treating hypertension ^[47][65]. Furthermore, peptides obtained from hemp show the inhibition of renin ^[48][66] and acetylcholinesterase (AChE) ^[49][67].

Chemical–physical modifications can alter the structural characteristics of hemp protein and improve its rheological properties. Some examples are shown below.

The ionic bonds of the protein scaffold can be destabilized by treatments that shift from a neutral pH. The molecular unfolding generated by the pH shift can improve the solubility and emulsifying activity of a vegetable protein ^[50][75].

The acylation and succinylation of amino acid residues are industrial processes widely used to modify the structures of various plant proteins ^[51][76]. If used at a pH above 5 they can improve protein solubility. Conversely, extensive modification or a working pH below 5.0 can worsen it. Heat treatment above 30 °C can modulate the molecular bonds of hemp protein extracts, improving their solubility for treatments up to 60 min but with enhancement even for 1–5 min ^[52][77]. Heat treatment can be further effective in improving the emulsifying activity of hemp proteins if performed at pH values far from the isoelectric point and, therefore, with both acidic and alkaline pH values ^[53][78]. Heat treatment also improves its water-holding capacity ^[54][79]. The application of high pressures and pH shifting to hemp seed milk showed an improved oxidative stability of the product ^[55][80].

The oil contained in hemp seeds currently represents the component with the greatest industrial interest. The fat content varies according to the cultivar, and, therefore, depends mainly on genetic aspects, and ranges from 25 to 35% ^[56][29]. However, cultivation conditions such as climatic, geographical and agronomic aspects can influence this percentage even if with a minor contribution ^[57][82]. The great interest in hemp fats derives from their high content of unsaturated fatty acids, which reaches almost 90% of the lipid fraction ^[58][83]. Their fraction of polyunsaturated fatty acids can reach up to 80% of the total fat ^[58][83].

As for many other vegetable oils, hemp seed oil has a high oleic acid content (OA; C18:1; w9) reaching almost 20% ^[59][84]. One exception is the Finola variety grown in Italy, which has an OA content that does not reach 10% ^[37][55]. OA in a omega 9 monounsaturated fatty acid commonly found in extra virgin olive oil, which is widely used in the Mediterranean area, shows well-known health benefits ^[60][85].

Linoleic acid (LA; C18:2; n6) is the main component of hemp seed oil and can exceed 50% of the fat fraction. The intake of LA has a favorable effect on cardiovascular health ^[61][86]; however, an excess in LA can limit the pathway of omega 3 biosynthesis through an enzymatic competition process ^[62][63][87,88]. The second most abundant fraction is represented by alpha-linolenic acid (ALA; C18:3; n3). It is the omega-3 fatty acid most represented in plant foods. Among the industrial hemp cultivars, Finola seems to show the highest concentrations of ALA, with percentages reaching 22% ^{[19][37][57][58]}[8,55,82,83]. Considering that in a vegetarian diet, the intake of long-chain polyunsaturated fatty acids is marginal, the World Health Organization advises to ensure adequate amounts of ALA to reach the daily recommendations of 1–2% of the total energy intake with omega 3 polyunsaturated fatty acids ^[64][89].

Of course, the extraction process must not cause the degradation of the highly reactive double bonds of the carbon scaffold of fatty acids, and for this reason several extraction techniques have been developed, which include the commonly used solvent-extraction technique and mechanical cold-pressing extraction ^[65][90].

It is well known that the fractions of omega-6 polyunsaturated fatty acids prevail among polyunsaturated fatty acids in commercially available vegetable oils ^[15][35]. At the same time, the main use of vegetable fat sources in the vegetarian diet can only guarantee the supply of short-chain essential fatty acids such as linoleic acid and alpha-linolenic acid, with negligible intakes of long-chain essential fatty acids such as eicosapentaenoic acid, docosahexaenoic acid and arachidonic acid ^[66][67][91,92]. The pool of enzymes capable of converting short-chain fatty acids to long-chain fatty acids is shared by the metabolic pathways of both the 3-series and 6-series of essential fatty acids. This means that in a vegetarian diet, a prevalence of linoleic acid can sequester the enzyme pool by interfering with the elongation and desaturation of alpha-linolenic acid into EPA and DHA. In this respect, it is beneficial in a vegetarian diet to guarantee sufficient sources of omega 3 fatty acids to ensure a proper balance with omega 6 ^[68][69][93,94]. In a vegetarian diet, hemp seed oils can be useful to promote this balance thanks to their omega-3 content. Given the high content in essential fatty acids, two to four tablespoons of hemp seed oil can meet the daily requirement of essential fatty acids in a 2000-calorie diet, providing up to 25 g of LA and 9 g of ALA ^[70][71][95,96].

