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Recent Edition
Review Article
Volume 5 Issue 2 - 2020
Opioid Use Disorder and Withdrawal: Rationale for Combining Multiple Micronutrients with Cannabidiol in Improving Current Management
Kedar N Prasad, PhD
Engage Global, 245 El Faisan drive, San Rafael, California 94903
*Corresponding Author: Kedar N Prasad, PhD, Engage Global, 245 El Faisan drive, San Rafael, California 94903, USA.
Received: March 11, 2020; Published: March 19, 2020
Keywords: Dementia; Nurses; Caregivers (cares); Elderly; (RNs) Registered nurses
Introduction
Opioids are a group of drugs, which act on opioid receptors in the brain. They include morphine (derived from the poppy plant), heroin (processed from morphine), fentanyl (a opioid based synthetic drug), and oxycodone and hydrocodone (semi-synthetic opioids from poppy plant). The opioid system consists of 3 G-protein-coupled opioid receptors mu (MOPr), delta (DOPr), and kappa (KOPr) in the brain, which mediate the action of opioids and opioid-related drugs.
Opioids are powerful pain-relieving prescription medications that can lead to opioid use disorder (OUD). This disorder has become a major national and international health concern. Opioids activate MOPr, which causes excessive release of dopamine in the brain that eventually lead to opioid-dependency and opioid-seeking behaviors. For example, heroin administration produces intense and rapid euphoria due to excessive release of dopamine in the brain [1]. The action of heroin is primarily mediated via its metabolites including morphine [2,3]. Prenatal exposure to heroin can influence the development of fetal brain that could adversely affect behavior and cognitive function later in life [4]. Although opioids are commonly used in relieving moderate to severe pain, their prolonged use can induce hyperalgesia [5]. The mechanisms that mediate cellular and molecular events leading to OUD are very complex and are not fully understood.
Cellular deficits such as increased levels of oxidative stress [6,7], inflammation [7-9], and glutamate [6] are associated with OUD and withdrawal symptoms. Therefore, it was thought that antioxidants, which reduce oxidative stress, inflammation, and prevents the release and toxicity of glutamate [10] might be useful in the management of OUD and withdrawal symptoms. Limited studies show that the use of single antioxidant has produced some benefits in animal and human models [6-11] and humans [12-14]. Since treatment with a single antioxidant has failed to produce expected benefits in other human neurological diseases such as Alzheimer’s disease [10], It is unlikely that that a single micronutrient would produce significant and consistent benefits in the management of OUD and withdrawal. Failure to obtain significant benefits from the use of single micronutrient led us to propose that a mixture of micronutrients may be more useful in the management of Alzheimer’s disease than a single antioxidant [10]. A similar approach could be useful in treatment of OUD and withdrawal symptoms in humans.
Opioid-induced excessive release of dopamine to the nucleus accumbens contributes to the opioid addiction. Cannabidiol (CBD) may act as a partial agonist of dopamine D2 receptor similar to the action of an antipsychotic drug aripiprazole [15].
Limited studies show that CBD treatment produced some benefits in animal and human models of OUD [16-20]. Since treatment with CBD alone produced limited benefits in human Parkinson’s disease [21] and no effect in Huntington’s disease [22], it is likely that CBD treatment alone may not produce optimal benefits in the management of OUD or withdrawal syndromes in humans. Since micronutrients and CBD act primarily by different mechanisms, the question arises whether combining the two could be more effective than the individual approach. There are no studies to answer this questions.
Current opioid substitution therapy of opioid addiction with methadone, a MOPr agonist, and buprenorphine, a partial agonist of MOPr, a full antagonist of KOPr, and naloxone and naltrexone, antagonists of opioid receptors has been useful, but it is not considered satisfactory [23,24]. Analysis of several articles showed that methadone treatment produced inconsistent results on craving for heroin varying from reduction in heroin craving in some cases, but not in others [23]. Despite treatment with methadone and buprenorphine, patients with opioid addiction relapse [25,26], show increased risk of misuse of drugs [27], decreased cognitive function [28], and increased sexual dysfunction [29,30]. Therefore, additional approaches for the improved management of opioid addiction should be developed. In order to develop such strategies, it is essential to identify cellular defects that are associated with opioid addiction and opioid withdrawal symptoms.
