Psychedelics go beneath the cell surface to unleash their potentially therapeutic effects.

These drugs are showing promise in clinical trials as treatments for mental health disorders (SN: 12/3/21). Now, scientists might know why. These substances can get inside nerve cells in the cortex — the brain region important for consciousness — and tell the neurons to grow, researchers report in the Feb. 17 Science.

Several mental health conditions, including depression and post-traumatic stress disorder, are tied to chronic stress, which degrades neurons in the cortex over time. Scientists have long thought that repairing the cells could provide therapeutic benefits, like lowered anxiety and improved mood.
Psychedelics — including psilocin, which comes from magic mushrooms, and LSD — do that repairing by promoting the growth of nerve cell branches that receive information, called dendrites (SN: 11/17/20). The behavior might explain the drugs’ positive outcomes in research. But how they trigger cell growth was a mystery.

It was already known that, in cortical neurons, psychedelics activate a certain protein that receives signals and gives instructions to cells. This protein, called the 5-HT2A receptor, is also stimulated by serotonin, a chemical made by the body and implicated in mood. But a study in 2018 determined that serotonin doesn’t make these neurons grow. That finding “was really leaving us scratching our heads,” says chemical neuroscientist David Olson, director of the Institute for Psychedelics and Neurotherapeutics at the University of California, Davis.

To figure out why these two types of chemicals affect neurons differently, Olson and colleagues tweaked some substances to change how well they activated the receptor. But those better equipped to turn it on didn’t make neurons grow. Instead, the team noticed that “greasy” substances, like LSD, that easily pass through cells’ fatty outer layers resulted in neurons branching out.

Polar chemicals such as serotonin, which have unevenly distributed electrical charges and therefore can’t get into cells, didn’t induce growth. Further experiments showed that most cortical neurons’ 5-HT2A receptors are located inside the cell, not at the surface where scientists have mainly studied them.

But once serotonin gained access to the cortical neurons’ interior — via artificially added gateways in the cell surface — it too led to growth. It also induced antidepressant-like effects in mice. A day after receiving a surge in serotonin, animals whose brain cells contained unnatural entry points didn’t give up as quickly as normal mice when forced to swim. In this test, the longer the mice tread water, the more effective an antidepressant is predicted to be, showing that inside access to 5-HT2A receptors is key for possible therapeutic effects.

“It seems to overturn a lot about what we think should be true about how these drugs work,” says neuroscientist Alex Kwan of Cornell University, who was not involved in the study. “Everybody, including myself, thought that [psychedelics] act on receptors that are on the cell surface.”
That’s where most receptors that function like 5-HT2A are found, says biochemist Javier González-Maeso of the Virginia Commonwealth University in Richmond, who was also not involved in the work.

Because serotonin can’t reach 5-HT2A receptors inside typical cortical neurons, Olson proposes that the receptors might respond to a different chemical made by the body. “If it’s there, it must have some kind of role,” he says. DMT, for example, is a naturally occurring psychedelic made by plants and animals, including humans, and can reach a cell’s interior.

Kwan disagrees. “It’s interesting that psychedelics can act on them, but I don’t know if the brain necessarily needs to use them when performing its normal function.” Instead, he suggests that the internal receptors might be a reserve pool, ready to replace those that get degraded on the cell surface.

Either way, understanding the cellular mechanisms behind psychedelics’ potential therapeutic effects could help scientists develop safer and more effective treatments for mental health disorders.

“Ultimately, I hope this leads to better medicines,” Olson says.

Nearly 3 million years ago, hominids employed stone tool kits to butcher hippos and pound plants along what’s now the shores of Kenya’s Lake Victoria, researchers say.

Evidence of those food preparation activities pushes back hominids’ use of these tool kits, known as Oldowan implements, by roughly 300,000 years, say paleoanthropologist Thomas Plummer of Queen’s College, City University of New York and colleagues. That makes these finds possibly the oldest known stone tools.

