Agmatine and Near-Death Experiences -- Neurotransmitter.net

The twenty-first century search for a scientific explanation of near-death experiences (NDEs) is likely to benefit from the rapidly growing knowledge base generated by neuroscientists and other researchers. To date, the most plausible theory has been outlined by Dr. Karl Jansen (1996). Conditions that may induce NDEs (low oxygen, low blood flow, low blood sugar, temporal lobe epilepsy, etc.) have also been shown to cause excess extracellular levels of glutamate to accumulate in the brain; when high concentrations of glutamate bind to N-methyl-D-aspartate (NMDA) receptors, excitotoxicity can result (Jansen, 1996). Jansen (1996) has proposed that an endogenous NMDA antagonist may be released under certain conditions to protect cells from excitotoxicity. An exogenous NMDA antagonist, ketamine, is known to be able to reproduce all of the features which are commonly associated with NDEs; thus, an endogenous NMDA antagonist with a primarily neuroprotective function may also induce NDEs under certain circumstances (Jansen, 1996).

Jansen (2004) has suggested that the identity of the endogenous NMDA antagonist may be NAAG (N-acetyl-aspartyl-glutamate), kynurenic acid, or magnesium. NAAG, however, has been shown to lack both antagonist and agonist activity in cerebellar granule neurons (Losi et al., 2004). If NAAG does interact with NMDA receptors, it is likely to be a weak partial agonist rather than an antagonist (Valivullah et al., 1994). In addition, kynurenic acid is an antagonist at the glycineB binding site on NMDA receptors rather than at a site within the NMDA channel pore (Harsing et al., 2001). Based on experiments involving rats, Karcz-Kubicha et al. (1999) have suggested that glycineB antagonists have a low psychotomimetic potential. With regards to magnesium ions, little evidence exists to support a role for these ions in near-death experiences.

To date, the only neurotransmitter or neuromodulator known to exhibit antagonist activity at NMDA receptors at a non-glycineB site is agmatine. In rat hippocampal neurons, agmatine has been shown to block NMDA channels because of an interaction between agmatine's guanidine group and the channel pores (Yang and Reis, 1999). Furthermore, in neurons and PC12 cells, agmatine blocks the induction of excitotoxicity by glutamate (Zhu et al., 2003). Agmatine also acts as an agonist at imidazoline receptors, inhibits nitric oxide synthase, and interacts with alpha-2-adrenoceptors (Berkels et al., 2004). In neonatal rats exposed to hypoxic-ischemic conditions, levels of agmatine increased 2- to 3-fold (Yangzheng et al., 2002). Yangzheng et al. (2002) have speculated that agmatine reduces brain injury in neonatal rats exposed to hypoxia and ischemia as a result of its inhibitory effect on nitric oxide synthase. In addition, Gilad et al. (1996) found that agmatine is neuroprotective in both in vitro and in vivo rodent models of neurotoxic and ischemic brain injuries. Because of its multiple interactions with receptors and enzymes, agmatine represents a neurotransmitter that could increase in concentration during conditions such as cardiac arrest to prevent a variety of injurious brain activities.

Agmatine may offer protective benefits such as neuroprotection and anxiolysis in response to certain stressful conditions (Aricioglu et al., 2003). In rats and mice, agmatine induces antidepressant-like effects (Li et al., 2003). In addition, agmatine reduces anxious behavior in rats exposed to the elevated plus maze task (Lavinsky, 2003). Halaris et al. (1999) have found that plasma agmatine concentrations are significantly elevated in depressed patients compared to healthy controls. Greyson (1986) reported that 16 of 61 (26.2%) patients admitted to a hospital for attempted suicide had experienced a near-death episode after the attempt. Thus, a role for agmatine as an anti-stress factor that could induce near-death experiences when released in sufficient quantities in a subset of individuals seems plausible.

Where in the brain might agmatine induce the features of a near-death experience? A key feature of many near-death experiences is the out of body experience. Penfield (1941) found that electrical stimulation of the right superior temporal gyrus in a patient with epilepsy could induce an out of body experience. Blanke et al. (2002) demonstrated that electrical stimulation of the right angular gyrus in a patient with epilepsy could induce an out of body experience as well. Both sets of stimulation sites lied in the right temporo-parietal region posterior to the post-central gyrus (Tong, 2003). In five patients that experienced out of body experiences of neurological origin, brain damage or brain dysfunction was localized to the temporo-parietal junction (Blanke et al., 2004). In patients with epilepsy, a small area in this region has been shown to have an integrative function for inputs from the somatosensory, auditory, and visual modalities (Matsuhashi et al., 2004). Blanke et al. (2004) suggested that ambiguous input from proprioceptive, tactile, visual, and vestibular sensory systems to the temporo-parietal junction could be involved in the precipitation of out of body experiences. Considering the fact that electrical stimulation to the right temporo-parietal junction can result in out of body experiences but not near-death experiences, a localized influence of agmatine on near-death experiences seems unlikely.

The NMDA receptor plays a critical role in a phenomenon known as auditory mismatch negativity; selective current flow through open, unblocked NMDA channels is likely to mediate mismatch negativity (Javitt et al., 1996). Ketamine, an NMDA receptor antagonist, has been shown to induce auditory mismatch negativity deficits in healthy volunteers (Umbricht et al., 2000; Kreitschmann-Andermahr et al., 2001). Visual mismatch negativity is a similar phenomenon that detects stimulus change in the visual modality; when standard visual stimuli are repeated, infrequently presented deviant stimuli produce an event related potential known as mismatch negativity (Stagg et al., 2004). Astikainen et al. (2001) found that mismatch negativity is likely to detect changes in somatosensory input as well. Although mismatch negativity has not been demonstrated for other sensory systems, it may play a similar role in detecting changes in vestibular and tactile input. Thus, the ambiguity of sensory input to the right temporo-parietal junction during out of body experiences as proposed by Blanke et al. (2004) may be a result of agmatine- induced NMDA antagonism in individuals undergoing near death experiences.

In conclusion, a variety of evidence seems to suggest that excess extracellular agmatine may induce near-death experiences in susceptible individuals. Because agmatine is an NMDA antagonist released in substantial quantities in hypoxic-ischemic conditions, it satisfies the two key criteria that must be satisfied by any potential endogenous mediator of near-death experiences. Future research should help to further clarify the role of agmatine in near-death situations.