1 The Wellness Revolution – Hemp and Cannabinoids

2 Total Word Count – 4,619 Words

3
4 Introduction – 281 Words
5 Endocannabinoid Dysfunction/Deficiency – 299 Words
6 Non-Cannabinoid Constituents of Hemp – 401 Words
7 Gastrointestinal System – 207 Words
8 Cancer – 426 Words
9 Integumentary System – 111 Words
10 Skeletal System – 160 Words
11 Alzheimer’s Disease – 195 Words
12 Depression and Anxiety – 132 Words
13 Epilepsy – 268 Words
14 Autism – 417 Words
15 Addiction – 334 Words
16 Pain and Inflammation – 130 Words
17 Dosage – 117 Words
18 Safety – 1,010 Words
19 Conclusion – 112 Words
20 Number of Figures – 13
21
22 1) What hypotheses or questions does this work address?
23 This work addresses the question of whether cannabis medicines present a safe,
24 effective treatment option for a number of health conditions.
25
26 2) How does this work advance our current understanding of agricultural science?
27 This work advances agricultural science by presenting evidence in favour of
28 cultivating cannabis for medicinal purposes, and by providing evidence in support of
29 further research into breeding techniques that can optimise levels and ratios of
30 cannabinoids and supporting constituents.
31
32 3) Why is this work important and timely?
33 Changes in the socio-political landscape and a rise in anecdotal reports of the
34 medicinal benefits of cannabis use increase the need for evidence-based practice
35 surrounding medicinal cannabis and the economic value of this crop.
36

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37 The Wellness Revolution – Hemp and Cannabinoids

38 Paul Benhaim, Elixinol LLC

39 Abstract

40 Use of cannabis, or hemp, for medicinal purposes has gained increased attention in recent
41 years due to a surge in anecdotal reports documenting possible benefits in treating a wide
42 variety of diseases, as well as an increase in scientific research focusing on cannabinoids.
43 This review will explore the current research supporting the use of non-psychoactive
44 cannabinoids, in particular cannabidiol, in the management of a number of chronic health
45 conditions. Research suggests that cannabinoids such as cannabidiol may exert therapeutic
46 effects against inflammatory bowel diseases, some cancers, skin conditions, bone fractures,
47 epilepsy, autism, Alzheimer’s disease, depression, anxiety and addictions, as well as chronic
48 pain and inflammation. Cannabidiol, in particular as a component of whole hemp extracts,
49 has been found to exhibit a superior safety profile to many pharmaceutical drugs, including
50 synthetic cannabinoids. However, human clinical trials and research on breeding techniques
51 are still scarce or lacking.

52 Keywords: Cannabis sativa, hemp, cannabidiol, cannabinoids, endocannabinoid system,

53 elixinol, CBD

54 Introduction

55 In recent years, the use of cannabis, also known as “hemp” or “marijuana”, for medicinal
56 purposes has received increased attention in the media, society and the political arena. This
57 has in turn led to increased research of cannabinoids in order to verify anecdotal claims and
58 build on past research, as well as discover new potential medical uses. Although the two
59 terms are commonly used interchangeably, “hemp” and “marijuana” are in fact chemically
60 different. “Hemp” contains less than 0.3% tetrahydrocannabinol (THC), and is higher in
61 cannabidiol (CBD), while “marijuana” is high in THC and lower in CBD [1]. Therefore,
62 larger amounts of hemp can be consumed without concern for psychoactive effects.

63 Of the 500 compounds in hemp, CBD is associated with the largest number of scientifically
64 verified health benefits [2] (Fig.1), and is the dominant medicinal compound found in hemp.
65 However, it is essential to acknowledge the “entourage effect”, as CBD does not naturally
66 occur in isolation. Evidence suggests that pharmacological benefits may be enhanced by
67 synergy between constituents of hemp which are not present in purified or synthetic
68 cannabinoid preparations [3, 4, 5]. These not only include compounds unique to hemp,
69 known as cannabinoids, but also other phytochemicals such as terpenes.

