text:
Get foliced! Now science is just a 'nice to have'
by Tim Watkin
If a majority of submissions said dragons were the biggest risk to our nation's defence, would National change its foreign policy? Such are the questions that arise when a minister shrugs off science in favour of "listening"
When it comes to making it mandatory to put folic acid in our bread, I've kept an open mind these past three years. Mandatory is a pretty big step, one that you should only take if you're utterly convinced of the science urging you in that direction.
Ah yes, science.
In 2009 when the new National-led government stalled on Labour's commitment to fortify all bread with folic acid, there was a fair bit of doubt floating about. Britain and Ireland had delayed their intended fortification because of three pieces of research that raised the possibility of a link with folic acid and cancer.
When you had ACT and the Greens both urging you to jam on the brakes, perhaps it was time to adhere to the old journalists' maxim "if in doubt, leave it out".
So the government set up a working group and spent a long, long three years working through the issue. In that time, so the likes of the Paediatric Society say, further research has down-played the cancer link. Any number of doctors are prepared to say that, without question, folic acid is safe, nothing more than a vitamin with no adverse side effects.
Now some still disagree. They seem to be in the minority, but if after three years of debate that was the consensus, fair enough. Or a minister might say that even the concerns of the expert minority are enough to make her pause. If after three years of working group work remaining voluntary was their considered advice, a minister could point to that as grounds for a difficult decision.
But surely one thing a minister wouldn't do, after all this time spent by the working group, the controversey and the screeds of global scientific research, is say 'meh' to science and that her priority was to listen to submissions in an eight week consultation period.
With the risk of several hundred more cancer cases per year being argued by one side and the potential to save 20 kids a year from spina bifida being argued by more doctors on the other, surely the one thing you don't do is say science doesn't matter.
And yet that's just what Food Safety Minister Kate Wilkinson has said. Or should we call her Food Choice Minister, because safety implies a focus on scientific evidence as to risk, and that's clearly something that doesn't trouble her.
Wilkinson blithely said on Q+A that:
"The decision that was made was really based on consumer choice rather than the science..."
She repeated the assertion (eg "consumer choice was really the one that made the most difference in terms of the decision"), mentioning that the science was conflicted and as she was no scientist, she wasn't well placed to judge. The cancer risk, however, didn't influence her decision. It really was all about choice and people making up their own mind. She stressed that as minister her job was to listen to consultation. Given that 88 of the 134 submissions favoured remaining voluntary – largely on the grounds of consumer choice – that was what she'd do.
Which is a quite remarkable statement. I'm sure many of you can think of examples when a majority of submissions has been ignored (mention them in comments). For one, if this government is so committed to listening, it'll surely announce an end to its partial asset sales programme today!
Is National now going to make policy simply on the weight of public submissions? Will no judgment be applied? Is all you have to do is convince National now is simply stack submissions? Is that good governance?
There are questions about the decision itself – such as whether "choice" is a sufficient reason when over 50% of people surveyed by her own ministry last year put 0,1, or 2 out of ten when asked if they knew much about folic acid. And there's the point that starting to take folic acid as soon as you learn your pregnant won't save the extra 20-odd kids a year from neural tube defects, such as spina bifida, that could have been saved by mandatory fortification.
But that's not what this post is about; it's about the decision-making process.
As we saw in the debate on the alcohol purchasing age, there can be there intense debate over what evidence means, but it's expected these days that good policy is evidence-based policy. I can't remember ever hearing a minister simply say that evidence wasn't part of her decision making and that she relied entirely on submissions.
So who were the submitters and what did they say? Here's the Ministry for Primary Industries' summary, which noted that 88 of the 134 submissions were against mandatory fortification and 39 were pro:
Submitters who favoured mandatory fortification considered that the benefits of fortification outweighed the costs and said the risks to the general population were minimal or non- existent. Submissions favouring mandatory fortification were mainly from professional medical associations, doctors and families affected by a neural tube defect (NTD) pregnancy.