Several dating techniques place discoveries at the Kenyan site, known as Nyayanga, at between around 2.6 million and 3 million years old. Based on where artifacts lay in dated sediment layers, these finds are probably close to about 2.9 million years old, the scientists report in the Feb. 10 Science.
Until now, the oldest Oldowan tools dated to roughly 2.6 million years ago at an Ethiopian site more than 1,200 kilometers north of Nyayanga (SN: 6/3/19). Excavations at another site in Kenya, called Lomekwi 3, have yielded large, irregularly shaped rocks dating to about 3.3 million years ago (SN: 5/20/15). But claims that these finds, which include some sharp edges, represent the oldest known stone tools are controversial.

Similarities of the Nyayanga artifacts to those found at sites dating to as late as around 1.7 million years ago “reinforce the long trajectory of Oldowan technology in the early stages of human evolution,” says archaeologist Manuel Domínguez-Rodrigo of Rice University in Houston and the University of Alcalá in Madrid. He did not participate in the new study.

Skeletal remains of at least three hippos unearthed near a total of 56 stone artifacts at Nyayanga display butchery marks, the investigators say. Wear patterns on another 30 stone tools from Nyayanga indicate that these items were used to cut, scrape and pound animal tissue and a variety of plants. And antelope fossils found at Nyayanga display damage from hominids removing meat with sharp stones and crushing bones with large stones to remove marrow.
These discoveries are among 330 Oldowan artifacts and 1,776 animal bones unearthed at Nyayanga from 2015 through 2017. Oldowan finds included three parts of an ancient tool kit — rounded hammerstones, angular or oval cores and sharp-edged flakes. Toolmakers struck a core held in one hand with a hammerstone held in the other hand, splitting off flakes that could be used to cut or scrape.

Whoever wielded stone tools at the Kenya site close to 3 million years ago “had access to a well-balanced diet for hunter-gatherers,” says coauthor Rick Potts, a paleoanthropologist at the Smithsonian Institution in Washington, D.C.
The evolutionary identity of ancient Nyayanga toolmakers remains a mystery. Plummer’s group unearthed two large, peg-shaped molars belonging to Paranthropus, a big-jawed, small-brained hominid line that inhabited eastern and southern parts of Africa until around 1 million years ago. The Nyayanga teeth are the oldest known Paranthropus fossils.

But there is no way to confirm that Paranthropus made and used the newly recovered stone tools. Individuals who died at Nyayanga and left behind their fossilized teeth were not necessarily part of groups that periodically butchered hippos there, Domínguez-Rodrigo says.

Members of the Homo genus appeared in East Africa as early as around 2.8 million years ago and could have made Oldowan tools at Nyayanga, says archaeologist Sileshi Semaw of the National Research Center for Human Evolution in Burgos, Spain (SN: 3/4/15). But Paranthropus can’t be discounted as a toolmaker. A large male Paranthropus skull discovered in 1959, dubbed Nutcracker Man, lay near Oldowan artifacts dated to 1.89 million years ago, says Semaw, who was not part of Plummer’s group (SN: 3/3/20).

Previous discoveries indicated that Oldowan toolmakers eventually occupied much of Africa, Asia and Europe, either via the spread of toolmaking groups or through independent inventions.

Discoveries at Nyayanga fit a current consensus that stone-tool making must have begun shortly after hominids evolved substantially smaller canine teeth around 5 million years ago, says archaeologist John Shea of Stony Brook University in New York, who was not involved in the new study. Stone tools did the work formerly performed by big canines, including slicing prey carcasses, mashing edible plants and helping individuals communicate anger or dominance over others, Shea suspects.

If that tool-crafting timeline is correct, then even Australopithecus afarensis, known for Lucy’s famous partial skeleton, might have made and used stone tools by around 3.4 million years ago (SN: 8/11/10).

Any way you slice it, Oldowan finds at Nyayanga now provide the earliest hard evidence of stone tools.