70 The potential significance of cannabinoids and the endocannabinoid system for human health
71 is reflected in Dr William Courtney’s statement that he considers phytocannabinoids “the
72 single most important dietary element outside of water that humans should have on a daily
73 basis…it is a dietary essential.” Additionally, Dr Ethan Russo has stated that “Cannabis is the
74 single most versatile herbal remedy and the most useful plant on Earth. No other single plant
75 contains as wide a range of medically active herbal constituents.”

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 76 Endocannabinoid Dysfunction/Deficiency

77 Discovery of the endocannabinoid system (ECS) gives supporting evidence of the

78 cannabinoids’ vital role in maintaining homeostasis, as the body produces its own
79 cannabinoids [6] (Fig.2). This is a system of receptors, neurotransmitters and enzymes, with
80 physiological stress causing an increase or decrease in specific ECS receptors and
81 neurotransmitters. Endocannabinoid receptors are a category of G-protein coupled receptors;
82 this suggests a significant potential role in health care as eight of the top ten best-selling
83 pharmaceuticals act on G-protein coupled receptors [7] (Fig.3).

84 Dysfunction of the ECS has been linked to various disease states. For example, autism
85 research has revealed that alterations in endocannabinoids levels are adaptations in an attempt
86 to re-establish normal homeostasis after disruption by the disease [8]. Tissue injury, or the
87 inflammation which may underlie autistic disorders, results in a rapid increase in local
88 endocannabinoid levels which appears to control immune responses. In research by Russo
89 [9], it was stated that migraines, fibromyalgia and IBS, among other conditions, display a
90 common endocannabinoid deficiency. There is also evidence suggesting that the
91 endocannabinoid system plays a key role in regulating cognitive function. Furthermore, there
92 is converging evidence showing a link between ECS defects and eating disorders, including
93 obesity, due to the effects of CB1 cannabinoid receptors on appetite [10]. A clinical trial
94 comparing CBD to the antipsychotic amisulpride, both at the dosage of 200-800mg daily,
95 revealed that CBD treatment did not only exert a stronger clinical improvement in
96 schizophrenia symptoms (Fig.4), but was markedly superior in terms of side effects [11].
97 Associated with clinical improvement was a significant rise in anandamide levels, an
98 endogenous cannabinoid, as CBD inhibits its degradation. Conversely, synthetic
99 cannabinoids, which can disrupt the ECS, are associated with more frequent and severe
100 negative side effects, such as psychosis and related conditions [12]. These are more potent
101 than THC, but contain no antipsychotic CBD.

102 Non-Cannabinoid Constituents of Hemp

103 While cannabinoids have been found to be effective in the management of a number of health
104 issues, alone they do not function at an optimal level. Instead, they work synergistically with,
105 and often require, other constituents found in hemp, including omega-3 and omega-6 fatty
106 acids. This is because the receptors and neurotransmitters that comprise the ECS are
107 themselves made from omega-3 and -6 fatty acids. In research on mice, it was found that a
108 lifelong omega-3 fatty acid deficiency resulted in cannabinoid receptor destruction [13]. In
109 omega-3 deficient mice, CB1 cannabinoid receptors that would normally respond to
110 endocannabinoids were uncoupled from their effector proteins, preventing their function. Just
111 as the correct quantity of omega-3 and omega-6 fatty acids is essential, so is the ratio between
112 the two. A 4:1 omega-6:omega-3 ratio was found to significantly improve brain function and
113 quality of life in patients with Alzheimer’s disease, and is also the most efficient in lowering
114 cholesterol while raising docosahexaenoic acid (DHA) levels in the brain [14]. This ratio also
115 resulted in the healthiest babies in a study on mice [15]. An omega-6:3 ratio of 3.7:1
116 produced the best results in learning, memory, pain threshold, temperature regulation and

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117 sleep in another study on rats [16]. Additionally, an omega-6:3 ratio of 3.8:1 was found to
118 reflect the daily consumption of these fatty acids by the brain [17]. Among rich plant sources
119 of the omega-6 essential fatty acid linoleic acid (LA), hempseed oil is the closest match to
120 both this ratio and the ratio proposed to be ideal for cardiovascular health [1].

