What if oxygen is a hallucinogen

Recently, researchers discovered that DMT binds to sigma-1 receptors , which are found throughout the human body and play a role in protecting cells from oxidative stress. This occurs when oxygen levels are too low, and can result in apoptosis , or cell death.

In a new study appearing in the journal Frontiers in Neuroscience , researchers investigated the protective effects of DMT on neurons and immune cells under hypoxic conditions, which refers to an extreme lack of oxygen. With oxygen concentrations of just 0. However, when tiny amounts of DMT were added to the equation, survival times were drastically increased, suggesting that the molecule does indeed protect cells from oxidative stress.

DMT may be responsible for the white lights and other "mystical" visions that people sometimes report following near-death experiences, although this cannot yet be confirmed. The team repeated the task using cells that had been engineered to lack sigma-1 receptors, and found that this completely eliminated the protective effects of DMT, confirming that the compound works by activating these receptors.

The driving force for diffusion of oxygen is determined by its partial pressure gradient between capillary blood and tissue cells and much less so by increased oxygen content [ 4 ].

The marked increase in oxygen tension gradient from the blood to metabolizing cells is a key mechanism by which hyperoxygenation of arterial blood can improve effective cellular oxygenation even at low rates of tissue blood flow. A recent surge of interest in the value of increasing the availability of oxygen to tissues in critical conditions yielded important studies like the one on early goal-directed therapy in sepsis [ 5 ] that assessed a resuscitation protocol aimed at increasing tissue oxygenation.

Regrettably, the specific value of oxygen therapy was not assessed in this study. The availability of oxygen to tissues is also determined by its effects on hemodynamic variables.

In healthy animals and humans, oxygen causes a temporary increase in blood pressure by increasing total peripheral vascular resistance secondary to systemic peripheral vasoconstriction [ 7 ]. This transient change is rapidly counterbalanced by a decrease in heart rate and cardiac output that prevents a sustained effect on arterial blood pressure [ 7 ].

The unique combination of hyperoxia-induced vasoconstriction and high blood oxygen tension affords an advantage by decreasing a vasogenic component of increased tissue hydrostatic pressure while preserving a high blood-to-tissue oxygen partial pressure gradient and is therefore considered beneficial in crush injury and compartment syndrome [ 8 ] as well as brain edema, particularly when the latter develops in situations in which additional indications for HBO therapy exist, such as carbon monoxide poisoning and air embolism [ 9 ].

Recent experimental evidence supports the role of hyperoxia in cerebral ischemic-anoxic insults such as stroke, head injury, near drowning, asphyxia, and cardiac arrest [ 10 ].

In the specific case of traumatic brain injury, it has repeatedly been shown that, although HBO causes cerebral vasoconstriction, it increases brain tissue pO 2 partial pressure of oxygen and restores mitochondrial redox potential [ 11 , 12 ].

NBO has also been shown to decrease intracranial pressure and improve indices of brain oxidative metabolism in patients with severe head injury [ 13 ]. A significant body of experimental data that suggested beneficial effects of hyperoxia in ischemic stroke was followed by clinical trials [ 14 - 16 ] that failed to demonstrate clear-cut benefits. Yet significant shortcomings of the available clinical data call for re-evaluation of the effect of hyperoxia on the outcome of stroke and on the possibility to use it to extend the narrow therapeutic time window for stroke thrombolysis [ 17 ].

Another area of controversy is the use of NBO in asphyxiated newborn infants. Later cumulative clinical experience [ 20 , 21 ] and systematic review of the literature [ 22 ] have not indicated a significant difference in the effectiveness of either gas source or in the final outcome in this specific group of patients.

Taken together, the available data definitely do not support an overall beneficial effect of hyperoxia in this condition, although the superiority of room air in neonatal resuscitation may still be regarded as controversial. In contrast to the knowledge on the effects of hyperoxia on central hemodynamics, much less is known about its effects on regional hemodynamics and microhemodynamics.

