- μ-opioid receptor (MOR) (Ki = 0.08–0.15 nM, competitive antagonist) [2][3][6]
- κ-opioid receptor (KOR) (Ki = 0.4–0.8 nM, competitive antagonist) [2][3]
- δ-opioid receptor (DOR) (Ki = 2.0–3.5 nM, weak competitive antagonist) [2][3]
- No significant binding to non-opioid receptors (e.g., GABAₐ, NMDA) at concentrations ≤10 μM [3][6]

1. Antitumor activity (low-dose): - In human breast cancer cell lines (MCF-7, MDA-MB-231), naltrexone (1–10 nM) inhibited cell proliferation by 20–35% via downregulating NF-κB activity; Western blot showed reduced p65 phosphorylation (Ser536) by 40–50% [1]
- In melanoma cells (A375), naltrexone (5 nM) induced apoptosis via caspase-9 activation, with apoptotic rates increasing from 4% (control) to 18% after 72 hours (Annexin V/PI staining) [1]
2. Opioid receptor antagonism: - In CHO cells stably expressing MOR, naltrexone (0.1–1 nM) blocked [³H]-dihydromorphine binding in a dose-dependent manner, with 50% inhibition at 0.12 nM (radioligand displacement assay) [3][6]
- In SH-SY5Y neuroblastoma cells (expressing KOR), naltrexone (0.5 nM) inhibited U50,488H (KOR agonist)-induced Ca²⁺ influx by 80% (fluorescence-based Ca²⁺ imaging) [3]

1. Tumor growth inhibition (low-dose): - In nude mice bearing MCF-7 breast cancer xenografts, oral naltrexone (0.1 mg/kg daily for 28 days) reduced tumor volume by 40% and tumor weight by 35% (vehicle: 1.8 ± 0.3 g; naltrexone: 1.2 ± 0.2 g); immunohistochemistry showed reduced Ki-67 (proliferation marker) positivity from 60% to 30% [1]
- In C57BL/6 mice with B16-F10 melanoma, naltrexone (0.05 mg/kg i.p. every other day) reduced lung metastatic nodules by 25% (vehicle: 42 ± 6; naltrexone: 32 ± 5) [1]
2. Opioid dependence reversal: - In rats with morphine-induced physical dependence, subcutaneous naltrexone (1 mg/kg) precipitated withdrawal symptoms (e.g., paw tremors, wet dog shakes) within 15 minutes, with symptom severity peaking at 60 minutes (behavioral scoring: 8/10 vs. vehicle: 1/10) [3]
- In rhesus monkeys trained to self-administer heroin, oral naltrexone (3 mg/kg daily) reduced heroin self-administration by 70% over 14 days (vehicle: 25 ± 4 infusions/day; naltrexone: 7 ± 2) [2]
3. Alcohol dependence reduction: - In C57BL/6 mice with chronic alcohol intake (10% ethanol), oral naltrexone (2 mg/kg daily) decreased ethanol consumption by 55% (vehicle: 12 ± 2 g/kg/day; naltrexone: 5.4 ± 1.1) [6]
- In rats with alcohol-induced conditioned place preference (CPP), naltrexone (1.5 mg/kg i.p.) blocked CPP expression, with preference score reduced from 45 ± 5 (vehicle) to 10 ± 3 [6]
4. Weight loss (combination with bupropion): - In diet-induced obese (DIO) Sprague-Dawley rats, oral naltrexone (3 mg/kg) + bupropion (10 mg/kg) daily for 4 weeks reduced body weight by 12% (vehicle: 520 ± 20 g; combination: 458 ± 15 g) and fat mass by 18% [5]

1. μ-opioid receptor binding assay: - Membranes isolated from CHO cells expressing human MOR were incubated with [³H]-dihydromorphine (0.5 nM) and naltrexone (0.01–10 nM) in binding buffer (50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 5 mM MgCl₂) at 25°C for 60 minutes. Bound ligand was separated by filtration through glass fiber filters, and radioactivity was measured by liquid scintillation counting. The assay was repeated in triplicate, and Ki was calculated using the Cheng-Prusoff equation [3][6]
2. NF-κB activity assay (for antitumor mechanism): - Nuclear extracts from MCF-7 cells treated with naltrexone (1–10 nM) were incubated with a biotinylated NF-κB consensus oligonucleotide in binding buffer (20 mM HEPES, pH 7.5, 50 mM KCl, 1 mM DTT) at 4°C for 30 minutes. Streptavidin-coated plates were used to capture the DNA-protein complex, and NF-κB binding was detected via a primary antibody against p65 and a horseradish peroxidase (HRP)-conjugated secondary antibody. Absorbance at 450 nm was measured, and activity was normalized to vehicle-treated controls [1]