121 Terpenes are another category of phytochemicals that may enhance the efficacy of
122 cannabinoids, and are responsible for the plant’s fragrance [18]. These include myrcene,
123 limonene, beta-caryophyllene, humulene and citronellol. Myrcene is able to lower the
124 resistance of the blood-brain barrier, allowing cannabinoids to penetrate it more effectively,
125 as well as possessing the ability to raise the saturation level of CB1 receptors [19]. Limonene
126 is also able to aid the absorption of chemicals such as cannabinoids through the skin,
127 gastrointestinal tract and mucous membranes, thus increasing bioavailability [19]. Humulene
128 and beta-caryophellene are antitumour and anti-inflammatory, and are known to synergise
129 together, thus aiding CBD in its effects against cancer [18, 19]. Citronellal, related to
130 citronellol, is able to inhibit proliferation of liver cancer cells by its effect on olfactory
131 receptors, and may therefore be another aid to the antitumour effects of CBD [20].

132 Gastrointestinal System

133 The ECS has been implicated in gastrointestinal homeostasis, modulating motility, sensitivity
134 and inflammation [2]. Recently, it has been associated with the pathogenesis of inflammatory
135 bowel disease (IBD), as investigations of the ECS in human IBD have shown that it is
136 unbalanced in these disease states [2]. Other research found an increased expression of
137 cannabinoid CB2 receptors in colonic tissue affected by IBD, implying an
138 immunomodulatory role [21]. Administration of cannabinoids resulted in enhanced wound
139 healing by acting on the CB1 cannabinoid receptors. An increase in CB2 receptors as well as
140 enzymes involved in the ECS was observed in colonic tissue affected by ulcerative colitis in
141 another study, further suggesting a role for cannabinoids to play in the treatment of IBD [22].
142 In one case [23], an eleven year old boy with Crohn’s disease began to take CBD-rich hemp
143 oil, after suffering from the condition since the age of four. He experienced gradual
144 symptomatic improvement to the extent that his need for hospitalisation was eliminated, his
145 prescription medication was reduced and he was deemed to be in remission for the first time.
146 A follow-up interview, with the boy then thirteen, revealed that his remission was sustained
147 long enough that he had not visited his gastroenterologist for four months.

148 Cancer

149 Mounting evidence suggest a potential role of cannabinoids in cancer treatment. For example,
150 one review describes “compelling evidence” of cannabinoid receptor expression in human
151 breast tumours, with other evidence showing anti-invasive, anti-migratory, anti-proliferative
152 and pro-apoptotic effects of cannabinoids on cancer cells [24]. While the most familiar use of
153 cannabinoids in cancer treatment is the palliative administration of THC to manage nausea,
154 vomiting and pain, CBD is the most extensively studied cannabinoid for its anti-tumour
155 effects [25]. In animal models, CBD has shown inhibitory effects on the progression of
156 cancers such as breast, prostate, colon and lung cancer, as well as glioblastoma. Using a panel

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157 of tumour cell lines, other research has found that of the five cannabinoids tested, CBD was
158 the most potent inhibitor of cancer growth [26]. Both CBD and a CBD-rich extract inhibited
159 growth of grafted human breast carcinoma in mice, as well as lung metastases. After CBD,
160 cannabigerol and cannabichromene followed in the rank of potency. The final and fatal step
161 in breast cancer progression is invasion and metastasis, but genetically is poorly understood
162 [27]. Id-1, however, has recently been shown to regulate metastasis of breast and other
163 cancers, with CBD being the first non-toxic agent reported to decrease Id-1 gene expression
164 in aggressive human breast cancer cells. Compared to THC and the synthetic cannabinoid
165 WIN55,212-2, CBD was significantly more effective in reducing the cancer’s invasiveness,
166 and was able to exert this effect at a concentration of 0.1μmol/L unlike the former two agents
167 (Fig.5). As for prostate cancer [3], research has also shown a significant effect of CBD
168 against cell viability, with several botanical extracts enriched in specific cannabinoids being
169 more potent than the pure cannabinoids (Fig.6). In a study on colon cancer, a standardised
170 Cannabis sativa extract containing high levels of CBD outperformed isolated CBD,
171 inhibiting carcinogenesis and inhibiting tumour growth in mice [28]. These are examples of
172 the “entourage effect”.