Studies that looked at hyperoxia-induced changes in regional hemodynamics in healthy animals both in normal atmospheric pressure [ 24 - 30 ] and in hyperbaric conditions [ 24 - 26 , 28 , 31 , 32 ] yielded conflicting results, indicating an increase, a decrease, or no change in regional blood flows to specific vascular beds. Only limited and scattered information on regional hemodynamic effects of hyperoxia in relevant models of disease is available.

In this regard, a study in an acute canine model of ischemia and reperfusion IR of the external iliac artery showed that HBO did not induce vasoconstriction in the affected regional vascular bed until oxygen deficit was corrected [ 33 ]. Such findings support suggestions that a dynamic situation may exist in which vasoconstriction is not always effective in severely hypoxic tissues and therefore may not limit the availability of oxygen during hyperoxic exposures and that hyperoxic vaso-constriction may resume after correction of the regional hypoxia.

Furthermore, in a severe rat model of hemorrhagic shock, we have shown that normobaric hyperoxia increased vascular resistance in skeletal muscle and did not change splanchnic and renal regional resistances.

This yielded redistribution of blood flow to the small intestine and kidneys 'at the expense' of skeletal muscle [ 34 ]. A similar divergent effect of normobaric hyperoxia that augmented hind-quarter vascular resistance without a significant effect on the superior mesenteric bed was also found in a rat model of splanchnic IR [ 35 ]. In this regard, NBO-induced redistribution of cardiac output to the hepatosplanchnic regions was recently reported in a pig model of severe sepsis [ 36 ].

NBO was also shown to redistribute blood flow to ischemic myocardium and improve contractile function during low-flow myocardial ischemia [ 37 ]. So the claim that hyperoxia is a universal vasoconstrictor in all vascular beds is an oversimplification both in normal and pathologic states. Furthermore, understanding of the effects of hyperoxia on regional hemodynamics cannot be based on simple extrapolations from healthy humans and animals and warrants careful evaluation in selected clinical states and their animal models.

Tissue hypoxia activates a large variety of vascular and inflammatory mediators that trigger local inflammation [ 38 ] and may lead to a systemic inflammatory response SIR that in many cases culminates in multiple organ dysfunction and multiple organ failure MOF [ 39 , 40 ]. The wish to prevent or treat hypoxia-induced inflammatory responses yielded studies that evaluated the effects of hyperoxia on the microvascular-inflammatory response.

The potential beneficial effects of hyperoxia are confronted by the understanding of the central role of reactive oxygen species ROS in IR injury [ 40 - 42 ]. The demonstration of increased production of ROS during exposure of normal tissues to hyperoxia evoked concerns that oxygen therapy could exacerbate IR injury. The seemingly rational unease related to the use of hyperoxia in IR must be weighed against a gradually growing body of evidence on beneficial effects of hyperoxia in diverse IR models [ 42 ].

Hyperoxia appears to exert a simultaneous effect on a number of steps in the proinflammatory cascades after IR, including interference with polymorphonuclear leukocyte PMNL adhesion and production of ROS. In this regard, HBO has been shown to decrease rolling and adhesion of PMNL in the microcirculation following IR of skeletal muscle [ 43 , 44 ], small bowel [ 35 , 45 ], skin flaps [ 46 ], heart [ 47 , 48 ], and liver [ 49 , 50 ] as well as after carbon monoxide poisoning [ 51 ].

Hyperoxia also reduces the expression of the endothelial adhesion molecules E-selectin [ 53 , 54 ] and ICAM-1 intracellular adhesion molecule-1 [ 42 , 52 ]. Hyperoxia is known to affect the production of nitric oxide NO mostly by inducing eNOS endothelial NO synthase protein production [ 55 ]. Increased NO levels may inhibit PMNL adhesion by inhibition of CD18 function and downregulation of endothelial adhesion molecule synthesis [ 55 , 56 ].