1. Tumor cell proliferation assay (MTT): - MCF-7/MDA-MB-231 cells (5×10³ cells/well) were seeded in 96-well plates and treated with naltrexone (0.1–100 nM) for 72 hours. MTT solution (0.5 mg/mL) was added, and plates were incubated at 37°C for 4 hours. Formazan crystals were solubilized with DMSO, and absorbance at 570 nm was measured. Cell viability was calculated relative to vehicle controls, and IC₅₀ for proliferation inhibition was 8–10 nM in MCF-7 cells [1]
2. Apoptosis assay (Annexin V/PI): - A375 melanoma cells (1×10⁵ cells/well) were treated with naltrexone (5 nM) for 48/72 hours. Cells were harvested, washed with PBS, and stained with Annexin V-FITC and PI for 15 minutes at room temperature in the dark. Flow cytometry was used to quantify early (Annexin V⁺/PI⁻) and late (Annexin V⁺/PI⁺) apoptotic cells, with triplicate samples per group [1]
3. Opioid agonist-induced Ca²⁺ influx assay: - SH-SY5Y cells (expressing KOR) were loaded with Fluo-4 AM (2 μM) in HBSS buffer at 37°C for 30 minutes. Cells were treated with naltrexone (0.1–1 nM) for 10 minutes, followed by U50,488H (1 μM, KOR agonist). Fluorescence intensity (excitation 488 nm, emission 525 nm) was measured every 5 seconds for 5 minutes to assess Ca²⁺ influx, with inhibition percentage calculated relative to U50,488H-only controls [3]

1. Breast cancer xenograft model (nude mice): - Female athymic nude mice (6–8 weeks old) were subcutaneously injected with 1×10⁷ MCF-7 cells (suspended in PBS:Matrigel = 1:1) into the right flank. When tumors reached 100 mm³, mice were randomized to vehicle (0.9% saline, 0.1 mL/10 g) or naltrexone (0.1 mg/kg, dissolved in vehicle) groups. Drugs were administered via oral gavage once daily for 28 days. Tumor volume was measured twice weekly using calipers (volume = length × width² × 0.52), and body weight was recorded weekly. On day 28, mice were euthanized, tumors were excised and weighed, and tumor tissues were fixed in 4% paraformaldehyde for immunohistochemistry [1]
2. Morphine dependence model (rats): - Male Sprague-Dawley rats (250–300 g) were implanted with subcutaneous morphine pellets (75 mg/pellet) once every 72 hours for 14 days to induce physical dependence. On day 15, rats were administered subcutaneous naltrexone (1 mg/kg, dissolved in 0.9% saline) or vehicle. Withdrawal symptoms (paw tremors, wet dog shakes, diarrhea) were scored every 15 minutes for 2 hours using a validated behavioral scale (0 = absent, 2 = severe) [3]
3. Long-acting naltrexone formulation (rhesus monkeys): - Male rhesus monkeys (4–6 kg) trained to self-administer heroin (0.1 mg/kg/infusion) were administered a single intramuscular injection of long-acting naltrexone depot (30 mg/kg, formulated as a microsphere suspension in aqueous buffer). Heroin self-administration was measured daily for 28 days, with infusions recorded via a computerized operant conditioning system. Blood samples were collected weekly to measure plasma naltrexone concentrations [2]
4. Diet-induced obesity model (rats): - Male Sprague-Dawley rats (180–200 g) were fed a high-fat diet (45% kcal from fat) for 8 weeks to induce obesity. Rats were then randomized to vehicle (0.5% methylcellulose), naltrexone (3 mg/kg, dissolved in vehicle), bupropion (10 mg/kg), or combination groups. Drugs were administered via oral gavage once daily for 4 weeks. Body weight was measured weekly, and food intake was recorded daily. At the end of the study, rats were euthanized, and epididymal fat pads were excised and weighed [5]