Those submitters who did not support mandatory fortification were concerned about the risks associated with adding folic acid to bread, questioned the proportionality of the response (fortifying all bread when only a very small subset of the population would benefit) and objected to the lack of choice mandatory fortification would impose on consumers. Submissions favouring voluntary fortification were mainly from individual consumers, industry associations and individual bakery firms.
So the baking industry won the day over the medical folk, not by the strength of their arguments or superiority of their science, but by the weight of numbers.
We're an anti-intellectual enough country at the best of times, but to be so cavalier about science is a terrible signal to send.
Of course Wilkinson may totally understand the science and may be stressing the importance of choice for political gain and to avoid taking sides in the scientific debate. But in a way that's even worse. It's like dumbing yourself down so you fit in with the cool kids.
I suspect politically she's with the majority here; New Zealanders hate being told what to do and public opinion tends stress that people don't want to be "dosed" without their consent or face "mass medication".
And if Wilkinson shared that view and was worried about the risk to the many over the benefit to the few, then she could and should have made that case.
But to simply shrug off the science and choose choice is to abdicate any responsibility as a minister. We might as well just have accountants in that role to tally up submission numbers.
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by Danyl Mclauchlan on September 03, 2012
I see miracles all around me
Stop and look around, it's all astounding
And I don't wanna talk to a scientist
Y'all motherfuckers lying, and getting me pissed
- Miracles, Insane Clown Posse.
by Dave Guerin on September 03, 2012
Umm, Tim , for a piece arguing that we should depend upon science, all you've done is link to transcripts of two duelling experts on Q+A and the Minister. If you'd linked to the working group's work, that might have been more in tune with your argument, but I recognise your posts are cross-promotion for Q+A.
You've also set up a false dichotomy of science being perfect and public opinion being bad. I'll trust you that the science shows that adding folic acid to bread will help save 20 kids from neural tube defects. Once you have that information though, you need to balance that up against the costs, which do include (unscientific as it may be) people being pissed off at having something added to their food..I'm not too fussed either way about it, but others are and they're allowed to have an opinion.
by Richard Aston on September 03, 2012
I am sorry Tim but I don't have the same level of faith in "science" as it seems you do.
I also find it in-congruent that the "scientific" view is against many supplements being sold over the counter but ok to add a supplement like Folic acid into everyone's bread.
I could say the arrogance is breathtaking but I'll try not to get emotive about it.
The bigger question for me is the crowd engineering idea , regulating an additive that all will consume to reduce the harm to a small number of people. The only precedent I am aware of is Iodine in our salt and fluoride in some water supplies.
Personally I am glad the debate on Folic acid was protracted and difficult , it at least constrained the impulse to manipulate the dietary intake of whole populations.
If Folic acid supplements truly do reduce the risk of Neural tube defects why can we not run education programmes for potential parents advising them to include folic acid in their diets - provided free if needed?
by Will de Cleene on September 03, 2012
I'm just glad they didn't put thalidomide in bread back in the day.
by nommopilot on September 03, 2012
@Richard
I don't think Tim's argument is that science is infallible, but that given the investigation done by the working group it seems the minister has been pretty quick to ignore the science because she doesn't feel qualified to judge the debate.
If this is the case it seems like relying on public submissions from interested parties (because only interested parties would really bother) is risky. As he points out if policy gets decided this way then anyone with any interest in a particular decision will know the best tactic is to drum up enough scientific controversy to confuse the minister and then stack the submission process as much as possible.
Good-bye evidence-based decision making . . . .
by Rich on September 03, 2012
<i>The only precedent I am aware of is Iodine in our salt and fluoride in some water supplies</i>
Vitamins in breakfast cereal - I'm not sure if NZ mandates these, but they were put in because of the tendency for people who replaced more traditional foods with cereal to suffer deficiency.
On a related topic, I saw a great piece of Hippie Quack Bollox at the Save The Children shop - a facial scrub that claimed to "remove toxins through electromagnetic attraction". The best bit of that is that it's actually true - any detergent would remove toxins (from S. Aureus or something) that might be present on the skin, and the process involves electromagnetic attraction. But that probably isn't what they mean.
by Tim Watkin on September 03, 2012
Dave, you're missing the point. I know you're no fool, but you're on an entirely different page from what I wrote. As I said, I'm not arguing with the decision itself but at the remarkable way the minister said she reached it.