173 Cancer is a group of diseases associated with a heavy burden of both economic and social
174 costs. For example, over 2000 Australians are treated for skin cancers, such as basal cell
175 carcinoma (BCC), every year, the most common of all cancers [29]. The current standard of
176 care for skin cancers is surgical removal [7], which often has disfiguring results (Fig.7). This
177 and other effects of standard treatments prompts a search for safe, non-toxic therapies. In
178 contrast to Fig. 7, one case of a man treating his recurrent BCC by applying a bandage soaked
179 in CBD-rich cannabis oil resulted in disappearance of the lesion after 8 weeks [7], without
180 leaving prominent scarring (Fig.8).

181 Integumentary System

182 The ECS plays a role in regulating skin cell growth and differentiation [30]. In one study,
183 administration of CBD to cultured human sebocytes and human skin organ culture revealed a
184 combination of lipostatic, anti-inflammatory and antiproliferative effects that may be useful
185 in the treatment of acne vulgaris. A review of the current knowledge surrounding the ECS
186 and skin health resulted in the conclusion that “therapeutic possibilities of cannabinoid usage
187 in skin diseases seem to be unquestionable” [31]. When the anti-inflammatory and wound
188 healing effects of CBD alone and with beta-sitosterol, a compound in hemp seed oil, were
189 compared, the compound was far more effective than CBD alone, suggesting a synergistic
190 effect (Fig.9).

191 Skeletal System

192 Bone fractures are highly prevalent, involving prolonged discomfort, reduced mobility and
193 recovery; however, CBD may aid in fracture healing. After 8 weeks in one study, CBD, but
194 not THC, strengthened bone tissue in comparison to the control group [32]. Maximal force
195 increased by approximately 35%, while work-to-failure increased by approximately 50%.
196 CBD was found to stimulate expression of the Plod1 gene, involved in collagen cross-linking

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197 and stabilisation, and the resulting increase in collagen crosslink ratio was deemed a likely
198 contributor to the improved bone strength.

199 A major complication of bone marrow transplants is Graft-versus-host-disease (GVHD). In a

200 Phase II clinical trial, 48 adult patients were given 300mg of CBD orally from 7 days before
201 transplantation until day 30 alongside standard prophylaxis, to test the hypothesis that CBD
202 may decrease GVHD incidence and severity [33]. No patients developed GVHD during
203 treatment with CBD, and the hazard ratio of developing grades II-IV acute GVHD was 0.3
204 (P=.0002) compared with 101 historical controls.

205 Alzheimer’s Disease

206 Alzheimer’s Disease is characterised by the deposition of beta-amyloid plaque and

207 hyperphosphorylation of tau proteins, resulting in neuronal cell death and the impairment of
208 neuronal communication [34]. It is also associated with oxidative stress, inflammation and
209 exitotoxicity. Campbell and Gowran [34] write that in brains obtained from patients with
210 Alzheimer’s disease, alterations of the ECS have been found, suggesting that the ECS plays a
211 role in the development of Alzheimer’s disease. They also stated that certain cannabinoids,
212 such as CBD, are able to reverse tau phosphorylation and protect against beta-amyloid-
213 induced neurotoxicity via antioxidant and anti-inflammatory effects. Cannabinoids may also
214 support intrinsic neurological repair mechanisms by increasing neurotrophin expression and
215 neurogenesis. Additionally, emerging evidence suggests that impaired clearance of beta-
216 amyloid proteins, partly due to reduced transport of this protein across the blood-brain barrier
217 (BBB), is the mechanism behind its deposition [35]. Upregulating endocannabinoid
218 receptors, or inhibiting cannabinoid-degrading enzymes, was able to double the clearance of
219 beta-amyloid protein across the BBB, thereby improving cognitive behaviour in animals. In
220 another study on transgenic mice, cannabidiol at a dose of 20mg/kg was able to reverse
221 impairments in social recognition and novel object recognition, but did not affect anxiety-
222 related behaviour [36].