Absorption, Distribution and Excretion
Naltrexone is well absorbed orally, but undergoes significant first-pass metabolism, with an estimated oral bioavailability of 5% to 40%. The parent drug and its metabolites are primarily excreted by the kidneys (53% to 79% of the dose), but less than 2% of the oral dose is excreted unchanged in the urine, and fecal excretion is less common. Renal clearance of naltrexone ranges from 30 to 127 mL/min, suggesting that renal excretion is primarily via glomerular filtration. 1350 L [intravenous administration] ~ 3.5 L/min [after intravenous administration] Naltrexone hydrochloride is rapidly and almost completely (approximately 96%) absorbed from the gastrointestinal tract after oral administration, but undergoes extensive first-pass metabolism in the liver. Only 5% to 40% of the drug enters the systemic circulation unchanged after oral administration. Significant individual variability in drug absorption has been reported within 24 hours after a single dose. The bioavailability of naltrexone hydrochloride tablets is reportedly similar to that of the oral solution (not marketed in the US). Following oral tablet administration, peak plasma concentrations of naltrexone and its major metabolite, 6-β-naltrexol, are typically reached within 1 hour; after oral solution administration, peak concentrations are reached within 0.6 hours. Due to significant first-pass metabolism of oral naltrexone, plasma concentrations of 6-β-naltrexol are significantly higher than those of the corresponding naltrexone. The area under the serum concentration-time curve (AUC) of 6-β-naltrexol is 10–30 times higher than that of naltrexone after oral administration. In healthy individuals, after a single or multiple (i.e., once daily) oral dose of 50 mg naltrexone hydrochloride, the average peak plasma concentrations of naltrexone and 6-β-naltrexol are 10.6–13.7 ng/mL and 109–139 ng/mL, respectively. With prolonged use of this drug, accumulation of naltrexone and/or 6-β-naltrexol appears to be rare, or even nonexistent. Following prolonged use of naltrexone, plasma concentrations of 6-β-naltrexol were at least 40% higher than those following a single dose. However, in most patients, plasma concentrations of naltrexone and 6-β-naltrexol were similar 24 hours after each dose following prolonged administration to those following a single dose. Naltrexone hydrochloride is widely distributed throughout the body, but significant individual variability in its distribution parameters has been reported within 24 hours following a single oral dose. In rats, the drug can be distributed into the cerebrospinal fluid within 30 minutes after subcutaneous injection of a radiolabeled drug. Cerebrospinal fluid naltrexone concentrations have been reported to be approximately 30% of the peak plasma concentration at the same time point in animals. Studies have shown that naltrexone and its metabolites can be distributed in saliva and erythrocytes in humans after oral administration. For more complete data on the absorption, distribution, and excretion of naltrexone (13 in total), please visit the HSDB records page. Metabolism/Metabolites Hepatic metabolism. Following oral administration, naltrexone undergoes extensive biotransformation, metabolizing into 6β-naltrexol (which may contribute to its therapeutic effect) and other minor metabolites. Naltrexone is primarily metabolized in the liver, where its 6-keto group is reduced to 6β-naltrexol (6β-hydroxynaltrexone). Naltrexone is also metabolized by catechol-O-methyltransferase (COMT) to 2-hydroxy-3-methoxy-6-β-naltrexol (HMN) and 2-hydroxy-3-methoxynaltrexone. Several minor metabolites have also been identified, including norhydroxymorphone and 3-methoxy-6-β-naltrexol. Because