Furthermore, it has been shown in ischemic skin flaps that hyperoxia increases local endothelial surface superoxide dismutase activity [ 46 ]. This action may diminish the more distal proinflammatory events initiated by ROS after IR, and indeed HBO has been shown to decrease lipid peroxidation and oxidative stress in a number of IR models [ 49 , 51 , 57 , 58 ].

HBO was also shown to exert beneficial effects in other inflammatory conditions, including experimental colitis [ 59 , 60 ], Crohn disease [ 61 ], carrageenan-induced paw edema [ 62 ], and zymossan-induced SIR [ 63 , 64 ]. Detailed mechanisms of the salutary effects of hyperoxia in some of these conditions have not yet been fully elucidated. In addition to a predominant hyperacute proinflammatory response orchestrated mostly by its effects on PMNLs and macrophages, tissue hypoxia has been shown to provoke subsequent anti-inflammatory responses in macrophages [ 65 - 68 ], to downregulate proinflammatory anti-bacterial functions of T cells via augmented HIF-1a hypoxia inducible factor-1a activity [ 69 ], and to weaken local hypoxia-driven and adenosine A 2A receptor-mediated pulmonary anti-inflammatory mechanisms [ 70 ].

These observations may represent important subacute effects of hypoxia that help to harness an initial powerful and potentially destructive proinflammatory effect, may be a part of tissue repair processes, or may be an important component of a hypoinflammatory response manifested by some patients with sepsis and acute respiratory distress syndrome ARDS.

All in all, the ameliorating effects of hyperoxia on the acute net proinflammatory response after IR and other conditions may be related to direct inhibitory effects of oxygen on mechanisms that enhance PMNL rolling, adhesion, activation, and transmigration to tissues. Hyperoxia may also exert indirect effects on the inflammatory response simply by ameliorating tissue hypoxia — a key trigger of inflammation [ 38 ].

The effects of hyperoxia on subsequent stages of tissue responses to hypoxia and especially on the anti-inflammatory arm of that response await clarification. Sepsis is one of the most common clinical causes of SIR. In a study of early hyperdynamic porcine septic shock, Barth and colleagues [ 36 ] demonstrated beneficial effects of NBO on apoptosis in the liver and the lungs, on metabolic acidosis, and on renal function.

Buras and colleagues [ 72 ] studied the effects of hyperoxia at 1, 2. They also presented data suggesting that augmented production of the anti-inflammatory cytokine interleukin may be an important mechanism of the salutary effects of HBO in this model [ 72 ]. The steadily growing body of data on beneficial effects of hyperoxia in severe local and systemic inflammation warrants appropriate clinical studies to define its role as a clinically relevant modifier of hyperinflammation. HBO has been studied and used in a large variety of infections for over 40 years.

Early demonstrations of its beneficial effects in clostridial myonecrosis gas gangrene [ 73 ] and in chronic refractory osteomyelitis [ 74 ] were followed by a large body of experimental data on in vitro effects of increased ambient oxygen partial pressures on microorganisms and reports on in vivo effects of HBO in infection [ 75 , 76 ]. HBO exerts direct bacteriostatic and bactericidal effects mostly on anaerobic microorganisms. These effects have been attributed to deficient defense mechanisms of anaerobic microorganisms against increased production of ROS in hyperoxic environments.

Beyond a direct activity against microorganisms, HBO has been shown to re-establish defense mechanisms that are critically impaired by the typically hypoxic microenvironment in infectious sites [ 77 ]. Both phagocytosis and microbial killing by PMNLs are severely impaired in hypoxic environments.

By increasing tissue oxygen tensions, HBO therapy restores phagocytosis and augments the oxidative burst that is needed for leukocyte microbial killing. Furthermore, the activity of a number of antibiotics is impaired in hypoxic environments and is restored and even augmented during exposure to HBO.