223 Depression and Anxiety

224 In 2013, the top-selling pharmaceutical was a drug prescribed for depression and anxiety, but
225 not without side effects (Fig.3). However, CBD may be a safe, effective alternative, as it has
226 been described in a review of animal studies which concludes with a recommendation that
227 CBD is to become a new drug for psychiatric disorders [37]. Furthermore, a study on World
228 Trade Center attack survivors suffering from post-traumatic stress disorder (PTSD) found a
229 significant reduction in the level of circulating cannabinoids, possibly pointing to
230 endocannabinoid deficiency as an underlying mechanism of PTSD [38]. In one anecdotal
231 case [39], a male veteran with PTSD began using medicinal cannabis due to the side effects
232 of the prescribed pharmaceutical drugs, and has since eliminated the need for these
233 prescriptions as he gained more benefits from cannabis.

234 Epilepsy

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235 Many of the anecdotal reports documenting beneficial effects of cannabis on human health
236 involve patients with epilepsy. One such report was of a ten-year-old girl whose seizures
237 were reduced from 20 to 2 daily, and whose cognitive abilities had doubled to the point that
238 at the time of writing, she could read at the level of a six-year-old [40]. It was also reported
239 that she had failed two brain surgeries and over 20 anti-epileptic medications. Though
240 anecdotal reports have gained much attention, the antiepileptic effects of cannabinoids are not
241 without scientific basis. One of the first studies, performed in the 1940s, documented
242 improvements in epileptic children upon cannabinoid administration [41]. These
243 anticonvulsive properties were serendipitously found by researchers in the Edgewood Arsenal
244 research program while searching for an antidote to nerve gas [42]. While the hostile climate
245 towards cannabis meant that these studies were never declassified, Dr Van Sim stated that
246 cannabis “is probably the most potent anti-epileptic known to medicine”. James Ketchum,
247 another researcher in the Edgewood program, asserts that refusal to look at the evidence
248 supporting the medicinal use of cannabis is maintaining prohibition. A 1980 study involved
249 15 epileptic patients divided into two groups, where they received either 200-300mg of CBD
250 daily or a placebo [43]. No patients receiving CBD experienced toxicity or adverse effects, 4
251 of the 8 CBD subjects were almost seizure-free for the experiment’s duration and another 3
252 saw partial improvement, with only 1 patient receiving no benefit. One anecdotal case of a
253 girl suffering from epilepsy, including violent rages, shows a dramatic reduction in symptoms
254 including elimination of the aforementioned rages [39].

255 Autism

256 Autistic disorders are neurodevelopmental disorders characterised by dysfunctional skills in

257 social interaction and communication, as well as stereotypic and repetitive behaviours [8].
258 Compelling evidence suggests that an essential role in regulating cognitive function can be
259 attributed to the ECS, therefore cannabinoids may be an effective treatment option for
260 patients with autism [9]. Immune system dysregulation is often displayed in children affected
261 by these disorders, including an altered response of peripheral blood mononuclear cells
262 (PBMCs). A study on cannabinoid receptor activity in these PBMCs has shown that CB2
263 receptor activity was increased by 500% in the cells of autistic children, in comparison to
264 non-autistic children [8]. This may be due to autistic disorders being inflammatory-mediated,
265 as a rapid rise in local endocannabinoid levels appears after inflammation or injury, in an
266 effort to mediate the immune response [8]. These altered endocannabinoid levels are
267 adaptations made in an attempt to re-establish normal homeostasis after disruption. However,
268 acetaminophen administration, when there is a sulphation deficiency, may cause an
269 imbalance in the ECS that triggers autism [44]. Acetaminophen exerts its analgesic effect by
270 activating cannabinoid receptors, and a resulting alteration may disrupt a child’s normal
271 development and trigger autism. An effective treatment for autism, along with evidence-
272 based prevention strategies, is vital for the quality of life of many families. One example of
273 this is a 2015 news article featuring a couple who relinquished their five-year-old son to
274 foster care because they could not cope with his severe autism [45]. The parents described
275 having to stay awake each night because their son would repeatedly pinch and bite himself, as
276 well as head bang to the point of knocking himself unconscious. Besides this account,

