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October 27, 2008

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How drugs cause hallucinations

Jan. 31, 2007
Special to World Science  

Sci­en­tists say they have part­ly ex­plained what causes the mind-bending ef­fects of hal­lu­cino­gens—drugs, such as LSD, mes­ca­line, and psil­o­cy­bin, that trig­ger states akin to dream­ing or mad­ness.

Peo­ple on psych­e­de­l­ic drugs, most of which are il­legal in most West­ern coun­tries, some­times re­port deep re­ve­la­tions, or ex­pe­ri­ence bi­zarre pat­terns or sounds that aren't there. There are art­works de­signed spe­cif­i­cal­ly to en­hance these ef­fects if viewed while un­der the in­f­lu­ence. The ef­fects of hal­lu­cino­gens such as LSD (Ly­ser­gic ac­id di­ethy­lamide) can range from pleas­ant to ter­ri­fy­ing. Heavy use may per­ma­nent­ly scar the mind.
The re­search­ers said their dis­co­very may il­lu­m­in­ate more than just the work­ings of these drugs, which be­came pop­u­lar in West­ern cul­ture in the 1960s though some had been used for mil­len­nia.

The find­ings al­so of­fer a path to un­der­stand­ing the func­tion of drugs used to treat brain dis­or­ders, some­times with no clear un­der­stand­ing of how they work, the re­search­ers said.

The scientists, with the Mount Si­nai School of Med­i­cine and Co­lum­bia Uni­ver­si­ty in New York, de­tailed the find­ings in the Feb. 1 is­sue of the re­search jour­nal Neu­ron.

Hal­lu­cino­gens—some­times taken rit­u­al­ly to in­duce what users feel are mys­ti­cal ex­pe­ri­ences—are known to act on brain mo­le­cules called 5-HT2A re­cep­tors. These sit on the sur­faces of brain cells and act as “key­holes” that can be “un­locked” by one of the sig­nal­ing chem­i­cals that nat­u­ral­ly flow through the brain. 

The re­cep­tor, nor­mal­ly “un­locked” by the brain chem­i­cal ser­o­to­nin, then causes chem­i­cal and elec­tri­cal changes in the cell, which may con­se­quent­ly re­lay sig­nals to neigh­bor­ing cells. This is all part of a com­plex elec­tri­cal cir­cuit­ry that un­der­lies men­tal ac­tiv­i­ty.

Yet hal­lu­cino­gens, al­so called psych­e­de­l­ics, pre­s­ent a puz­zle. They “un­lock” the same re­cep­tors as ser­o­to­nin, or si­m­i­lar non-hallucinogenic chem­i­cals. So why do they cause such dif­fer­ent ef­fects?

The re­search­ers com­pared dif­fer­ences be­tween the ef­fects of LSD and a non-hal­lu­c­in­o­genic chem­i­cal that al­so ac­ti­vates the re­cep­tors in mice. Since the ro­dents could­n’t re­port the mind-altering ex­pe­ri­ences that drugged peo­ple re­late, the re­search­ers gauged these ef­fects by meas­ur­ing a head twitch the mice char­ac­ter­is­ti­cally showed when un­der hal­lu­cino­gens, but not the other com­pounds.

The sci­en­tists fo­cused on the cor­tex, an ad­vanced part of the brain in mam­mals that is re­spon­si­ble for much of thought, per­cep­tion, mem­o­ry, ad­vanced mo­tor func­tion, so­cial abil­i­ties, lan­guage and prob­lem solv­ing. The re­search­ers found that LSD pro­duced an ar­ray of elec­tri­cal and cell sig­nal­ing re­sponses in the cor­tex very dif­fer­ent from those in­duced by the non­hal­lu­ci­nogen.

The ap­par­ent key to the dif­fer­ence was that LSD ac­ti­vat­ed the re­cep­tor in a sub­tly dif­fer­ent way from nat­u­ral chem­i­cals, said Mount Si­nai’s Stu­art C. Seal­fon, a co-author of the pa­per. The re­cep­tor seems to be “like a switch that can go on in more than one di­rec­tion,” he ex­plained.

When the mind-bending drug ac­ti­vat­ed the re­cep­tor, it not on­ly trig­gered the typ­i­cal changes in the cell, it caused ad­di­tion­al cell re­s­pon­ses, he said. The ev­i­dence for this, the group re­ported, was that the LSD seemed to cause a char­ac­ter­is­tic chain re­ac­tion of brain chem­is­try in­volv­ing a class of mo­le­cules called G pro­teins, which are of­ten in­volved in nor­mal sig­nal­ing pro­cesses. 

G pro­teins can be linked to sig­nal­ing re­cep­tors, such as HT2A. When a sig­nal ar­rives, the pro­teins can change the cell in ways that, for ex­am­ple, make ei­ther it more or less prone to pass on si­m­i­lar sig­nals in the fu­ture. The al­ter­ations can last for pe­ri­ods rang­ing from a few min­utes to a life­time; they’re key to the way our men­tal world changes over time, for in­stance with learn­ing and mem­o­ry for­ma­tion.