This review briefly describes (a) potential causes of opioid use disorder, (b) opioid substitution therapy and its limitations, (c) the role of increased oxidative stress, inflammation, and glutamate in opioid use disorder (OUD) and withdrawal symptoms, (d) the evaluation of individual antioxidants as well as CBD alone in the management of opioid dependency and withdrawal symptoms, and identify the gaps in knowledge. This review proposes a hypothesis that a mixture of micronutrients containing multiple dietary and endogenous antioxidants together with CBD may be more effective than the individual agents in the management of OUD and withdrawal symptoms. This strategy may improve the effectiveness of opioid substitution therapy.
Potential Causes of Opioid Use Disorder
Opioid use disorder has become epidemic in the USA. At this time, this disorder has become serious health concerns not only in the United Sates, but also in the worldwide. Increased number of deaths is reported due to opioid overdose. Major causes of opioid use disorder include patients who demand frequent prescriptions for opioid to manage their pain, and doctors who are willing to meet their demands. In addition, misleading advertising by the pharmaceutical companies implying that time-release opioid capsules can reduce the risk of addiction has also contributed to this disorder [31].
Statistics on the number of death from overdose of opioid and the number of people misusing opioid and It was determined that 400,000 people died from an overdose of prescription opioids between 1999 and 2017 in the USA [32]. Statistics on deaths due to overdose of opioids and incidence of misuse of opioid-related drugs for 2018 and 2019 are listed in Table 1.
Number of Death Opioid Overdose
Over 130 every day Opioid-related drugs
47,600 in 2018 Opioid
32,658 in 12-month ending Feb 2019 Synthetic opioid
15,349 in 12- months ending in Feb 2019 Heroin
Number of people misusing opioids Drug name
2 million people Prescription opioids
808,000 people Heroin
From: US Department of Health and Human Services, HHS.Gov/opioid, 2019
Table 1: Statistics on deaths due to overdose of opioid use disorder and
number of people misusing opioids in the USA
Opioid Receptors Mediate Opioid effects in the Brain
The importance of opioid receptors in regulating the effects of opioids is demonstrated by the genetic deletion of specific receptor. Opioids control pain, reward, and dependency through their receptors MOPr, DOPr, and KOPr. Endogenous peptides, such as enkephalins, dynorphins, and endorphin, and exogenous agents such as morphine and methadone activate opioid receptors. Studies on genetic deletion of opioid receptors suggest that MOPr and DOPr regulate emotional reactivity in an opposite manner [33]. Mice lacking the MOPr gene show a loss of morphine-induced analgesia, reward, and dependency, and increased sensitivity to painful stimuli, reduced reward to non-opioid drugs, and altered emotional responses [34,35]. The effects of opioids are abolished in MPOr knockout mice, suggesting the importance of MOPr in the mechanisms opioid action [36]. In addition, an antagonist of MOPr in the nucleus accumbens prevented evoked release of dopamine [37]. On the other hand, agonist of KOPr produces opposite effects [38,39] by decreasing dopamine release in the nucleus accumbens [40].
The opiate receptor reward pathway includes part of cerebral cortex, ventral tegmental area, and nucleus accumbens. Opioids bind to opioid receptors, which send signals to dopamine terminals to release excessive amounts of dopamine. Thus, dopamine is the most important neurotransmitters, which plays a central role in reward and addiction.
Deletion of dopamine receptors enhanced opioid-seeking behavior, and opioid-induced rewarding effect [9,41-44]. In addition to dopamine receptors, glutamate receptor NMDA (N-methyl-d-aspartate)-mediated release of glutamate may also be involved in heroin-dependency [45].
Increased Oxidative Stress and Inflammation Associated with Opioid Use Disorder
The levels of markers of oxidative stress and inflammation increase in the brain following exposure to opioids. These cellular defects are likely to contribute to the development of neurological abnormalities observed in patients who exhibit opioid dependency and withdrawal symptoms. Several investigations on the above are described here.
Animal Studies: Morphine treatment increased oxidative stress in the brain as evidenced by progressive increase in the levels of malondialdehyde (MDA), nitric oxide (NO), and glutamate, and reduced glutathione level and glutathione peroxidase activity in mice [6]. Morphine treatment enhances the levels of MDA and reduces the level of vitamin E in rats. The induction of naloxone-precipitated withdrawal symptoms further enhanced the level of MDA in rats [46].