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277 approximately 14 families in Queensland alone relinquish a disabled child to state care each
278 year, including autistic children [45]. In stark contrast, one case of a boy with severe, self-
279 harming autism sees a progression from continuous headbanging without CBD-rich oil, to
280 being able to sit up and give some response to verbal communication only minutes after
281 administration of CBD-rich oil [7]. Additionally, a case from Australia, documented by the
282 family doctor, shows another pronounced improvement in severe autistic symptoms in a
283 young boy [7]. After 5 weeks of CBD-rich oil, the child was sleeping 10 hours per night
284 instead of 4; could get out of bed by himself and experienced an almost total reduction in
285 compulsive hand movements. Additionally, he experienced a total resolution of anxiety,
286 itching skin rashes and constipation, along with improved mood and communication.

287 Addiction

288 One barrier to legalisation of cannabis products is the fear of creating widespread addiction to
289 the substance. However, cannabinoids may in fact assist in safely overcoming drug
290 addictions. Research using an experimental rat model found that CBD at a dose of 5-20mg/kg
291 caused the subjects to lose their desire for heroin following exposure to condition stimulus
292 cues [46]. These effects were safe and long-lasting, continuing up to two weeks after
293 administration, and were thought to be due to an effect on the endocannabinoid system,
294 which heroin over-stimulates. As for the “food addiction” commonly linked to obesity, CBD
295 is able to inhibit the hyperphagic effect caused by upregulating CB1 receptors in humans
296 [10].

297 The endocannabinoid system may also play a role in nicotine addiction. In a randomised,
298 double-blind, placebo-controlled trial on human cigarette smokers, it was found that the
299 subjects who received an inhaler containing CBD reduced their cigarette intake by an average
300 of 40% during the first week [47]. There was no change in number of cigarettes smoked in
301 the placebo group. It was also stated that CBD had a superior safety profile to the drug
302 Rimonabant, which has been shown to increase depression. Therefore, use of CBD could
303 pose a great economic and social benefit; for example, cigarette smoking directly causes
304 15,000 deaths each year in Australia, and costs the nation $31.5 billion in social and
305 economic costs [48].

306 In one case [7], a woman began taking CBD-rich hemp oil in order to manage chronic neck
307 and back pain. She had also previously smoked two packs of cigarettes daily for 39 years,
308 including numerous failed attempts at cessation. Within weeks of the first administration, she
309 was able to stop taking the drugs Aleve, Hydrocodone, Celebrex and Lidocaine that were
310 previously prescribed to manage her chronic pain. Additionally, her cigarette cravings were
311 alleviated, and at the time of writing had been a nicotine-free non-smoker for six months
312 without withdrawal symptoms. Improved sleep and job performance were also reported.

313 Pain and Inflammation

314 Another proposed medicinal use of CBD is in the treatment of pain and inflammation.
315 However, isolated CBD has been shown to only produce these effects within a limited dosage
316 range, thus limiting clinical use [4]. When research on a mouse model of pain and

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317 inflammation compared CBD-enriched Cannabis sativa extract with isolated CBD, the
318 whole-plant extract was more effective in relieving pain and inflammation, doing so in a
319 dose-dependent manner [4] (Fig.10). The Cannabis sativa extract also exhibited superior
320 anti-inflammatory properties to aspirin and Tramadol. Therefore, there are significant
321 potential clinical applications of CBD-rich cannabis oil. In one case, a man suffering from
322 chronic pain was able to reduce his dosage of Oxycontin by half after 7 days of use, and
323 reported improved sleep, energy, strength, memory and nerve function [7].

