Saturday, March 14, 2009

Hallucinations

A little more of the plumbing underlying hallucinations comes to light.

One fascinating sub-field of molecular biology, particularly pharmacology, is the hunt for things called "orphan receptor ligands". Receptors are proteins at the cell surface that recognize hormones, neurotransmitters, inflammatory molecules, and other signaling molecules, and then alert their cell about that message. They are the eyes and ears of the cell, and humans have over 800 of one family of them, the GPCR receptors, including ~350 olfactory receptors that sit in nasal membranes a detect aromatic chemicals. This family mediates many important messages in the body, and more to the point, constitutes the single largest class of drug targets, since interfering with such specialized signaling systems is an effective way to influence a cell's functions. Getting drugs to these receptors is also easy, since they sit right on the surface of the cell, pointing outwards. In contrast, getting drugs inside cells can be quite difficult.


The human genome project identified the genes encoding all these receptors, (which occur only in eukaryotes), but could not tell us what they do. Evolutionarily, they all arose as accidental copies of an ancestral version, forming a family with conserved sequences and structures. But our interest is all in their differences- what distinct signalling molecule (or ligand) each one binds, and what that signal means to the cell. Currently about half of all human non-olfactory GPCR receptors have known ligands, and the rest are called "orphan" receptors, since their partners in signalling ("ligands") are unknown. Thus the search for orphan receptor ligands, especially by drug companies, who stand to benefit enormously from new ways to twiddle with our biology. Recent successes have found receptors for the appetite hormone orexin, the circadian hormone melatonin, adrenaline, nociceptin, and many others.

Recent papers in Science nail down some new data about two erstwhile orphan GPCR receptors in the brain- one, the receptor for the hallucinogen DMT, and the other, active in the development of Alzheimer's disease. The second study does not identify the ligand for its orphan receptor (GPR3), rather, it demonstrates that it is expressed in areas of the brain typically affected in Alzheimer's, that its overexpression stimulates excess amyloid peptide production, the hallmark of Alzheimer's, and that deletion of the gene both eliminates amyloid peptide production and reliably prevents the disease in mice that otherwise develop it. Finding the ligand of this receptor will be even more interesting now that its importance is so clearly laid out.

Perhaps more interesting, however, is the first article reporting that another orphan GPCR (sigma-1) turns out to be the receptor for the hallucinogen DMT. Several hallucinogens have already had their receptors characterized. Marijuana binds to a sub-family of GPCRs called the cannabinoid receptors, which also bind the endo-cannabinoids which have physiological roles in, as one would expect, mood, learning, pain, and general cognition. LSD binds to a variety of dopamine and serotonin GPCR receptors, of which a serotonin receptor appears to be the key mediator of action.

Little is known about the sigma-1 receptor, other than that it might influence functions as diverse as schizophrenia, cell death, immune suppression, and sterol metabolism. It is known to be a receptor for the antipsychotic haloperidol as well as cocaine, but (before this work) not for any endogenous ligand. Yet mice with this gene knocked out appear fine- viable and fertile. The one assay that this article reports for DMT action is hypermobility, where mice placed in an open space move twice as much when under the influence. This effect was completely abrogated when the gene for the sigma-1 receptor was deleted, indicating that at least some of what the mice experience during their bout of exogenous DMT is due to the action of this GPCR receptor.

It is, however, quite frustrating to not know more about what the mice are experiencing- are they hallucinating? Do they have spiritual experiences on DMT? Does loss of this receptor make their lives dull? With this new knowledge, however, drugs can be devised to specifically (and reversibly) activate and de-activate this receptor, which should eventually lead to better (non-recreational) experiments in humans.

Thus one more receptor has found an endogenous ligand, and one more hallucinogen has found its binding partner in the brain. DMT is the key ingredient of one of the most potent hallucinogens- the ayahuasca mixture from South America, and is closely related to the active chemical in psilocybin mushrooms. It is quickly metabolized and non-addictive, and seeing increased use in Europe and the US. Not much is known about DMT's role or action in the brain, since it is a minor and very transient metabolite. However one article indicates that at lower doses, it might function as a relaxant:
"In these studies, administration of a non-hallucinogenic dose of DMT (0.05 mg/kg) produced a relaxed and comfortable mental state in many subjects. We propose that the main effect of endogenous DMT may resemble low-dose, non-hallucinogenic DMT administration, providing a homeostatic response to alleviate, rather than promote, psychotic symptoms."

"At intravenous doses of 0.2 and 0.4 mg/kg, there was a “nearly instantaneous onset of visual hallucinatory phenomena, bodily dissociation, and extreme shifts in mood, which totally replaced subject’s previously ongoing mental experiences.”"

"At low levels, DMT may be an endogenous anxiolytic, whereas higher, “unnatural” levels (such as those associated with psychedelic/hallucinogenic activity) produce extreme shifts in consciousness."

The near-death experience may then be a final spasm of DMT production, passing from the calming amounts that relieve anxiety and pain to the prodigious amounts that induce hallucinations.

This receptor-ligand system is extremely complex and far from understood- the many roles of the sigma-1 receptor and those of DMT indicate that hallucination is probably a side-effect rather than the central point of their function. Indeed, why do hallucinations happen at all? We live in what might be termed a finely tuned hallucination all the time, with one's brain constantly spinning scenarios, images, and ideas, more or less tethered to reality. Dreaming is even more clearly a matter of ongoing hallucination. One of the most important recent themes of neurobiology is that cognition is a creative process, where our inner structures and activities play a leading role in shaping perceptions, focusing attention, and filtering emotions. Perception is as much a top-down process as it is a bottom-up process driven by the sensors of the eyes, ears, etc.

The tuning by which consciousness is created and kept on an even keel requires complex timing adjustments, keeping various inputs in register and adjusting perceptual time for our state of attention, whether bored, focused, or doodling. The same goes for conscious contents, such as daydreams, perceptions, ideas, emotions. It all seems a terrible mess, since a huge amount of unconscious material needs to get in, and yet not overwhelm the thread of consciousness.

Clearly, natural selection would promote accuracy of perception and focus on critical tasks in the outside world, such as when time slows down dramatically during dramatic events, and our minds become oddly clear. But the need to accommodate many other contents and situations necessitates major and ongoing adjustments, which may be what DMT and other chemicals may be doing at a gross level, tweeking normal consciousness in ways that cause what we call hallucinations when pumped to extremes.

One last question is why people routinely take hallucinatory experiences to have great spiritual significance. Many practices tread this path, such as meditation, fasting, ecstatic prayer, and Sufi whirling, not to mention peyote, ayahusca, and the Delphic visions of ancient Greece. Muhammed is thought to have had a form of epilepsy that is associated with intense visions, and the desert sojourn of Jesus laid the foundation of all his later preaching.

Naive views of spirituality assume that there are other planes of existence or reality where spirits reside, in accordance with our dreams, fairy tales, and native intuition- the supernatural, of which we get glimmers through this smoky glass of psychedelia. But there has to be more. Hallucinations are not just perceptual voyages through uncharted ethereal realms, but also affective experiences of great power, notoriously subject to the emotional tenor of the setting (causing good or bad "trips" on LSD). This is the forte of the shaman, who sets the parameters of such activities with great care. A single extraordinary emotional experience can motivate a lifetime of dedication, so it should not surprise that drugs that send the mind to its emotional and conceptual boundaries might leave unshakeable imprints.

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