oral administration, rather than intramuscular injection, of naltrexone results in significant first-pass hepatic metabolism, the concentration of 6-β-naltrexol after intramuscular injection is significantly lower than that after oral administration. Long-term use of naltrexone does not appear to inhibit or induce its own metabolism. Cytochrome P-450 (CYP) isoenzymes are not involved in the metabolism of naltrexone. Naltrexone and its metabolites are bound to glucuronic acid. The main components of drugs and their metabolites in plasma and urine are conjugated metabolites. Drugs and their metabolites may undergo enterohepatic circulation. Metabolites of naltrexone may contribute to its opioid receptor antagonistic activity. Similar to naltrexone, 6-β-naltrexol is a relatively pure opioid receptor antagonist, with an efficacy of approximately 6-8% that of naltrexone in inducing withdrawal symptoms in morphine-dependent dogs and approximately 1.25-2% in mice. Because 2-hydroxy-3-methoxy-6-β-naltrexol (HMN) has a weak affinity for opioid receptors, it may not contribute significantly to the opioid receptor antagonistic activity of naltrexone; however, the in vivo opioid receptor antagonistic activity of HMN or 2-hydroxy-3-methoxynaltrexone has not been studied. Normethoxymorphone, a minor metabolite of naltrexone, is a potent opioid agonist and may explain the occasional agonist activity (e.g., miosis) observed in patients taking naltrexone. Naltrexone and its metabolites (unbound and bound forms) are primarily excreted in the urine via glomerular filtration; 6-β-naltrexol, bound 6-β-naltrexol, and bound naltrexone are also excreted via tubular secretion. Naltrexone may also be partially reabsorbed by the renal tubules. After a single or multiple oral dose of naltrexone hydrochloride, approximately 38-60% or 70% of the dose is recovered in the urine, primarily in the form of 6-β-naltrexol (bound and unbound). Most of the oral dose of naltrexone is excreted in the urine within 4 hours. Within 24 hours, less than 2% of the oral dose is excreted unchanged in the urine. Approximately 5-10%, 19-35%, 7-16%, 3.5-4.6%, and 0.45% of the oral dose are excreted in the urine as conjugated naltrexone, 6-β-naltrexol, conjugated 6-β-naltrexol, 2-hydroxy-3-methoxy-6-β-naltrexol (HMN), and 2-hydroxy-3-methoxynaltrexone, respectively. Following a single or multiple oral administration, less than 5% of the dose is excreted in the feces within 24 hours, primarily as 6-β-naltrexol. In a patient who has taken 50 mg of radiolabeled naltrexone orally, approximately 93% of the radiolabeled dose is excreted within 133 hours; of this, approximately 79% and 14% are excreted in the urine and feces, respectively. Following intramuscular injection of naltrexone extended-release formulation, the half-lives of naltrexone and 6-β-naltrexol are 5-10 days. For more complete data on the metabolism/metabolites of naltrexone (a total of 6 metabolites), please visit the HSDB record page. Known metabolites of naltrexone include naltrexone-3-glucuronide. Hepatic metabolism: After oral administration, naltrexone undergoes extensive biotransformation, metabolizing into 6β-naltrexol (which may contribute to its therapeutic effect) and other minor metabolites. Elimination pathway: The parent drug and its metabolites are primarily excreted by the kidneys (53% to 79% of the dose), but less than 2% of the oral dose is excreted in the urine as unmetabolized naltrexone, and fecal excretion is a secondary elimination pathway. Renal clearance of naltrexone ranges from 30 to 127 mL/min, suggesting that it is primarily cleared by glomerular filtration. Half-life: naltrexone is 4 hours, and the active metabolite 6β-naltrexol is 13 hours.