Altogether, direct activity on bacteria for example, pseudomonas, some strains of Escherichia , and Clostridium perfringens , improvement of cellular defense mechanisms, synergistic effects on antibiotic activity, modulation of the immune response, and augmentation of mechanisms of tissue repair form the basis for the use of HBO as adjunctive therapy in combination with antibiotics and surgery for treating tissue infections involving both anaerobic and aerobic microorganisms in hypoxic wounds and tissues [ 75 - 78 ] and in sepsis-induced SIR [ 79 ].

A third study [ 82 ] on patients undergoing various open abdominal procedures reported a higher incidence of SSI in the higher oxygen group and ignited a yet unsettled debate on the routine use of normobaric hyperoxia to prevent SSI.

Hyperoxia has also been shown to inhibit the growth of some fungi [ 83 - 85 ] and to potentiate the antifungal effect of amphthericin B [ 84 ]. Data from case reports, small groups of patients, and compilations of previous reports support the use of adjunctive HBO treatment together with amphotericin B and surgery in invasive rhinocerebral mucormycosis [ 85 - 87 ].

The level of evidence on the effects of HBO in other fungal infections is less compelling. The proven pathophysiologic profile of actions of hyperoxia set the basis for its use in selected clinical conditions. Sufficient clinical evidence is available for the use of HBO in carbon monoxide poisoning, decompression sickness, arterial gas embolism, radiation-induced tissue injury, clostridial myo-necrosis, problem wounds, crush injury, and refractory osteomyelitis [ 1 ]. Effects of NBO in these and in other potentially relevant clinical states are much less studied.

Studies that evaluate a range of oxygen doses in both the normobaric and hyperbaric pressure range are largely unavailable and should be encouraged by appropriate allocation of research funding. The major limitation confronting a much more liberal clinical use of hyperoxia is its potential toxicity and the relatively narrow margin of safety that exists between its effective and toxic doses.

However, an awareness of the toxic effects of oxygen and an acquaintance with safe pressure and duration limits of its application, combined with the ability to carefully manage its dose, provide an acceptable basis for expanding the current list of clinical indications for its use.

The most obvious toxic manifestations of oxygen are those exerted on the respiratory system and central nervous system CNS [ 88 ]. Oxygen toxicity is believed to result from the formation of ROS in excess of the quantity that can be detoxified by the available antioxidant systems in the tissues. Although mechanisms of free radical damage to a substantial array of cellular systems proteins, enzymes, membrane lipids, and nucleic acids have already been characterized [ 88 - 90 ], large gaps exist in our understanding of the intermediate stages in the pathophysiologic cascades that follow such reactions and result in functional deficits and clinical phenomena.

The lungs are exposed to higher oxygen tensions than any other organ. At exposures to ambient oxygen pressures of up to 0. The response involves the entire respiratory tract, including the airway epithelium, microcirculation, alveolar septa, and pleural space. Pulmonary oxygen toxicity is characterized by an initial period in which no overt clinical manifestations of toxicity can be detected — termed the 'latent period'. The duration of this 'silent' clinical interval is inversely proportional to the level of inspired oxygen [ 90 , 91 ].

Acute tracheobronchitis is the earliest clinical syndrome that results from the toxic effects of oxygen on the respiratory system. It does not develop in humans breathing oxygen at partial pressures of below 0. It can start as a mild tickling sensation, later followed by substernal distress and inspiratory pain, which may be accompanied by cough and, when more severe, by a constant retrosternal burning sensation.

Tenacious tracheal secretions may accumulate. Upon termination of hyperoxic exposure, the symptoms subside within a few hours, with complete resolution within a few days [ 90 , 92 , 93 ].

Longer exposures to oxygen usually more than 48 hours at 0. The clinical symptoms as well as the laboratory, imaging, and pathologic findings of oxygen-induced DAD are not significantly different from those of ARDS from other causes [ 94 ]. Resolution of the acute phase of pulmonary oxygen toxicity or prolonged exposures to oxygen at sublethal concentrations such as during prolonged hyperoxic mechanical ventilation may result in a chronic pulmonary disease characterized by marked residual pulmonary fibrosis and emphysema with tachypnea and progressive hypoxemia [ 94 , 95 ].