324 Dosage

325 Recommended dosages of CBD are often mentioned in the scientific literature, however this
326 is usually in relation to consuming the isolated cannabinoid. For example, in the US
327 government patent on using CBD for the treatment of issues such as stroke, it is stated that
328 the effective oral human dose ranges from 1-40mg per kilogram of body weight daily, in
329 particular a dose of 20mg/kg [49]. Among children treated with the CBD-rich oil known as
330 “Charlotte’s Web”, the therapeutic range is commonly 2-6mg per pound of body weight [50].
331 In another anecdotal case, a 70 year old Queensland woman was reported to be making
332 significant gains in recovery after a stroke using less than 1mg/kg of CBD-rich oil [7].

333 Safety

334 Statements on the safety of cannabinoids in the research described above appear to be
335 consistently positive. This is in contrast to the Australian Medical Association’s statement
336 that only “cannabis-based medicines” should be tested or legalised and that “raw” cannabis is
337 unsafe [51]. Also in contrast to this are many published results of research on legally-
338 approved pharmaceutical medications. Fig. 3 lists some serious adverse effects of the top-
339 selling pharmaceutical drugs, while Fig. 11 shows a comparison between the numbers of
340 recorded fatal poisonings of a variety of substances. While more toxic than
341 phytocannabinoids, the number of poisonings from synthetic cannabinoids still pales in
342 comparison to drugs such as those prescribed for anxiety and depression, over-the-counter
343 painkillers and opioid painkillers. Opioid painkillers have also been found to cause more
344 deaths annually than street heroin (Fig.12) [52]. According to Gøtzsche, psychiatric drugs
345 may be responsible for over half a million deaths among those aged 65 and older each year in
346 the West [53]. Additionally, animal studies suggest that these drugs can cause brain damage,
347 and many FDA submissions for new schizophrenia drugs show improvements far below
348 clinical relevance. Furthermore, Scandinavian researchers have found that the risk of
349 committing homicide may increase by 31% with antidepressant use, by 45% with
350 benzodiazepines, by 206% with anti-inflammatory drugs and by 92% with the use of opioid
351 painkillers [54]. In people under 26 years of age, there appeared to be a 95% increased risk of
352 committing homicide while using benzodiazepines and a 223% increased risk with opiate
353 painkiller use. An analysis of labelled Adverse Drug Events (ADEs) found a mean average of
354 70 ADEs for each pharmaceutical drug, with the mean for psychiatric drugs at 150 ADEs and
355 neurological drugs reaching up to 525 possible ADEs per drug [55].

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356 As stated above, the drug Rimonabant, used to treat cigarette addiction and obesity, has been
357 shown to increase risk of depression. A clinical trial of 18,695 participants, aiming to
358 determine benefit of the drug in preventing cardiovascular disease, was prematurely
359 terminated due to concerns among regulatory authorities about suicide risk [56]. Among the
360 patients receiving Rimonabant, 32% suffered neuropsychiatric side effects compared to 21%
361 in the placebo group, 2.5% as opposed to 1.3% suffered serious psychiatric effects and four
362 treated patients committed suicide compared with one in the placebo group. Rimonabant
363 exerts its effects by blocking the CB1 cannabinoid receptor.

364 However, the safety profile of CBD has been reported to be vastly different. Several studies
365 suggest that CBD is only cytotoxic to cancerous cells and does not affect heart rate, blood
366 pressure, body temperature or food intake [57]. It also does not alter gastrointestinal transit,
367 does not induce catalepsy and does not affect psychological or psychomotor functions.
368 Alongside this safety profile, CBD may also possess a protective effect against alcohol.
369 Researchers comparing the effects of alcohol, with and without CBD, found that the
370 combination of alcohol and CBD, at a dose of 200mg, resulted in significantly lower blood
371 alcohol levels compared to alcohol alone [58].