The main essential fatty acids in hemp are linoleic acid and alpha-linolenic acid, with a beneficial omega 6/omega 3 ratio of 2.5–5.5 ^[56][29]. The adequate-intake ratio has been estimated to be 3:1 to 5:1, which reflects the observed proportion in the traditional Mediterranean diet ^{[19][72][73][74]}[8,97,98,99]. This ratio is decisive if people take into consideration that in the Western diet, there is a tendency for higher ratios, which is associated with inflammatory events, cardiovascular pathologies and cancer ^[75][76][100,101]. Unfortunately, it has been estimated that this ratio is about 10:1 in the Western diet, and more generally in industrialized countries, due to the prevalence of polyunsaturated fatty acids of the 6 series ^[77][102].

A high ratio of unsaturated to saturated fatty acids is also considered protective against cardiovascular disease ^[78][103]. The consumption of hemp seed oil can be beneficial to health due to its low content of saturated fatty acids (from 9.4 to 11.7%) ^[37][55] and its high content of unsaturated fat, which makes it suitable to adopt an intake of fats with a profitable high PUFA/SFA ratio ^[79][104].

Another relevant polyunsaturated fatty acid molecule present in hemp is gamma-linolenic acid, known for its anti-inflammatory properties ^[80][105]. This fatty acid quickly converts to dihomo-gamma-linolenic acid (DGLA: 20:3; n6). Although hemp seed oil is a good source of GLA, there are other plant sources with higher concentrations such as borage oil, which contains up to 23%, albeit with negligible amounts of omega 3 ^[81][106]. In addition to this, hemp, like the entire cannabaceae family, represents a source of stearidonic acid ^[82][107]. It is an essential fatty acid of the omega 3 series that is obtained from alpha-linoleic acid through the catalytic action of the enzyme delta-6 desaturase. This enzyme operates on the first step of the polyunsaturated fatty acid maturation pathway and appears to be one of the most rate-limiting steps of the PUFA metabolic pathway ^[68][93]. A high intake of linoleic acid could sequester this enzyme by diverting it from the maturation pathway of omega 3 essential fatty acids to the omega 6 series. Furthermore, delta-6 desaturase also participates in the subsequent conversion step of docosapentaenoic acid to docosahexaenoic acid following the Sprecher pathway ^[83][108]. An intake of stearidonic acid could bypass this limiting step and favor the biosynthesis pathway of long-chain omega-3 fatty acids ^[84][109]. Figure 1 shows the metabolic role of the delta-6 desaturase enzyme in the polyunsaturated fatty acid pathway.

Studies suggest that the fatty acid content varies according to the cultivar. The Finola cultivar shows the most efficient genotype for the formation of gamma-linolenic and alpha-linolenic acid, with the lowest content of saturated fatty acids such as palmitic and stearic, but also with low concentration of oleic acid ^[57][82]. As in the case of the ALA and GLA content, the STA content is also higher in Finola compared to other cultivars ^{[19][57][58][77]}[8,82,83,102]. This may be particularly relevant in a vegetarian diet where plant sources of omega 3 fatty acids are scant. There are also other plant foods rich in omega 3, mainly seeds and nuts, which can promote a good nutritional balance of omega 3 with omega 6 fatty acids. However, given their limited availability (mainly flax seeds, walnuts and chia seeds), in a vegetarian diet hemp seed oil can also help maintain dietary variability and reach the quota of omega 3 both through the contribution of its alpha-linoleic acid content and also through stearidonic acid intake. It should not be underestimated that hemp seed oil has a particularly high content of essential fatty acids compared to other vegetable oils, and this can shift the preference towards other edible oils, which can contain a higher content of saturated fats that negatively affect human health ^[19][85][8,110]. Even if the presence of polyunsaturated fatty acids favors the oxidation of the hemp oil, the presence in hemp of carotenoids, chlorophyll, sterols and other compounds in the unsaponifiable fraction increases the stability of the extracted oil ^[86][111]. Gamma tocopherols, in particular, give a high oxidation stability to hemp seed extracts ^[56][29]. However, it has been hypothesized that the antioxidant properties of hemp seeds are related to phenolic compounds in general such as phenylpropionamides (lignans), and more than tocopherols specifically ^[57][82]. However, hemp oil degrades easily above 130 °C, and this tendency towards oxidation suggests its use as a condiment oil and not for cooking ^[9][30]. However, it shows greater heat resistance than flaxseed oil ^[87][112].

While there are numerous preclinical studies on the use of hemp and its derivatives, clinical studies on humans are currently very limited and mostly use hemp seed oil with beneficial effects on atopic dermatitis ^[88][113] and multiple sclerosis ^[89][90][91][114,115,116]. A central role in the health-promoting effect of hemp could be linked to its high content of essential fats and their anti-inflammatory role in the production of eicosanoids (including ceramides) such as SDA, ALA and GLA.