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Biological half-life
Naltrexone has a half-life of 4 hours, and its active metabolite 6β-naltrexol has a half-life of 13 hours.
After a single oral dose or during long-term use, the plasma concentrations of naltrexone and its major metabolite 6β-naltrexol show a biphasic decrease within the first 24 hours. After single or multiple oral doses of naltrexone hydrochloride, the mean plasma half-lives of naltrexone and 6β-naltrexol in the initial phase (t1/2 α) are 1.1–3.9 hours and 2.3–3.1 hours, respectively, and the mean plasma half-lives in the terminal phase (t1/2 β) are 9.7–10.3 hours and 11.4–16.8 hours, respectively. It has been reported that after oral administration of naltrexone and 6-β-naltrexol, their plasma concentrations exhibit a three-phase decrease. The terminal elimination half-lives of naltrexone and 6-β-naltrexol at 24 hours post-administration are 96 hours and 18 hours, respectively, which may be due to the initial distribution of the drugs to tissues followed by redistribution into the systemic circulation. This study investigated the pharmacokinetics of naltrexone hydrochloride (NTX) and naltrexone glucuronide in dogs using high-performance liquid chromatography-electrochemical detection with naloxone as an internal standard. Following intravenous injection of 5 mg NTX or oral administration of 10 mg NTX, the elimination half-lives of NTX were 78 ± 6 minutes and 74 ± 6 minutes, respectively. …The major metabolite of NTX in canine plasma is a β-glucuronidase-hydrolyzable conjugate. Following intravenous injection and oral administration of NTX, the elimination half-lives of glucuronide from plasma were 3.4 hours and 12.6 hours, respectively.

Toxicity Summary
Identification and Uses: Naltrexone is an anesthetic antagonist. It is also used to treat alcohol dependence. Naltrexone hydrochloride is designated an orphan drug by the U.S. Food and Drug Administration (FDA) for opioid withdrawal. Human Studies: Naltrexone competes with opioid receptors and displaces opioids from these receptors, thereby reversing their effects. It is capable of antagonizing all opioid receptors. The mechanism of action of naltrexone in treating alcohol dependence is not yet clear. In one study, patients received 800 mg of naltrexone hydrochloride daily for one week without toxicity. However, lower doses have been reported to be hepatotoxic in some patients. In several healthy subjects, no serious adverse reactions were observed after a single injection of up to 784 mg of naltrexone (extended-release intramuscular injection). Naltrexone is not associated with the high neonatal mortality rate or congenital abnormalities commonly seen in newborns exposed to methadone. In vitro studies have shown that naltrexone can cause mutations and chromosomal damage in human lymphocytes. Animal studies: Acute toxicity of naltrexone in mice, rats, and dogs resulted in tonic-clonic seizures and/or respiratory failure, ultimately leading to death. Subcutaneous injection of 100 mg/kg in monkeys caused weight loss, while subcutaneous injection of 300 mg/kg caused collapse, seizures, and death. Oral administration of 1 g/kg in monkeys caused decreased activity, salivation, and vomiting, while oral administration of 3 g/kg caused seizures and death. In unanesthetized dogs, intravenous injection of 5–80 μg/kg naltrexone hydrochloride caused bradycardia, but respiratory rate, blood pressure, arterial blood gas, and electroencephalogram remained unchanged throughout the dose range. In cats, intravenous injection of 1 mg/kg resulted in a decrease of approximately 48% in whole-brain oxygen consumption and approximately 40% in whole-brain and pontine blood flow within 20 minutes. A two-year study on the carcinogenicity of naltrexone found an increased incidence of mesothelioma in male rats and an increased incidence of vascular tumors in both male and female rats. In several other two-year mouse or rat studies, no evidence of carcinogenicity was observed with daily administration of naltrexone at doses of 30 or 100 mg/kg. Daily administration of naltrexone at a dose of 100 mg/kg to rats increased the incidence of pseudopregnancy and decreased the pregnancy rate in mated rats. Naltrexone did not show chromosomal breakage in vivo mouse micronucleus assays. No evidence of genotoxicity was observed in a range of other in vitro assays, including bacterial and yeast gene mutation assays and another mammalian cell line chromosomal aberration assay. However, mutagenic changes and chromosomal damage were observed in in vitro assays using Chinese hamster ovary cells, Drosophila recessive lethal assays, and nonspecific DNA repair assays using E. coli and WI-38 cells. Ecotoxicity Study: To assess the effect of season (gonadal maturation stage) on the regulation of luteinizing hormone (LH) secretion by endogenous opioid peptides in fish, sexually mature male carp (Cyprinus carpio L.) were intravenously injected with naltrexone (5 or 50 μg/kg)—an opioid receptor antagonist—during the natural spawning period (June) or the gonadal recovery period (December). In June, naltrexone significantly reduced LH levels compared to male carp injected with saline. In December, there was no difference between carp injected with saline and those injected with naltrexone. Naltrexone is a pure opioid antagonist with virtually no agonist activity. The mechanism of action of naltrexone in treating alcohol poisoning is unclear; however, preclinical data suggest that the endogenous opioid system may be involved. Naltrexone is thought to act as a competitive antagonist of mc, κ, and δ receptors in the central nervous system, with the highest affinity for μ receptors. Naltrexone competitively binds to these receptors and may block the effects of endogenous opioids. This antagonizes most of the subjective and objective effects of opioids, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opioid antagonist and may contribute to the drug's antagonistic activity.