If you want more, here's the Paediatrics Society's submission on its website (you don't have to 'trust' me, I did credit them and the link to the Andrew Marshall interview is the Chair of the Society spelling out very cleary why they think as they do). Or I'm sure you're capable of googling 'folic acid working group'!
But I don't think I need to walk people through the science to make my point, which is simply that it disturbs me when a minister making a decision about food safety says science isn't her primary concern.
Same with your second par – I never said public opinion is right or wrong. For one, the submissions don't represent all public opinion. And two, it's irrelevant to my argument. Again, at the risk of belabouring it, my point is that 134 submissions shouldn't be what decides a minister of the Crown, should it? Don't we want our leaders to listen to evidence, whichever side they come down on?
Richard, Mic has helped me out. If you're looking for infallability, you'll need the divine! I'm just asking for judgment based on evidence, is all. It's a pretty basic post-enlightment argument, I would have thought. I'm kind of amazed you'd even question that!
As you say, it's good the debate was difficult. Indeed, my exact point was that after all that debate and given all the science available the minister said that wasn't what her decision was based on. So essentially you're saying the same thing as me... It feels like no-one read the post! I also said anything mandatory should be seriously and carefully considered.
And there are additives in most foods, are there not? Why is this one any different? Do you know every additive you consume? And how do you define additive? This one's a pretty humble vitamin... Oh, and another mandatory precedent – pasteurised milk.
@ Will. Where did that come from? Again, you're a smart man, why on earth make a comparison between two utterly different things?
Yeah, I should have included a paragraph or two before that pronouncement.
I have become less averse to mandatory folate in bread than when I wrote this post on the subject, but the point remains that I'm in the half of the population who doesn't need the extra folate. Just as marketing wonks have got women drinking green or yellow top milk, there's nothing stopping breadmakers making "women's bread." Burgen have taken this path with a dazzling array of must-have bread for women. So why the need to spike everyone else's bread?
Thaildomide is an extreme example of bad side effects from bad medicine sold to us by the powers that be (doctors with rubber stamps from the MoH). With the amount of bread some blokes I know eat, can mandatory folaters guarantee that there are no contraindications or toxicity from folate?
The other worry is that food is getting hollowed out by additives as it is. Already I'm wondering how much of the store-bought milk is fresh cow juice and how much is glorified milk powder. Is it too much to ask for 100 percent pure unadulterated bread flour to bake with?
by Rab McDowell on September 04, 2012
We need a whole range of nutrients in our diets if we are to be healthy. Many of them are not present in our foods in optimum amounts. Iodine, selenium and fluorine are just three of them. These three are deadly in excess but essential in traces. In most of NZ they are present in suboptimal amounts.
Iodine is added to salt but many who believe natural salt is, well, more natural get less than optimal amounts. In many parts of NZ selenium is available in the food in sufficient amounts primarily because the bread available locally is made from Australian wheat which is grown in soils higher in selenium than NZ soils.
Fluorine can be added to the drinking water.
Tim, keep the argument the same but change the subject of your post to fluorine and see what reaction you get in the debate between science and consumer choice.
Good reframe Rab - yes it would be interesting to change the debate to Fluorine in drinking water. Its the same essential issue for me around the morality of social/medical engineering ie adding stuff to people's diets whether they want it or not because certian experts have decided what is good for us.
And Will good point about consumer choice , ie woman's bread, though I imagine it would have to be supplied at the cheap end as well as Burgan. Those on lower incomes are less likely to be spending money on dietry additives.
When it comes to the actual folate debate, you get closer to the problem in your last comment, Richard. Marketing, especially a line of women's bread that is likely to be high end, doesn't cut it for the poor and young, who are the folk the mandatory fortification would be trying to save.
Of course the more you put it in different ranges of food -- there's nothing special about bread, I'm told, except that it's so widely eaten -- the more kids are saved. But to get the maximum impact (of around 20 kids) the uncomfortable fact is that mandatory's the only way. Of course you pay the price in choice. Which is more important?
(Although that wasn't the point of the post!).
Rab, to pick up your line of thought, perhaps there are already 'additives' in all bread -- or other foods -- that aren't there to begin with. So why do we obsess on this one? One example that leaps to mind - sugar and salt is added to all... I don't know... pre-made pizzas? Because that's bad for everyone. Something else? I know there's a difference between mandatory and universal, but I'm wondering out loud if they're that great and if there are other examples of additives in everything...