In the experiments, one type of G pro­tein was ac­ti­vat­ed by both non-hal­lu­cino­gens and hal­lu­cino­gens; but on­ly the lat­ter al­so switched on a sec­ond type, called Gi/o, Seal­fon said.

The sig­nif­i­cance of the dif­fer­ence is un­known. But it was par­tic­u­larly no­tice­able in a spe­cial lay­er of cells in the cor­tex, called Lay­er 5, Seal­fon said. This is often de­s­cribed as the “out­put” lay­er of the cor­tex: it es­sen­tial­ly gath­ers up de­ci­sions made in that struc­t­ure and re­lays them on to oth­er brain re­gions, in­clud­ing cen­ters that ex­e­cute phys­i­cal move­ments. 

Lay­er 5 al­so has ex­ten­sive in­ter­con­nec­tions to oth­er parts of the cor­tex, Seal­fon said. It’s al­so hy­poth­e­sized to con­trib­ute to a cer­tain fil­ter­ing func­tion, in which it helps squelch un­im­por­tant infor­ma­tion so that this does­n’t overwhelm oth­er brain ar­eas that don’t need it. Hal­lu­cino­gens may thus dis­rupt this fil­ter­ing, Seal­fon spec­u­lat­ed. “You have a sen­so­ry overload, a less fil­tered ex­pe­ri­ence of your sen­so­ry in­put.”

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Scientists say they have partly explained what causes the mind-bending effects of hallucinogens—drugs, such as LSD, mescaline, and psilocybin, known to trigger states akin to dreaming or madness. The researchers said their discoveries may shed light on more than just the workings of these drugs, which became popular in Western culture in the 1960s, though people have used some of them for millennia. The findings also offer a path to understanding the function of drugs used to treat brain disorders, which sometimes are used without a complete understanding of how they work, the researchers said. Researchers with the Mount Sinai School of Medicine and Columbia University in New York detailed the findings in the Feb. 1 issue of the research journal Neuron. Hallucinogens—sometimes used in traditional rituals to induce what users feel are mystical experiences—are known to act on brain molecules called 5-HT2A receptors. These sit on the surfaces of brain cells and act as “keyholes” that can be “unlocked” by one of the signaling chemicals that naturally flow through the brain. The receptor, normally “unlocked” by the brain chemical serotonin, then induces chemical and electrical changes in the cell, which may consequently relay signals to neighboring cells. This is all part of a complex electrical circuitry that underlies mental activity. Yet hallucinogens, also called psychedelics, present a puzzle. They “unlock” the same receptors as serotonin, or similar non-hallucinogenic chemicals. So why do they cause such different effects? The Mount Sinai and Columbia researchers compared differences between the effects of LSD and a non-hallucinogenic chemical that also activates the receptors in mice. Since the rodents couldn’t report the mind-altering effects experienced by drugged people, the researchers gauged these effects by measuring a head twitch the mice character istically showed when under hallucinogens, but not non-hallucinogens. The scientists focused on the cortex, an advanced part of the brain in mammals that is responsible for much of thought, perception and memory and serves as the seat of advanced motor function, social abilities, language, and problem solving. The researchers found that LSD produced an array of electrical and cell signaling responses in the cortex very different from those induced by the nonhallucinogenic compound. The apparent key to the difference was that LSD activated the receptor in a subtly different way from natural chemicals, said Mount Sinai’s Stuart C. Sealfon, a co-author of the paper. The receptor seems to be “like a switch that can go on in more than one direction,” he explained. When the mind-bending drug activated the receptor, it not only triggered the typical changes in the cell, it also caused additional cell responses. The evidence for this, the group reported, was that the LSD seemed to cause a character istic chain reaction of brain chemistry involving a class of molecules called G proteins, which are often involved in normal signaling processes. G proteins can be linked to signaling receptors, such as HT2A. The proteins can change the cell in ways that, for example, make either it more or less prone to pass on similar signals in the future, for periods ranging from a few minutes to a lifetime. These alterations are key to the way our mental world changes over time, for instance with learning and memory formation. One type of G protein was activated by both non-hallucinogens and hallucinogens; but only the latter also switched on a second type, called Gi/o, Sealfon said. The significance of the difference is unknown. But the change affected in particular a special layer of cells in the cortex, designated Layer 5, Sealfon said. This layer of cells is well known as the “output” layer of the cortex: it essentially gathers up decisions made in the cortex and relays them on to other brain regions, including centers that execute physical movements. Layer 5 also has extensive interconnections to other parts of the cortex, Sealfon said. It’s also hypothesized to contribute to a certain filtering function, in which it helps squelch unimportant information so that this doesn’t overwhelm other brain areas that don’t need it. Hallucinogens may thus disrupt this filtering, Sealfon speculated. “You have a sensory overload, a less filtered experience of your sensory input.”