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Hepatotoxicity
Naltrexone treatment is typically used in patients with a high prevalence of underlying liver disease (injector drug use or alcoholism), and the incidence of elevated serum enzymes varies (0% to 50%). Approximately 1% of patients experience serum enzyme levels exceeding three times the upper limit of normal, sometimes leading to discontinuation of treatment. However, multiple studies have shown that the incidence of ALT elevation during naltrexone treatment is similar to that in the placebo group. Most elevations in serum transaminases during naltrexone treatment are mild and self-limiting, returning to normal with continued treatment. Although several rare cases of acute, clinically significant liver disease have been reported in patients taking naltrexone, the role of this drug in liver injury is not always clear, and the clinical characteristics of this injury have not been clearly described. Therefore, although naltrexone is generally considered to be hepatotoxic, there is no conclusive evidence that it is associated with cases of clinically significant liver injury. Probability Score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Use ◉ Overview of Lactation Use
Limited data suggest that naltrexone is minimally excreted into breast milk. If a mother needs to take naltrexone, this is not a reason to discontinue breastfeeding.
◉ Effects on Breastfed Infants
A mother who took 50 mg of naltrexone orally daily during pregnancy and lactation reported that her 1.5-month-old breastfed infant was healthy and did not experience any naltrexone-related adverse reactions.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date. Protein Binding: 21% binds to plasma proteins within the therapeutic dose range. Toxicity Data: LD50: 1,100–1,550 mg/kg (oral, mouse) LD50: 1,450 mg/kg (oral, rat) LD50: 1,490 mg/kg (oral, guinea pig) Interactions: Naltrexone may enhance the central nervous system effects of yohimbine (anxiety, tremor, nausea, palpitations) and increase plasma cortisol levels. Naltrexone is a clinically approved treatment for alcohol addiction. We aimed to investigate the efficacy of naltrexone in combination with cocaine and the association of these substances with early gene expression in the prefrontal cortex of rats. We used a chronic operated alcohol self-dosing model and pharmacy-prescribed alcohol addiction treatments to maximize predictive validity in humans. We performed real-time PCR analysis to determine gene expression levels in the prefrontal cortex. Only the highest doses of naltrexone (1, 3, and 10 mg/kg, orally) reduced the response to ethanol. Cocaine increased ethanol self-administration in a dose-dependent manner (2.5, 10, and 20 mg/kg, intraperitoneally) and reversed the naltrexone-induced reduction in ethanol self-administration. Naltrexone failed to prevent the increase in motor activity induced by cocaine in these animals. Long-term ethanol self-administration reduced the expression of the C-fos gene in the rat prefrontal cortex by 4 to 12-fold and increased the expression of COX-2 (up to 4-fold) and Homer1a genes. Naltrexone prevented long-term ethanol self-administration, but cocaine completely reversed this effect. These results suggest that cocaine may counteract the efficacy of naltrexone as a treatment for alcohol addiction. The ethanol-induced reduction in C-fos gene expression in the prefrontal cortex reveals abnormal activity in these neurons, which may be related to compulsive ethanol intake, control of reward-related areas, and the behavioral phenotype of ethanol addiction. In appetite studies, drugs are often introduced into clinical trials based on outcomes (reduced food intake/weight gain), with insufficient attention paid to the process (behavioral analysis). Although bupropion and naltrexone (alone or in combination) reduce food intake in rodents and humans, their effects on behavior in feeding tests have not been adequately studied. This study aimed to evaluate the behavioral specificity of anorexia induced by bupropion, naltrexone, and their combination. Using video analysis, the behavioral effects of acute systemic treatment with bupropion (10.0–40.0 mg/kg), naltrexone (0.1–3.0 mg/kg), and bupropion (20 mg/kg) combined with naltrexone (0.1–1.0 mg/kg) were characterized in undeprived male rats exposed to palatable pureed food for 1 hour. A focus was placed on the behavioral satiety sequence (BSS). In Experiment 1, an anorexia induced by 40 mg/kg bupropion was accompanied by significant psychomotor arousal and complete disruption of the BSS. In Experiment 2, anorexia induced by 3 mg/kg naltrexone was accompanied by an accelerated BSS, but other aspects remained normal. In Experiment 3, concurrent administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorexia (including reduced food intake), but the addition of an opioid receptor antagonist also simultaneously reduced the psychomotor excitatory response induced by atypical antidepressants. Low-dose combination therapy with naltrexone and bupropion was more effective in suppressing appetite than either drug alone, and also had the advantage of reducing some of the adverse effects of bupropion. Opioid antagonists (e.g., naltrexone) and positive modulators of γ-aminobutyric acid A (GABAA) receptors (e.g., alprazolam) can slightly reduce the abuse-related effects of stimulants such as amphetamines. Using higher doses to achieve better efficacy is not feasible due to side effects. Combination therapy with naltrexone and alprazolam may safely and effectively improve efficacy while avoiding the adverse effects of single-component drugs. This preliminary study aimed to verify the hypothesis that acute pretreatment with naltrexone and alprazolam does not produce clinically problematic physiological effects or negative subjective effects, and significantly reduces the positive subjective effects of dextroamphetamine compared to either drug alone. Eight non-treatment-seeking, stimulant users participated in an outpatient trial. Subjects received acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg) followed by oral dextroamphetamine (0, 15, and 30 mg). Subjective effects, psychomotor task performance, and physiological parameters were collected. Oral dextroamphetamine produced typical physiological effects and stimulant-like positive subjective effects (e.g., scores of "active/alert/energetic," "well-behaved," and "excited" on the Visual Analogue Scale (VAS)). Pretreatment with naltrexone, alprazolam, or their combination did not produce clinically significant acute physiological effects or adverse subjective reactions. Both naltrexone and alprazolam significantly reduced some of the subjective reactions to dextroamphetamine. Combination therapy was more effective than either drug alone in reducing a variety of subjective reactions. Current findings support further evaluation of the efficacy of combination therapy of opioid receptor antagonists with GABAA positive modulators, using more clinically relevant experimental conditions, such as investigating the long-term effects of these drugs on methamphetamine self-administration.
For more complete data on naltrexone interactions (7 items), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice: 1.1–1.55 g/kg
Oral LD50 in rats: 1.45 g/kg
Oral LD50 in guinea pigs: 1.49 g/kg
Oral LD50 in monkeys: 3.0 g/kg
For more complete data on naltrexone non-human toxicity values (8 items), please visit the HSDB record page.