Human Studies: Frequent use of opioids generates excessive amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines, which may contribute to opiate-dependency [7]. Patients with opioid use disorder exhibited lower superoxide and catalase activities leading to increased oxidative stress, and higher MMP-9 (matrix metallopeptidase-9) and TNF-alpha (tumor necrosis factor-alpha) leading to increased inflammation compared to controls subjects. In opioid-dependent patients, the levels of MDA were increased [47,48]. These studies suggest that treatment with antioxidants may be of therapeutic value in patients with opioid addiction.
Increased Oxidative Stress and Inflammation Associated with Opioid Withdrawal Symptoms
Animal Studies: Pre-treatment with inhibitors of nitric oxide synthase (NOS) reduced naloxone-precipitated opioid withdrawal syndromes in morphine-addicted animals [49]. Inhibitor of phospholipase A2 attenuated naloxone-precipitated opioid withdrawal syndromes in morphine-addicted animals [50]. Phospholipase A2 is an enzyme, which cleaves fatty acids, leading to increased production of arachidonic acid that causes inflammation and pain, while nitric oxide synthase is responsible for production of nitric oxide (NO), which can increase the levels of peroxinitrite. Thus a combination of these two inhibitors may decrease production of free radicals and inflammatory agents [51-52]. These studies suggest that increased free radicals and inflammation are involved in opioid withdrawal syndromes.
The level of mRNA of superoxide dismutase-2 (SOD-2), a mitochondrial SOD, is reduced in cells treated with morphine, suggesting the role oxidative stress in drug dependency. Polymorphisms in SOD-2 gene have been associated with the increased risk of heroin dependency [53].
Human Studies: Oxidative stress in heroin-addicted individuals, naloxone- precipitated withdrawal symptoms resulted in increased markers of oxidative damage and depressed antioxidant systems [11]. In patients with opioid addiction undergoing methadone therapy, the higher plasma levels IL-6 were associated with higher plasma morphine levels. In contrast, plasma levels of C-reactive protein (CRP), transforming growth factor beta1 (TGF-beta1), and brain-derived neurotrophic factor (BDNF) were decreased during methadone maintenance therapy [17]. This study suggests that addicted individuals, who were subjected to naloxone –precipitated withdrawal symptoms, also showed increased markers of oxidative stress and inflammation in the brain similar to those produced by morphine during withdrawal symptoms.
Increased Glutamate Level Associated with Opioid Use Disorder and Withdrawal Symptoms
Animal Studies: Abnormality in glutamatergic transmission in the brain reward circuit has been suggested in relapse in patients who have been free of taking opioids and or illicit drugs [54]. Glial glutamate transporter -1 (GLT-1) maintains homeostasis of glutamate by removing excess glutamate from the extrasynaptic space. Opioids and illicit drugs decrease the expression of GLT-1 causing increased levels of glutamate. Treatment with n-acetylcysteine (NAC), an antioxidant, and minocycline, an antibiotic with anti-inflammatory property, increased the expression of GLT-1 and decreased the levels of glutamate [54,55]. Heroin-induced reinstatement increased extracellular levels of glutamate in the nucleus accumbens core in self-administered animal model. An inhibitor of glutamate non-NMDA receptors (AMPA/ kainite) the above effect in the nucleus accumbens core [56]. Microinjection of glutamate into locus coeruleus (LC) initiated morphine withdrawal syndromes during active phase in rats. This effect of glutamate was blocked by pre-treatment with SB-334867, an antagonist of orexin type 1 receptor, during active phase. Based on these results, it was suggested that orexin-A peptide plays a role in glutamate-induced opiate withdrawal syndromes [57].
Human Studies: Administration of ketamine, an antagonist of glutamate receptor N-methyl-D aspartate (NMDA) improved abstinence rates in opioid and alcohol use disorders and other substance use disorder [58]. The levels of glutamate in the nucleus accumbens were higher than control group in patients with opioid use disorder. Higher levels of glutamate were associated with higher impulsive behavior [59]. The levels of glutamate were higher, while the levels of Gamma-aminobutyric acid (GABA) were lower in the prefrontal cortex of patients with opioid use disorder compared to control. It was further demonstrated that higher glutamate levels were associated with higher impulsivity with no influence on cognitive function, whereas lower levels of GABA was associated with lower cognitive function, but higher impulsivity [60]. Treatment of heroin-dependent patients with methadone enhanced the levels of glutamate in the anterior cingulated cortex, but not in the thalamus [61].
