Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial

Abstract

Objective. Agmatine, decarboxylated arginine, was shown in preclinical studies to exert efficacious neuroprotection by interacting with multiple molecular targets. This study was designed to ascertain safety and efficacy of dietary agmatine sulfate in herniated lumbar disc-associated radiculopathy. Study Design. First, an open-label dose escalation study was performed to assess the safety and side-effects of agmatine sulfate. In the follow-up study, participants diagnosed with herniated lumbar disc-associated radiculopathy were randomly assigned to receive either placebo or agmatine sulfate in a double-blind fashion. Methods. Participants in the first study were recruited consecutively into four cohorts who took the following escalating regimens: 1.335 g/day agmatine sulfate for 10 days, 2.670 g/day for 10 days, 3.560 g/day for 10 days, and 3.560 g/day for 21 days. Participants in the follow-up study were assigned to receive either placebo or agmatine sulfate, 2.670 g/day for 14 days. Primary outcome measures were pain using the visual analog scale, the McGill pain questionnaire and the Oswestry disability index, sensorimotor deficits, and health-related quality of life using the 36-item short form (SF-36) questionnaire. Secondary outcomes included other treatment options, and safety and tolerability assessment. Results. Safety parameters were within normal values in all participants of the first study. Three participants in the highest dose cohort had mild-to-moderate diarrhea and mild nausea during treatment, which disappeared upon treatment cessation. No other events were observed. In the follow-up study, 51 participants were randomly enrolled in the agmatine group and 48 in the placebo. Continuous improvement of symptoms occurred in both groups, but was more pronounced in the agmatine (analyzed n = 31) as compared with the placebo group (n = 30). Expressed as percent of baseline values, significantly enhanced improvement in average pain measures and in quality of life scores occurred after treatment in the agmatine group (26.7% and 70.8%, respectively) as compared with placebo (6.0% [P </= 0.05] and 20.0% [P </= 0.05], respectively). No treatment-related adverse events were noted. Conclusions. Dietary agmatine sulfate is safe and efficacious treatment for alleviating pain and improving quality of life in lumbar disc-associated radiculopathy. Study Registration. ClinicalTrials.gov Protocol Registration System Identifier: NCT00405041.

Attenuation of insulin resistance in rats by agmatine: role of SREBP-1c, mTOR and GLUT-2

“…AGM possesses an insulin-like action; it increases insulin release from pancreatic islet β-cells and decreases advanced glycated end products that control many of diabetic complications (Piletz et al 2013). AGM is considered to be safe when used for prolonged periods of time in humans (Keynan et al 2010;Gilad 2013, 2014).…”

Subcutaneous Toxicity of Agmatine in Rats

“…The agmatine sulfate powders or pills generally contain 250-750 mg agmatine sulfate per serving where daily intake can be up to 7500 mg/ day. 35 There are limited studies or case reports which stated that long-term agmatine use is safe in humans. 23,35 In one case, a daily dose of 2.67 g oral agmatine sulfate for 5 years was reported to be safe without evidence of any adverse effects.…”

“…35 There are limited studies or case reports which stated that long-term agmatine use is safe in humans. 23,35 In one case, a daily dose of 2.67 g oral agmatine sulfate for 5 years was reported to be safe without evidence of any adverse effects. The authors indicated that the periodic physical examinations and laboratory analyses revealed no adverse reactions.…”

“…In this study, only three patients had mild-to-moderate diarrhea and nausea as adverse effects. 35 On the other hand, limited animal studies also introduced evidence about the safety of agmatine. 36 In an animal study, oral agmatine sulfate administration with a daily dose of 100 mg/kg/day of adult Wistar albino rats for 95 days was reported to be also safe.…”

Effects of imidazoline I2 receptor ligands on acute nociception in rats

“…Imidazoline I 2 receptor ligands such as the purported endogenous I 2 receptor ligand, agmatine, and the selective synthetic I 2 receptor agonist, CR4056, have robust antihyperalgesic activity in animal models of inflammatory and neuropathic pain [4][5][6]. Agmatine is also effective in alleviating pain and facilitate recovery in humans suffering from lumbar disc-associated radiculopathy [7], and CR4056 is in the process of phase I clinical trial for neuropathic pain [4].…”