[1]. Low Doses Naltrexone: The Potential Benefit Effects for its Use in Patients with Cancer. Curr Drug Res Rev. 2021;13(2):86-89.

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[3]. Mannelli P, Peindl KS, Wu LT. Pharmacological enhancement of naltrexone treatment for opioid dependence: a review. Subst Abuse Rehabil. 2011 Jun;2011(2):113-123.

[4]. Swift R, Oslin DW, Alexander M, Forman R. Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review. J Stud Alcohol Drugs. 2011 Nov;72(6):1012-8.

[5]. Makowski CT, Gwinn KM, Hurren KM. Naltrexone/bupropion: an investigational combination for weight loss and maintenance. Obes Facts. 2011;4(6):489-94.

[6]. Hulse GK. Improving Clinical Outcomes for Naltrexone as a Management of Problem Alcohol Use. Br J Clin Pharmacol. 2012 Sep 5. doi: 10.1111/j.1365-2125.2012.04452.x.

[7]. Naltrexone.

Naltrexone is an organic heteropentacyclic compound, a substituted derivative of naloxone in which the allyl group attached to the nitrogen atom is replaced by a cyclopropylmethyl group. It is a μ-opioid receptor antagonist used to treat alcohol dependence. It also has multiple functions, including as a μ-opioid receptor antagonist, central nervous system depressant, antidote for environmental pollutants, exogenous substances, and opioid poisoning. It is an organic heteropentacyclic compound belonging to the morphine class and is also a cyclopropane class of compounds. It is the conjugate base of naltrexone (1+). It is a derivative of norhydroxymorphone and an N-cyclopropylmethyl analog of naloxone. It is an anesthetic antagonist, effective orally, with a longer duration of action and greater potency than naloxone, and has been proposed for the treatment of heroin addiction. The U.S. Food and Drug Administration (FDA) has approved naltrexone for the treatment of alcohol dependence. Naltrexone is an opioid receptor antagonist. The mechanism of action of naltrexone is as an opioid receptor antagonist. Naltrexone is a synthetic opioid receptor antagonist used to prevent relapse into opioid addiction and alcohol dependence. Elevated serum enzyme levels are rare during naltrexone treatment, and clinically significant liver damage is uncommon. Naltrexone is a norhydroxymorphone derivative with competitive opioid receptor antagonism. It reverses the effects of opioid analgesics by binding to various opioid receptors in the central nervous system, including μ, κ, and γ opioid receptors. This results in inhibition of the typical effects of opioid analgesics, including analgesia, euphoria, sedation, respiratory depression, mydriasis, bradycardia, and physical dependence. Naltrexone has a longer duration of action and greater potency than naloxone. Naltrexone is a norhydroxymorphone derivative and an N-cyclopropylmethyl analogue of naloxone. It is an anesthetic antagonist, orally effective, with a longer duration of action and greater potency than naloxone, and has been proposed for the treatment of heroin addiction. The U.S. Food and Drug Administration (FDA) has approved naltrexone for the treatment of alcohol dependence. [PubChem]
Naltrexone is a derivative of norhydroxymorphone and an N-cyclopropylmethyl analogue of naloxone. It is an anesthetic antagonist, orally effective, with a longer duration of action and greater potency than naloxone, and has been proposed for the treatment of heroin addiction. The U.S. Food and Drug Administration (FDA) has approved naltrexone for the treatment of alcohol dependence.
See also: naltrexone hydrochloride (salt form).
Pharmaceutical Indications

For use as adjunct to a medically supervised behavior modification program to maintain opioid withdrawal in patients who have previously developed physical dependence on opioids and have successfully completed withdrawal treatment. It may also be used in combination with a behavior modification program to treat alcohol dependence.
FDA Label
Mechanism of Action

Naltrexone is a pure opioid receptor antagonist with little or no agonist activity. The mechanism of action of naltrexone in treating alcohol dependence is not fully understood; however, preclinical data suggest that the endogenous opioid system may be involved. Naltrexone is believed to act as a competitive antagonist of mc, κ, and δ receptors in the central nervous system, with the highest affinity for μ receptors. Naltrexone competitively binds to these receptors and may block the effects of endogenous opioids. This results in the antagonization of most subjective and objective effects of opioids, including respiratory depression, pupillary constriction, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opioid antagonist and may contribute to the drug's antagonistic activity. Naltrexone competes with opioids for opioid receptors and displaces them from these receptors, thereby reversing their effects. It is capable of antagonizing all opioid receptors.
Therapeutic Uses
Anesthetic Antagonist
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). Naltrexone is listed in the database. Naltrexone hydrochloride is designated an orphan drug by the U.S. Food and Drug Administration (FDA), is administered orally, and utilizes its opioid antagonistic effect as an adjunct to supervised behavioral modification programs to maintain opioid withdrawal (opioid-free status) in patients who have previously developed physical dependence on opioids and have successfully completed withdrawal treatment. /Listed on US Product Label/
Naltrexone is available orally or intramuscularly for the treatment of alcohol dependence and should be used in conjunction with a comprehensive treatment regimen that includes psychosocial support. /Listed on US Product Label/
For more complete data on the therapeutic uses of naltrexone (31 items in total), please visit the HSDB record page.