Folic acid is not the first nutrient supplement that has been suggested for bread.
Let us put aside fluorine for a moment and consider selenium. New Zealand soils are generally low in selenium. North Islanders generally eat bread made from Australian wheat which is grown in soils with higher selenium content and this goes a fair way to redressing their suboptimal selenium intake. South Islanders, on the other hand, eat bread made from locally grown wheat so don't get this boost and their intake, on average, is about 20 micrograms a day less than what is considered optimal.
Let me put this into perspective. A microgram is one millionth of a gram. The population of the South Island is one million. Twenty micrograms each is 20 grams of selenium per day for the whole South Island. That is one tablespoon of sodium selenate. That's all the South Island is short of each day.
An infinitesimal amount like that could be added, in very dilute quantities to the salt, sugar, flour, butter, water, or almost any part of the diet and so very cheaply. But this was regarded as mass medication so, about 7 years ago, it was suggested that south island wheat growers should apply selenium enriched fertiliser to their wheat fields. It would have no effect on the wheat yield. But it would have meant farmers charging around thousands of hectares of wheat fields burning diesel and wearing out machinery just so a tablespoon of selenium would have been made available to the whole island in a way that was considered "natural".
The cost would have been many many times more expensive than adding it closer to the consumer. Fortunately, from the farmers' point of view, the idea was shelved. Presumably, south islanders, apart from the few that take supplements, are still deficient in selenium and suffer the health problems that go with that.
"Beer contains significant amounts of magnesium, selenium, potassium, phosphorus, biotin, and is chock full of B vitamins." - I love the internet.
Tim, thanks for the reply. We disagree, but on rereading your piece I take your point about your concern about the decisionmaking process. I underemphasised that before.
You also wrote that "it disturbs me when a minister making a decision about food safety says science isn't her primary concern." But of course this isn't about food safety at all - it's about whether something should be added to food to improve population health. And public health is a pretty poltiical area, as it straddles social and science issues.
Will - Beer, at least real beer, is made of hops barley malt and water. If the hops and barley are grown in soils that are deficient in some ot hese nutrients then it ain't necessarily so that "Beer contains significant amounts of magnesium, selenium, potassium, phosphorus, biotin, and is chock full of B vitamins."
by Ross on September 07, 2012
I tend to agree with Richard Ashton.
A few years back we saw "science" triumph over common sense when the MeNZB vaccine was rolled out by the Healthy Ministry, the biggest health campaign in history. Some $250 million later, experts revealed that maybe one life had been saved. At the time of roll-out we were (wrongly) told that many lives would be saved and it was imperative that we have a vaccine for meningococcal disease. Photos of children without their limbs were shown to frightened parents, showing just how essential vaccination was. The public were treated shabbily, by both officials and scientists. (Ironically, more scare-mongering has recently occurred with the death of a child from meningococcal disease, notwithstanding that the child had been vaccinated against the B strain.)
"I'm just asking for judgment based on evidence, is all."
Well, yes, but in this case, we're talking very small numbers of affected kids, similar to the situation with meningococcal disease. And we're also talking about estimates of what will happen to X if we do Y. As I've shown, the same argument was made with respect to MeNZB and it turned out to be a huge waste of taxpayer's money to go with the "science".
by danniel on February 09, 2013
So what's wrong with putting folic acid in bread after all? It's for our best health as far as scientists can say, that's enough to know for me. I rather drink calcium milk and eat folic acid bread instead of staying in a hospital and doing a long treatment for a long term condition that I didn't even know I had. My husband is getting prepared for a teleradiology next week, he's been feeling ill lately, we all hope it's nothing serious.
science, neural tube defects, mass medication, Kate Wilkinson, folic acid in bread, evidence-based policy
National's folic tangle
Mike Joy answers the PM, with hard facts
Kate Wilkinson: Conservation's lame blue duck?
The Minister "who took the fish out of fish and chips"
To folate or not to folate?
Also by Tim Watkin
Gabriel Makhlouf's already had three strikes. Can he really avoid being 'out'?
Three Christians walk into a bar... and none of them win election
Another chance to be transformational rejected... Labour's cautious welfare response
The impossibility of being Simon Bridges
Jacinda Ardern thuds back to earth thanks to NZF's 'carefully generated torpedo' (CGT)