Currently Used Drugs in Opioid Substitution Therapy
Animal Studies: Bupropion, an antidepressant drug, has no effect on analgesic activity, but it attenuated morphine-induced tolerance and dependency in mice. It also suppressed morphine-induced increase in the levels of glutamate, inflammation, and oxidative stress [24].
Human Studies: Methadone and buprenorphine are most commonly used in the opioid substitution therapy. Each patient must have sufficiently high levels of these drugs in the brain in order to avoid withdrawal symptoms. Opioid overdoses cause death primarily by respiratory depression. This is due to the fact that respiration is more sensitive than analgesia to opioid effects [62]. Methadone is a full agonist of opioid receptor MOPr [63], which exhibits high potency and effectiveness in opioid addiction that increases the risk of overdose.
Buprenorphine, an antagonist of KOPr, exhibits an antidepressant effect [64]. It does not cause severe respiratory depression at analgesic doses [65]. In addition, opioid substitution therapy preserves immune system [66], cognitive function [67], and reduces psychiatric problems [68] and poly-drug abuse [69].
Methadone and buprenorphine have been equally effective as maintenance therapy for people with opioid dependency [70]. The effects of methadone, buprenorphine or dihydrocodeine on patients addicted with heroin and other opioid drugs were evaluated on the criteria of drug-related poisoning. The lowest mortality risk was found after 4 weeks of treatment and the highest risk was observed in the first 4 weeks after cessation of treatment [71].
In heroin addicted patients, the serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were decreased [72]. Treatment of heroin-dependent patients with methadone increased serum level of BDNF [73].
Opioid receptor antagonists are useful in preventing opioid overdose deaths [74]. Naloxone is the only opioid antagonist approved for the treatment of overdose because it has shorter half-life and multiple intravenous injections can reverse respiratory depression [75]. Naloxone reverses buprenorphine-induced respiratory depression [76], but it can also cause opioid withdrawal symptoms [77].
Despite the treatment with methadone and buprenorphine patients often relapse [25,26], show increased risk of misuse of drugs [27], decreased cognitive function [28], and increased sexual dysfunction [29,30]. In addition, methadone treatment can cause increased death and pulmonary edema [78,79].
Treatment with Antioxidants in the Management of Opioid Use Disorder and Withdrawal Symptoms
Animal Studies
 Curcumin: Curcumin treatment reduced morphine-induced oxidative damage, caspase-3 and caspase-9 activities, while elevating the levels of BCl2 (B-cell lymphoma-2), a protein, which prevents cell death in the rat hippocampus [80].
Alpha Lipoic Acid: Co- administration of alpha-lipoic acid with morphine inhibited the development of morphine tolerance and dependency as well as naloxone-precipitated withdrawal symptoms in mice. Addition of an NMDA receptor antagonist (dizocilpine) and n-acetylcysteine enhanced the effects of alpha-lipoic acid [6].
Melatonin, Vitamin E, or Selenium: Melatonin or vitamin E plus selenium prevented increases in markers of oxidative damage and enhanced antioxidant systems during naloxone-precipitated heroin withdrawal symptoms [11]. Co-administration of melatonin and morphine together prevented withdrawal symptoms of morphine such as hyperalgesia (hypersensitivity to pain) and glial reactivity. This effect of melatonin was mediated by inhibition of protein kinase C (PKC) activity and elevation of cyclic AMP [81].
Thymoquinone: Co-administration morphine and thymoquinone, which exhibit antioxidant and anti-inflammation activities, reversed the morphine-induced changes in the brain. Co-administration of thymoquinone with naloxone blocked naloxone-induced biochemical changes in the brain of mice. Inhibitors of nitric oxide synthase also reduced naloxone-induced withdrawal symptoms in morphine-addicted rats [49].
These results show that compounds with antioxidants activity can reduce the development of morphine tolerance and dependence as well as inhibiting withdrawal symptoms.
Epigallocatechin Gallate: Treatment with epigallocatechin gallate, a major component of green tea, which exhibits antioxidant and anti-inflammation activity, prevented naloxone –precipitated withdrawal symptoms in morphine addicted animals [82].
Vitamin C: Treatment with a high-dose vitamin C orally reduced the symptoms of withdrawal in heroin-addicted individuals guinea pigs [83].
Omega-3-fatty Acids: Omega-3-fatty acids rich diet decreased oxicodone –seeking behaviors and reduced anxiety. In addition, it restored deficiency of gut microorganisms, which is induced during opioid withdrawal symptoms to normal levels [13].