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Drug Warning
Naltrexone hydrochloride is contraindicated in: 1. Patients currently receiving opioid analgesia. 2. Patients currently dependent on opioids, including those currently receiving maintenance therapy with opioid agonists (e.g., methadone) or partial agonists (e.g., buprenorphine). 3. Patients in the acute phase of opioid withdrawal. 4. Individuals who have failed a naloxone challenge test or have a positive urine opioid screening. 5. Individuals with a history of hypersensitivity to naltrexone hydrochloride or any other component of this product. It is currently unknown whether there is cross-sensitivity between this product and naloxone or phenanthrene-containing opioids. Cases of hepatitis and clinically significant liver dysfunction associated with naltrexone hydrochloride exposure have been observed during clinical development programs and post-marketing surveillance. Transient, asymptomatic elevations of liver transaminases have also been observed during clinical trials and post-marketing surveillance. When patients develop elevated transaminases, other potential pathogenic or contributing factors are often identified, including a pre-existing alcoholic liver disease, hepatitis B and/or C virus infection, and concomitant use of other potentially hepatotoxic medications. While clinically significant liver dysfunction is not typically considered a sign of opioid withdrawal, sudden opioid withdrawal can lead to systemic sequelae, including acute liver injury. Patients should be informed of the risk of liver injury and advised to seek medical attention if they develop symptoms of acute hepatitis. Naltrexone hydrochloride should be discontinued immediately if symptoms and/or signs of acute hepatitis develop. Naltrexone AUC has been reported to be approximately 5-fold and 10-fold higher in patients with compensated and decompensated cirrhosis, respectively, compared to subjects with normal liver function. These data also suggest that altered naltrexone bioavailability is associated with the severity of liver disease. Currently, no studies have been conducted evaluating potential interactions between naltrexone hydrochloride and medications other than opioids. Therefore, caution is advised if naltrexone hydrochloride is to be taken concurrently with other medications. The safety and efficacy of naltrexone hydrochloride used concurrently with disulfiram are not well understood, and the concurrent use of two potentially hepatotoxic drugs is generally not recommended unless the potential benefits outweigh the known risks. Drowsiness and somnolence have been reported after taking naltrexone hydrochloride and thioridazine. Patients taking naltrexone hydrochloride may not benefit from opioid-containing medications (such as cough and cold medicines, antidiarrheal medications, and opioid analgesics). In emergency situations, if opioid analgesics must be administered to patients receiving naltrexone hydrochloride, the required opioid dose may be higher than usual, and the resulting respiratory depression may be deeper and more persistent. For more complete data on naltrexone (36 in total), please visit the HSDB records page.

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Pharmacodynamics
Naltrexone is a pure opioid antagonist, a synthetic analogue of hydroxymorphine, and does not possess opioid agonist properties. Naltrexone is indicated for the treatment of alcohol dependence and for blocking the effects of exogenous opioids. It can significantly attenuate or completely block (reversibly) the subjective effects of intravenously administered opioids. When used in combination with morphine long-term, naltrexone can block physical dependence on morphine, heroin, and other opioids. In patients with physiological opioid dependence, naltrexone can induce withdrawal symptoms.

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- Background: Naltrexone is a synthetic opioid receptor antagonist that was approved by the FDA in 1984 for the treatment of opioid dependence, in 1994 for the treatment of alcohol dependence, and in 2010 (in combination with bupropion) for chronic weight management [2][5][6]
- Mechanism of action: - For addiction: Blocks μ-opioid receptor (MOR)-mediated reward pathways (e.g., the mesolimbic dopamine system), thereby reducing cravings for opioids/alcohol and enhancing their effects [2][3][6]
- For cancer (low dose): Inhibits NF-κB activation (reducing inflammation and tumor cell proliferation) and modulates immune function (enhancing natural killer cell activity) [1]
- For weight loss (combination therapy): Naltrexone blocks hypothalamic opioid receptors (reducing food cravings), while bupropion inhibits dopamine/norepinephrine reuptake (suppressing appetite) [5]
- Clinical efficacy: - Opioid dependence: Daily oral administration of naltrexone 50 mg reduced the relapse rate by 40-50% within 6 months compared to placebo [3]
- Alcohol dependence: Daily oral administration of naltrexone 50 mg reduced the number of days of heavy drinking by 30-40% compared to placebo [6]
- Weight loss: Naltrexone (8 mg) + bupropion (90 mg) twice daily reduced the weight of obese patients by 5-7% after 1 year compared to placebo [5]
- Cancer (preclinical): Low-dose naltrexone enhanced the efficacy of chemotherapy (e.g., paclitaxel) in MCF-7 xenograft tumors (tumor volume reduction rate increased from 40% to 65% after combination therapy) [1]
- Adherence challenge: Due to the lack of synergistic effect, oral naltrexone has poor adherence in addicted patients (30-40% at 6 months); long-acting extended-release formulations can improve adherence to 70-80% [2][4]
- FDA Warning: There is a risk of opioid withdrawal if used in patients with opioid dependence; avoid use in patients with acute hepatitis or severe liver dysfunction [2][6]

C20H23NO4

341.40

341.162

C, 70.36; H, 6.79; N, 4.10; O, 18.75

16590-41-3

Naltrexone-d4;2070009-29-7; 16590-41-3 (free);16676-29-2 (HCl);

5360515

White to off-white solid powder

1.5±0.1 g/cm3

558.1±50.0 °C at 760 mmHg

168-170ºC

291.4±30.1 °C

0.0±1.6 mmHg at 25°C

1.709

1.8

2

5

2

25

621

4

C1CC1CN2CC[C@]34[C@@H]5C(=O)CC[C@]3([C@H]2CC6=C4C(=C(C=C6)O)O5)O

DQCKKXVULJGBQN-XFWGSAIBSA-N

InChI=1S/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19+,20-/m1/s1

(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

naltrexone; 16590-41-3; Vivitrol; Vivitrex; Celupan; N-Cyclopropylmethylnoroxymorphone; Naltrexona; Naltrexonum;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 31 mg/mL (90.80 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)