text:
Q: PHP - Multiselect require field if option is selected This is part of a form that is sent via e-mail. When you select the option state the textfield state is required, if you don't it isn't, same for county and zip code.
What I want is the php to validate this so I can send the e-mail but so far I haven't been able to accomplish it.
Here is the HTML:
<select multiple="multiple" name="geographic" id="geographic">
    <option value="state">State</option>
    <option value="county">County</option>
    <option value="zip">Zip Code</option>
</select>
What state?
<input id="state" name="state" type="text">
What County?
<input id="county" name="county" type="text">
What is the Zip Code? *
<input id="zipcode" name="zipcode" type="text">

A: You could use Javascript which allows the validation on the front end and doesn't require a page load, something like the following should work for you:

And your form:
<form>
<select multiple="multiple" name="geographic" id="geographic">
    <option value="state">State</option>
    <option value="county">County</option>
    <option value="zip">Zip Code</option>
</select>

What state?
<input id="state" name="state" type="text">

What County?
<input id="county" name="county" type="text">

What is the Zip Code? *
<input id="zipcode" name="zipcode" type="text">

<button type="button" onclick="SelectValidator()">Display index</button>
</form>

A: first of you need to wrap your code in a form but you probably did that already? if not you should take a look at http://www.w3schools.com/php/php_forms.asp
the php file where the form is posted to receives it with $_POST, in the case of geographicit is $_POST['geographic'], same goes for state. Now you know how  to access that value, you can validate it.
so
if($_POST['geographic'] == 'state'){

     if(empty($_POST['state'])){
          echo 'state is required';
     }else{
          echo 'state is given, proceed';
     }

}

redpajama_set_name: RedPajamaStackExchange


We highlight some of the best red carpet fashion and the winners who took home a trophy.
LOS ANGELES — It was music's biggest night as the industry awarded the best of the best at the 2019 Grammy Awards.
Stars walk the red carpet before the 61st Grammy Awards on Sunday.
Some of the many talented singers, rappers who took home a Grammy.