The relative contributions of hyperoxia, the underlying clinical condition, and mechanical ventilation to the occurrence of chronic pulmonary fibrosis and emphysema in human adults have yet to be clarified. CNS oxygen toxicity occurs in humans at much higher oxygen pressures, above 0.

Hence, CNS toxicity does not occur during normobaric exposures but is the main limitation for the use of HBO in diving and hyperbaric treatments.

The 'latent' duration until the appearance of symptoms of CNS oxygen toxicity is inversely related to the oxygen pressure. It may last for more than 4 hours at 0. The most dramatic manifestation of CNS oxygen toxicity is a generalized tonic-clonic grand mal seizure [ 96 ].

Hyperoxia-induced seizures are believed to be reversible, causing no residual neurologic damage and disappearing upon reduction of the inspired oxygen partial pressure [ 7 , 96 ]. Early abnormal changes in cortical electrical activity were reportedly seen on exposure to HBO a few minutes prior to the full development of the electrical discharges [ 97 ].

Unfortunately, no real-time on-line definition of the preseizure electroencephalogram EEG activity which could serve as an early EEG indicator of CNS oxygen toxicity is available [ 98 ]. Other symptoms of CNS toxicity include nausea, dizziness, sensation of abnormality, headache, disorientation, light-headedness, and apprehension as well as blurred vision, tunnel vision, tinnitus, respiratory disturbances, eye twitching, and twitching of lips, mouth, and forehead.

CNS toxicity does not appear to have warning signs as there is no consistency in the pattern of appearance of symptoms and no typical gradual sequence of minor signs appearing prior to the full development of the seizures [ 88 ]. The most dramatic personal factor that may modify the sensitivity to CNS oxygen toxicity is an increase in blood pCO 2 partial pressure of carbon dioxide [ 99 , ].

Hypercapnia occurs in patients due to hypoventilation, chronic lung diseases, effects of analgesics, narcotics, other drugs, and anesthesia and should be taken into consideration in designing individual hyperoxic treatment protocols. Various pharmacologic strategies were tested in animal models for postponing hyperoxic-induced seizures. However, none of them has shown clinically relevant efficacy [ 88 ].

Reversible myopia is a relatively common manifestation of the toxic effects of HBO on the lens [ 88 ]. Cataract formation has been reported after numerous HBO sessions and is not a real threat during standard protocols. Other possible side effects of hyperbaric therapy are related to barotraumas of the middle ear, sinuses, teeth, or lungs which may result from rapid changes in ambient hydrostatic pressures that occur during the initiation and termination of treatment sessions in a hyperbaric chamber.

Proper training of patients and careful adherence to operating instructions decrease the incidence and severity of hyperbaric chamber-related barotraumas to an acceptable minimum. Due to its potential toxic effects, HBO is currently restricted to short sessions less than 2 hours , at pressures below the threshold of CNS toxicity 0. The heart stops circulating blood, and as a result the brain is deprived of oxygen while carbon dioxide increases. Carbon dioxide is toxic in high concentrations, starting at about 1 percent of the inhaled air 10, parts per million.

For comparison, the gas occurs naturally in a concentration of about 0. Not only are the symptoms of anoxia oxygen deprivation very similar to the symptoms of an NDE, but patients who had the highest concentrations of carbon dioxide in their blood reported significantly more NDEs than those with lower levels.

In response to the stress of the heart attack, pain-killing endorphins are released, which can create elation and hallucinations. Several drugs have also been found to cause near-death or out-of-body experiences , including ketamine a hallucinogen similar to PCP, used mainly as an anesthetic.

Though many believe that near-death experiences provide evidence of life after death, the fact that they can be chemically induced suggests a natural—instead of supernatural—cause.