372 While this article focuses on consumption of non-pyschoactive strains of cannabis and
373 cannabinoids, research on the safety of smoking psychoactive cannabis is still pertinent.
374 According to the United Nations, over 200 million people around the world consume
375 cannabis, but zero deaths have been reported [59]. In fact, Dr Lester Grinspoon, professor
376 emeritus at Harvard, stated that “There are no deaths from cannabis use. Anywhere. You
377 can’t find one” [60]. Additionally, United States Congressman Steve Cohen has stated that
378 “Nobody dies from marijuana”, but added that heroin use can result in death [61].

379 It has been suspected that recreational use of cannabis could lead to cancer, much like
380 tobacco smoking, which has prompted research into the link between cannabis smoking and
381 cancer. In a 20-year study of 5,115 men and women, lung function was compared between
382 tobacco smokers, marijuana smokers and non-smokers [62]. The researchers found that
383 cannabis use was not associated with adverse effects on pulmonary function, particularly at
384 low levels of use. While tobacco smoking resulted in a decrease in pulmonary function, these
385 parameters were improved in cannabis smokers (Fig.13). Donald Tashkin, professor of
386 medicine at UCLA, stated that these results were “essentially confirmatory” of the findings
387 from other studies on cannabis smoking and lung function [63]. Although Tashkin expected
388 an increased cancer risk from “heavy” use, i.e. more than 500-1000 lifetime uses, even those
389 who had smoked cannabis over 20,000 times did not have a higher risk of lung cancer [64].
390 Tobacco use, at two packs per day, increased lung cancer risk by 2000%, whereas smoking
391 cannabis negatively correlated with lung cancer risk [65]. Additionally, a pooled analysis of
392 2,159 lung cancer cases and 2,985 controls found no association between intensity, duration
393 or cumulative use of cannabis and lung cancer risk [66]. The overall pooled relative risk for
394 habitual users, compared to non-habitual or never users, was 0.96 (95% CI: 0.66–1.38), while
395 the summary relative risk was 0.88 (95%CI: 0.63–1.24).

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396 Besides no negative effects on cancer risk, legalising cannabis may result in positive effects
397 on mortality rates. Research has found that states legalising medical cannabis experience an
398 immediate 25% reduction in deaths due to opioid overdose, and by the fifth year this
399 reduction increases to 34% [67]. Additionally, homicides in Denver, Colorado, dropped
400 52.9% in the first year after cannabis legalisation.

401 Safety of cannabis use during pregnancy is another common concern. However, a six-year,
402 controlled study on Jamaican women and their children found that the mothers who used
403 cannabis during pregnancy bore babies deemed superior in development [68]. Similar results
404 were found in follow-up research conducted in California. In the cannabis-using group, three
405 women previously deemed sterile conceived children, the mothers were eight times more
406 likely to breastfeed for over a year in comparison to the non-users, all users gave birth
407 naturally and there were zero developmental problems in their babies [69]. The presence of
408 the ECS from the early embryonic stages is a likely contributing factor to the benefits found
409 in these studies [68]. In fact, human breast milk is known to contain cannabinoids [70].

410 Conclusion

411 The endocannabinoid system is implicated in many chronic disease states, with its
412 dysfunction underlying the pathophysiology of conditions such as Alzheimer’s disease and
413 schizophrenia. Conversely, supplementation with phytocannabinoids, particularly as whole
414 extracts of hemp, may be an effective treatment for these conditions, with a superior safety
415 profile to their current pharmaceutical treatments and synthetic cannabinoids. However, while
416 the volume of preclinical research has expanded, human clinical trials are still sparse.
417 Proposals for future research are human trials to verify clinical efficacy of CBD and other
418 cannabinoids, including research on individualisation of cannabinoid ratios, and research on
419 breeding techniques in order to produce optimum levels of these and supporting constituents
420 such as terpenes.

421 Competing Interests

422 Paul Benhaim is the CEO of the Elixinol Company.

423

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