Vitamin E, Coenzyme Q10 or Vitamin B12: Administration of vitamin E, coenzyme Q10 or vitamin B12 individually inhibited the release and consequent toxicity of glutamate [84-87].
Overall while the use of single antioxidants has shown significant benefits in animal models of opioid use disorder and withdrawal symptoms. Limited studies have been performed in humans.
Human Studies
Vitamin C: Treatment with a high-dose vitamin C orally reduced the symptoms of withdrawal in heroin-addicted individuals [12].
Vitamin D3: Administration of high dose (50,000 IU) vitamin D3 to patients on methadone led to improved quality of sleep, reduced depression, and enhanced antioxidant status [14].
From the above limited studies, it is apparent that individual micronutrient produces some benefits in patients with opioid use disorder as well as in opioid withdrawal syndrome in both animals and humans. However, the use of single antioxidant in other human chronic diseases produced no effect, modest beneficial effects or adverse effects. For example, treatment with vitamin E alone was ineffective in patients with Alzheimer’s disease [88] or prevented the rate of decline in cognitive function in early phase Alzheimer’s disease [89]. Administration of Vitamin E alone was also produced no beneficial effect in patients with Parkinson’s disease [90,91] . Administration of beta-carotene alone in male heavy tobacco smokers increased the risk of cancer [92]. The exact reasons for these inconsistent results with single micronutrient are not known; however, the use of single micronutrient may not the best strategy to treat either opioid use disorder or withdrawal syndrome. The following scientific rationales provide additional support for the idea that treatment with single micronutrients may not produce optimal benefits in patients with opioid use disorder or withdrawal syndromes.
  • It is well established that a single antioxidant when oxidized acts as a pro-oxidant rather than as an antioxidant. Studies described in this manuscript show that markers of increased oxidative stress are elevated in patients with opioid use disorder and withdrawal syndromes. Therefore, administered single antioxidant in a high oxidative environment would be oxidized, which would then as a pro-oxidant rather than as an antioxidant.
  • Different antioxidants are distributed differently in the sub-cellular compartments of cells and possess different mechanisms of action; thus, a single antioxidant cannot protect all parts of the cell.
  •  The gradient of oxygen pressure varies within cells. Some antioxidants, such as vitamin E, are more effective as quenchers of free radicals in reduced oxygen pressure, whereas beta-carotene and vitamin A are more effective in higher atmospheric pressure [93].
  • The body protects against oxidative damage by elevating the levels antioxidant enzymes and dietary and endogenous antioxidants. Antioxidants neutralize free radicals by donating electrons to those molecules with unpaired electron, whereas antioxidant enzymes destroy free radicals by catalysis, converting them to harmless molecules such as water and oxygen.
  • Single antioxidant cannot protect both the aqueous and lipid compartments of the cell
  • A single antioxidant cannot optimally elevate intracellular level of glutathione, one of the most important intracellular antioxidants for protection against oxidative damage.
  • Coenzyme Q10 and nicotinamide (vitamin B3) are important for increasing mitochondrial energy generation. Vitamin B12 prevents the release of glutamate [94,95]. Vitamin E and coenzyme Q10 decreased the release and neurotoxicity of glutamate [84,85,96]. A single antioxidant cannot perform all these essential functions that are essential in improving the management of opioid disorder and withdrawal syndromes,
  • Antioxidants enhance the production of protective proteins within the cells by altering the expression of different microRNAs [97]. For example, some antioxidants can activate Nrf2 by upregulating miR-200a that inhibits its target protein Keap1, whereas others activate Nrf2 by downregulating miR-21 that binds with 3’-UTR Nrf2 mRNA [98]. A single antioxidant cannot achieve this goal.
In order to avoid the limitations of use of single antioxidant, it has been proposed that in order to reduce the levels of oxidative stress, chronic inflammation and glutamate at the same time, it is important to increase the levels of antioxidant enzymes by activating the Nrf2 pathway, as well as elevating the levels of dietary and endogenous antioxidant compounds, and vitamin B2 by oral administration [10,99]. A similar approach would be useful in the management of opioid use disorder and withdrawal syndromes.
