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Low-Dose Naltrexone
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Low-dose naltrexone (1 mg to 5 mg), very low-dose naltrexone (0.001–1 mg), and ultra-low-dose naltrexone (ULDN) (<0.001 mg) have been investigated for their immune-modulatory and anti-inflammatory effects.6 The most apparent effect at low doses is naltrexone’s antagonism of toll-like receptor 4 (TLR4) within the microglia. Many studies have shown that TLR4 antagonism results in the downregulation of inflammatory cytokines and immune mediators such as interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), and granulocyte colony-stimulating factor (G-CSF), among others. There has also been an observed compensatory release of endogenous opioids, such as opioid growth factor (OGF, [Met5]-enkephalin) in response to low-dose naltrexone therapy, as well as a modulatory effect on the OGF–OGF receptor (OGFr) axis in cancer cell proliferation. The low concentration of naltrexone at the opioid receptors causes intermittent binding, which sends feedback to the central nervous system (CNS), mimicking opioid depletion and resulting in a compensatory release of endogenous opioids. Opioid growth factor is an inhibitory peptide in the human body exhibiting a role in cell proliferation as well as tissue organization in many biological and pathological conditions (e.g., cancer, wound healing, angiogenesis). The OGFr is an integral membrane protein that, when bound to OGF, modulates the signal transduction resulting in DNA activity.7 It is important to note that to get the intermittent binding effect of LDN it must be prepared as an immediate-release formulation. According to Dr. Pradeep Chopra, using a sustained-release formulation would be detrimental because it is the “transient and reversible blockade of the opioid receptor” that is responsible for the upregulation of OGF. This effect is not seen with higher doses or sustained-release formulations of naltrexone (Yeazel D, e-mail communication, January 2018). Additionally, using fillers such as calcium carbonate during compounding can reduce absorption of naltrexone, thereby affecting the pharmacokinetic profile, and should be avoided.8 Instead, inactive fillers such as Avicel®, sucrose, or lactose should be used in compounding.9
Naltrexone at low doses (LDN) and its relevance to cancer therapy
Published in Expert Review of Anticancer Therapy, 2022
In vivo studies performed in 1980s, highlighted the importance of dose in determining the overall effect as mice that were treated with clinically conventional doses of 10 mg/kg induced a continuous occupancy of the opioid receptors, which was associated with increased tumor growth [22]. However, if doses were reduced to 1 or 0.1 mg/kg, the receptor blockade was incomplete. Binding sites were thus available to exogenous opiates and endogenous endorphins, resulting in activation of their anti-tumor actions. In addition to dose, the schedule of naltrexone administration was also crucial, with intermittent administration of low-dose naltrexone achieving the greatest anti-tumor response. The reason for this still remains elusive, but it has been suggested that the extent to which opioid receptors are antagonized, can induce changes in the types and numbers of opioid receptors expressed. For example, a study in albino mice reported LDN was able to increase the expression of the opioid growth factor receptor (OGF-R), which was also associated with alterations to key signaling pathways, a number of which were directly linked to cell growth and death [23].
Behavioral, histopathological, and biochemical evaluations on the effects of cinnamaldehyde, naloxone, and their combination in morphine-induced cerebellar toxicity
Published in Drug and Chemical Toxicology, 2022
Soraya Mahmoudi, Amir Abbas Farshid, Esmaeal Tamaddonfard, Mehdi Imani, Farahnaz Noroozinia
In this study, cinnamaldehyde and naloxone caused comparable neuro-protective effects with superior effect of cinnamaldehyde. In addition, a combined treatment with these two chemical compounds also caused neuroprotective effect. Although, there are no reports showing the interaction between cinnamaldehyde and opioid receptors, cinnamaldehyde interaction with cell membrane proteins such as transient receptor protein ankyrin 1 (TRPA1) and toll-like receptor 4 (TLR4) has been reported (Sui et al. 2010, Zhao et al. 2016 ). A positive synergistic anti-oxidant effect between cinnamaldehyde and resveratrol has been reported against cyadox-induced cytotoxicity in rabbit erythrocytes (Farag et al. 2017). Opioid antagonists such as naloxone and naltrexone are frequently used alone for their therapeutic target or as standard drugs or in combination with medicinal plants and their active constituents to study peripheral and central mechanisms of action of natural and synthetic materials. For example, chronic (28 d) administration of naltrexone (0.1 and 1 mg/kg) increased bone mass as a result of increasing osteoblast number caused by blocking signaling pathway of opioid growth factor receptor (OGFR) (Tanaka et al. 2019). Crocin, a constituent of saffron, and morphine caused similar antinociceptive effects, and prior administration of naloxone did not inhibit crocin-induced antinociception indicating involvement of non-opioid mechanisms (Tamaddonfard and Hamzeh-Gooshchi 2010). These findings indicate that cinnamaldehyde may interact with opioid receptor to cause protective effects against chronic morphine-induced lesion.