In some clinical trials, hemp seed oil has shown beneficial effects in mental and neurological disorders ^[92][117], with a potentially favorable effect on cardiovascular risk factors ^[93][94][118,119].

Dietary fiber can be found the carbohydrate matrix of the seed. Most of the hemp seed fiber resides in the hull and it can be found in both the insoluble and soluble fractions in a ratio of 4:1 ^[19][8]. Hemp appears to be one of the most concentrated dietary sources of insoluble fiber ^[95][120]. However, industrial transformation processes that expose seeds to high pressures and temperatures (such as extrusion) tend to destroy the structure of the polysaccharides by increasing the proportion of soluble fiber compared to insoluble fiber ^[96][121]. The dietary fiber component can range from 27 to 34% ^[19][97][8,122].

The beneficial effects of fiber on human health are well known ^{[98][99][100][101]}[123,124,125,126]. Its action is mediated at least in part by the production of short-chain fatty acids (SCFAs) in the bowel lumen by the microbiota, which exhibit anti-inflammatory and immunomodulatory effects capable of contributing to both intestinal and systemic health ^{[102][103][104]}[127,128,129]. Hemp seeds can help reach the dietary fiber quota recommended, taking into account that in Western countries, there is a reduced consumption of fiber in favor of processed and calorically dense foods ^[105][106][130,131]. However, in a well-planned vegetarian diet, fiber intake is usually sufficient. On the other hand, the excess of fiber, especially in childhood, could interfere with the absorption of other nutrients ^{[107][108][109]}[132,133,134]. The hulling of hemp seeds can reduce the fiber component and, thus, increase the proportion of other nutrients such as protein and fat fractions. This suggests that, based on an individual’s nutritional needs, the use of hulled or whole seeds should be favored. In a vegetarian diet, hulled seeds could allow for better protein bioavailability due to the increase in digestibility, deriving from the removal of fiber and anti-nutrient compounds present in the hull, limiting the intake of dietary fiber in the overall diet.

Hemp seeds are considered a good source of minerals ^[56][29]. In a vegetarian diet, some micronutrients can be critical if the diet is not well planned ^[110][111][135,136]. Some critical minerals such as iron, zinc and calcium have been identified. Interestingly, elevated calcium and iron concentrations of up to 955 mg/100 g and 240 mg/100 g, respectively, were detected in hemp seeds ^[112][137]. Hemp may, thus, be useful to ensure sufficiently rich sources of calcium to reach the daily requirement of a vegetarian diet ^[113][114][138,139]. Seeds and nuts, legumes, and dehydrated fruit can be good sources of calcium ^[115][140]. Among the sources with the best bioavailability of calcium (defined by fractional absorption), people can find cruciferous vegetables such as kale, broccoli, cabbage, cauliflower, mustard and arugula ^[116][141]. However, it is unlikely that these foods are represented daily in the diet. Even if the fractional absorption of hemp seeds is not known, consuming different sources of calcium throughout the day can promote enough dietary variability to ensure adequate intake. Despite the above-stated concentration of calcium found in hemp, there is still a wide variability among cultivars, with lower values such as 90 mg/100 g ^[117][142].

As far as iron is concerned, it is well known that inorganic iron is less bioavailable than its organic form (heme iron), the latter present in foods of animal origin ^[118][143]. It is therefore useful in a vegetarian diet to increase one’s iron intake by up to an additional 80% of the requirement of the general population to compensate for the lower bioavailability ^[119][144]. However, in a healthy diet, vegetable sources should be sufficiently represented, limiting the intake of red meat due to health-related risks ^{[120][121][122]}[145,146,147]. Some guidelines account for low iron bioavailability by implying that a prevalence of plant food must be eaten. In fact, in the fourth revision of the DRV of Nutrients and Energy for the Italian population (LARN) by the Italian Society of Human Nutrition (SINU), as an example of a Mediterranean country, the main source of iron in the Italian diet came from grains ^[123][148]. Heme iron is more prone to create oxidative stress through the formation of free radicals through Fenton reactions ^{[124][125][126]}[149,150,151]. Along with other iron-rich plant foods, such as legumes and whole grains, hemp can help meet the daily requirement. In the literature, the iron concentrations detected for hemp seeds are highly variable ^[19][77][8,102]. Values up to 240 mg/100 g can be justified by iron-rich soils used experimentally for the growth of hemp ^[112][137]. Nevertheless, the iron content in hemp seeds is higher than that of any other grains ^[59][84]. Unlike grains, whose iron concentration seems higher in the case of whole grain foods, the hulling of hemp seeds increases the net percentage of iron found (up to 25% more) and allows the zinc content to double ^[117][142], even if not all researchers confirm this hypothesis ^[97][122].