Cannabidiol (CBD) in the Management of Opioid Use Disorder and Withdrawal Symptoms
Animal studies: Cannabidiol (CBD) is one of the major phytocannabinoids from the hemp plant (a variant of Cannabis sativa), which is safe and legal. CBD treatment is one of the few non-opioid medication options for reducing drug-induced craving and anxiety, which contribute to addicted behavior and relapse in drug-abstinent individuals with heroin addiction [16]. CBD enhances morphine-induced antinociception in animals. CBD reduced the reward facilitating effects of morphine. This effect of CBD is mediated by activating serotonin receptor 5-HT1A in rats. Thus, CBD may be useful in inhibiting the rewarding effects of opioids [100]. CBD treatment disrupts the reconsolidation of drug-related memories and consequently, it may reduce the risk of relapse in rats [101].
Human Studies: CBD has been proposed as an effective treatment in the management of substance use disorders by reducing the risk of relapse and craving for drugs [18]. Treatment with CBD caused extinction of drug memories and improved drug-induced mental disorders [17]. Several studies suggest that endcannabinoid system plays an important role in reducing craving and relapse in abstinent substance users. CBD has been proposed to be useful in the management of a range of substance use disorder involving opioids, nicotine, alcohol, psychostimulants, and cannabis [18,102].
Endocannbinoid System (ECS) in the Management of Opioid Use Disorder and Withdrawal
 Animal studies: CBD, which is relatively safe, also acts as a non-competitive negative allosteric modulator of cannabinoid receptor 1 (CB1R), and thereby, indirectly reduces the binding ability of an agonist by interacting at he secondary site on the receptor [103,104]. Thus, CBD acts functionally as an antagonist of CB1R. Therefore, CBD may be more useful than the synthetic antagonist of CB1R in the management opioid use disorder. Treatment with a synthetic inhibitor of FAAH (fatty acid amide hydrolase), which increases the level of anandamide, one of the ligands of ECS, which mediates its action vis endocannabinoid receptors, reduced heroin-seeking behavior in chronic pain model, using a self-administration paradigm in mice [105]. CBD also acts as an inhibitor of FAAH [19,106]; therefore, CBD treatment is likely to produce similar effects. Administration of a synthetic inhibitor of FAAH (URB597) to morphine-addicted rats before naloxone-precipitated withdrawal symptoms reduced most of the morphine withdrawal symptoms [20]. Since CBD also acts as an inhibitor of FAAH [19,106], CBD treatment may produce similar effects. Treatment with 2-arachidonoylglycerol (2-AG), one of ligands of ECS, which mediates its action via endocannabinoid receptors, inhibited some of the naloxone-precipitated withdrawal symptoms in morphine-addicted mice [107]. These studies suggest that an elevation of both ligands anandamide and 2-AG reduce some of the withdrawal symptoms induced by naloxone in morphine addicted animals.
The expressions of mRNA and protein level of cannabinoid receptor CB1R were elevated in cortex and hippocampus area of the brain, which are responsible for opioid use disorder. In addition, the levels of IL-6, a pro-inflammatory cytokine, increased in these regions. These results suggest that CB1R play an important role in opioid use disorder and withdrawal symptoms [108]. The expression of CB1R in nucleus accumbens during morphine withdrawal phases increased in rats. This rise in CB1R expression induced relapse and opioid-seeking behavior after morphine withdrawal [109].
Human Studies: Several studies have suggested that ECS signaling is involved in opioid use disorder, reward, and withdrawal symptoms. Treatment with a synthetic antagonist of cannabinoid receptor 1 (CB1R) rimonabant was useful in the management of opioid use disorder; however, the appearance of serious psychiatric adverse events led to its abrupt recall from the market [110,111].
Rationale for Combining a Mixture of Micronutrients with CBD in the Management of Opioid Use Disorder and Withdrawal Symptoms
Rationale for combining multiple micronutrients with CBD includes difference between the actions of micronutrients and CBD, and failure to obtain significant benefits by treatment with single antioxidant or CBD alone.
Differences between Function of Antioxidants and CBD
Their functions are summarized here.
Functions of antioxidants: The functions of antioxidants include:
  • Donation of electrons to molecules with an unpaired electron to neutralize them,
  • Activation of ROS-resistant Nrf2/ARE pathway to enhance the levels of cytoprotective enzymes including antioxidant enzymes,
  • Restoration of dietary and endogenous antioxidant compounds to normal or higher levels,
  • Changes in expressions of numerous genes, and
  • Alteration in the expression of microRNAs in a way to allow translation of protective proteins from their respective mRNAs.