Overall, using hemp seed flour can be an excellent source of minerals with wider applications.

Hemp is rich in phenolic compounds but the levels may vary according to the cultivar ^[9][30]. The anatomical part of the seed containing the greatest amount appears to be the hull, with smaller concentrations in the kernel ^[127][152]. However, a greater radical-scavenging capacity was found in the cotyledon fraction compared to the hull. It seems that hemp pectin can create a matrix that traps polyphenols in a continuum dispersed-liquid phase ^[128][153]. Hydrogen bonds and hydrophobic bonds explain the interactions between dietary fiber and water-soluble phytochemicals ^[129][154]. Based on these observations, hemp oil could be the hemp derivative with the lowest total phenolic content, with meal showing intermediate concentrations compared to the hull and oil ^[130][155]. The exposure of the sprouts to specific radiations can increase the content of flavonoids and polyphenols, and, therefore, improve their antioxidant activity compared to raw seeds ^[131][156].

The two classes of compounds that have attracted the most interest for potential antioxidant effects are hydroxycinnamic acids and lignanamides. The latter are classified into Cannabisins and other compounds based on the type of lateral residues present in the molecular structure, and include about 20 different molecules ^[9][30].

The unsaponifiable fraction of hemp represents less than 2% of the oil and includes sterols, tocopherols and water-soluble vitamins, which show beneficial effects for human health and could lead to the greater consumption of hemp for health purposes ^[132][157]. For example, hemp sterols, mainly beta-sitosterol, represent about 15% of the unsaponifiable fraction of hemp oil; in comparison, olive oil contains about half of this concentration ^[132][157].

Phytosterols have a structure similar to cholesterol but cannot be synthesized by humans and can only be found in plants. Their beneficial feature for health is to modify the solubility of cholesterol in the intestine, reducing its absorption through a process of exclusion from the lipid fraction, through a mechanism of competition in the lipid micelles ^[133][158]. Although the literature on the subject is scarce, the phytosterol component has been quantified in almost 280 mg/100 g in the oil ^[132][157] and about 124 mg in the whole seed ^[134][159]. The most representative isoform in hemp is beta-sitosterol, which ranges from 190 to 54 mg/100 g with the highest values in the case of the oil compared to the seed ^{[77][132][134]}[102,157,159]. In addition to its cholesterol-lowering effect, anti-inflammatory and antineoplastic effects have been described ^[134][159]. Along with pistachio, hemp appears to be one of the richest sources of beta-sitosterol ^[56][29].

Among the carotenoids present in hemp, lutein is the most abundant (1.4–3.4 mg/100 g of the whole hemp seed) ^[57][82]. Like zeaxanthin, lutein accumulates in macular cells, showing protection against light-induced oxidative stress ^[135][136][160,161].

Furthermore, hemp oil contains about 80 mg/100 g of total tocopherols: plant-derived fat-soluble molecules with antioxidant activity that can be found in foods. Hemp seed oil is one of the most concentrated sources of these phytochemicals ^[137][162]. Thanks to their free-radical scavenger action, they play a crucial role in preserving hemp oil from oxidative stress, and can be found in different isomers such as the most represented delta-tocopherol. The concentrations of this isomer in hemp seed oil are higher than in sesame and sunflower oil ^[117][142]. It seems that this isomer has the best antioxidant activity in lipid matrices compared to others ^[78][103]. The literature is very heterogeneous regarding the concentrations of tocopherols in hemp, with amounts ranging from 14 to 135 mg/100 g depending on the matrix studied (oil or the whole seed) or on the extraction method ^[56][29]. Similarly, the presence of delta-tocopherol ranges from 0.5 to 116 mg/100 g. Instead, alpha-tocopherol is less represented in hemp. Despite the heterogeneous concentrations of phenolic compounds in hemp seed oil, its antioxidant power seems to be higher than flaxseed oil, soybean oil, and grapeseed oil ^[138][163].

Other molecules such as sativamides may have potential use in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease ^[139][164]. Furthermore, some phenolic compounds extracted from hemp have shown arginase inhibition activity, with a consequent increase in nitric oxide levels, which can improve endothelial function in cardiovascular diseases ^[140][165].

Currently, the HEMPEDOCLE observational study organized by a REICA and sponsored by Istituto Zooprofilattico Sperimentale del Mezzogiorno (Italy) is aiming to evaluate the health effects of the use of cannabis and its derivatives on hundreds of users, which includes the use of hemp-based foods, supplements and nutraceuticals ^[141][166].