The above issues have been discussed in detail in a recent book and reviews [97,112].
Functions of CBD: The major functions of CBD include:
  • CBD behaves as an antagonist of CB1R [113] and thereby, prevents the euphoric effects of THC. CBD also inhibited side effects of THC [114],
  • CBD enhances the level of anandamide by inhibiting FAAH, a degrading enzyme of anandamide [19]. Elevated level of anandamide acts as an agonist for both CB1R and CB2R [106].
  • CBD also directly acts as an agonist of CB2R leading to a reduction in the levels of inflammation and pain [115].
  • CBD also acts as an agonist of serotonin (5-HT1A) receptor [116].
  • CBD also acts as an inhibitor of serotonin reuptake that keeps higher levels of anandamide at the synapse. CBD treatment prevented long-lasting anxiety and fear in an animal model of PTSD by stimulating serotonin receptor 5-HT1A [117].
  • CBD acts as an agonist to non-cannabinoid receptors, such as serotonin receptors [116,117] and adenosine receptors [118].
  • CBD acts as a partial agonist to dopamine receptor D2 [15].
  • CBD prevents the release of glutamate by activating anandamide, which stimulates CB1R that acts as an antagonist of glutamate receptor NMDR [119].
  • CBD under certain conditions also exhibits antioxidant and anti-inflammation activities [120-122]. However, the mechanisms of activities are different from those produce by antioxidants.
Proposed Hypothesis
Because of Limited or no Benefits with single micronutrient in human Alzheimer’s disease and Parkinson’s disease [88,90,91] or CBD alone in human Parkinson’s disease and Huntington’s disease [21,22,123,124], and different mechanisms of action by micronutrients, a hypothesis that combination of a micronutrient mixture containing multiple dietary and endogenous antioxidants with CBD may be more effective than either strategy alone in the management of opioid use disorder and withdrawal symptoms is proposed. The same mixture of micronutrient could improve the effectiveness of opioid substitution therapy. Preclinical and clinical studies should be conducted to test the validity of the proposed hypothesis.
Supporting evidence for Proposed Hypothesis from patients with Other Diseases
Although the role of multiple micronutrients in management opioid use disorder and withdrawal syndromes remains unknown, the beneficial effects of multiple micronutrients have been reported in other human diseases. For example, administration of multiple micronutrients reduced the risk of cancer in men [125] and delayed the progression of HIV disease and provided an effective low-cost means of prolonging the time period for initiating the anti-viral therapy [126].
Conclusions
Opioids, one of the commonly prescribed drugs, to relieve pain, can cause opioid use disorder in humans. This effect of opioids is mediated via activating mu opioid receptor (MOPr), which induces excessive release of dopamine in the nucleus accumbens. Thus, dopamine is one of neurotransmitters, which plays an important role in opioid dependency and opioid-seeking behavior. The incidence of opiod use disorder and opioid-related deaths has become a major national and international health concern. Increased levels of oxidative stress, inflammation, and extracellular glutamate appear to be involved in the opioid use disorder and withdrawal symptoms in animal and human models.
Opioid substitution therapy with methadone, buprenorphine, naloxone, and naltrexone has been useful, but it is not considered satisfactory. Limited studies show that supplement with individual antioxidant reduced some of the addictive behaviors and naloxone-precipitated withdrawal symptoms in animal and human models. Limited studies reveal that treatment with CBD alone also reduced addictive behaviors and withdrawal symptoms in animal human models. Individual antioxidant or CBD alone produced no effect or limited benefits in humans. These observations together with the fact that the mechanisms of protection by antioxidants are entirely different from those produce by CBD led us to propose a hypothesis that combination of a micronutrient mixture containing multiple dietary and endogenous antioxidants together with CBD may be more effective than the individual agents in the management of opioid use disorder and withdrawal symptoms. The same combination may improve the effectiveness of opioid substitution therapy. Preclinical and clinical studies should be performed to test the validity of the proposed hypothesis in patients with opioid use disorder or opioid withdrawal syndromes.
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Citation: Kedar N. Prasad. “Opioid Use Disorder and Withdrawal: Rationale for Combining Multiple Micronutrients with Cannabidiol in Improving Current Management”. Current Opinions in Neurological Science 5.2 (2020): 46-59.
Copyright: © 2020 Kedar N. Prasad. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.