text:
À propos du cabinet
Ressources Médiatiques
McDermott Appoints Financial Regulatory Partner In Frankfurt
Droit des Sociétés et Transactions Financement Marchés de Capitaux et Sociétés Cotées Germany
Andrea will strengthen the Firm's Finance offering to clients in Germany and globally
Frankfurt, February 4, 2020 – McDermott Will & Emery, a leading international law firm, has announced that Andrea A. Stockhorst joined its Frankfurt office as a partner.
"Andrea's practice focuses on advising national and international investment companies, banks and financial services institutions on all aspects of German banking supervisory and investment law, as well as on regulatory law issues relating to M&A transactions and this meets a growing client demand here in Germany," said says Dr. Oliver Lieth, head of McDermott's financial practice in Germany.
"McDermot has a reputation as being both client centric while having a great work culture and environment and also I am thrilled to be joining McDermott at such an exciting time and to work with an accomplished group of lawyers in Germany and around the work," added Andrea.
Prior to joining McDermott, Andrea was a managing associate in the financial regulatory practice at Linklaters, a leading global law firm. She had previously worked as in-house counsel at Deutsche Beteiligungs AG, a listed private equity company, and in the financial regulatory practice at Clifford Chance, a leading global law firm.
McDermott now has 13 lawyers in Germany that focus on Finance, including six partners. Our Frankfurt team and individual lawyers are recognized for the quality, consistency and creativity of our legal counsel by publications such as Chambers Global, JUVE Handbook, The Legal 500 and Euromoney Legal Group. As part of a global, full-service law firm, the lawyers in our Frankfurt office are prepared to help clients wherever their business interests take them.
McDermott Will & Emery partners with leaders around the world to fuel missions, knock down barriers and shape markets. With more than 20 locations on three continents, our team works seamlessly across practices, industries and geographies to deliver highly effective—and often unexpected—solutions that propel success. More than 1,100 lawyers strong, we bring our personal passion and legal prowess to bear in every matter for our clients and the people they serve.
STEPHEN HASTING
Shastings@mwe.com
Associé | Düsseldorf
Afficher le profil
Andrea Stockhorst
Associé | Frankfurt
Bureau à distance McDermott
Sites associés:

redpajama_set_name: RedPajamaCommonCrawl


Added on September 24, 2007 by Cole Pierce.
Yall read alot of music reviews? I do. If you're tired of pitchfork check out almostcool.org and tinymixtapes.com.
I just spent some time reading almost cool, which is one guy writing about maybe 4 albums a week. So far I trust his judgement, we'll see what happens when I listen to more.


text:
package seedu.address.testutil;

import java.io.File;
import java.io.IOException;
import java.lang.reflect.Field;
import java.lang.reflect.Method;
import java.lang.reflect.Modifier;
import java.util.ArrayList;
import java.util.Arrays;
import java.util.List;
import java.util.concurrent.TimeoutException;
import java.util.stream.Collectors;

import org.loadui.testfx.GuiTest;
import org.testfx.api.FxToolkit;

import com.google.common.io.Files;

import guitests.guihandles.PersonCardHandle;
import javafx.geometry.Bounds;
import javafx.geometry.Point2D;
import javafx.scene.Node;
import javafx.scene.Scene;
import javafx.scene.input.KeyCode;
import javafx.scene.input.KeyCodeCombination;
import javafx.scene.input.KeyCombination;
import junit.framework.AssertionFailedError;
import seedu.address.TestApp;
import seedu.task.commons.exceptions.IllegalValueException;
import seedu.task.commons.util.FileUtil;
import seedu.task.commons.util.XmlUtil;
import seedu.task.model.YTomorrow;
import seedu.task.model.tag.Tag;
import seedu.task.model.tag.UniqueTagList;
import seedu.task.model.task.EndDate;
import seedu.task.model.task.Group;
import seedu.task.model.task.Name;
import seedu.task.model.task.ReadOnlyTask;
import seedu.task.model.task.StartDate;
import seedu.task.model.task.Task;
import seedu.task.storage.XmlSerializableTaskManager;

/**
 * A utility class for test cases.
 */
public class TestUtil {

    public static final String LS = System.lineSeparator();

    /**
     * Folder used for temp files created during testing. Ignored by Git.
     */
    public static final String SANDBOX_FOLDER = FileUtil.getPath("./src/test/data/sandbox/");

    public static final Task[] SAMPLE_PERSON_DATA = getSamplePersonData();

    public static final Tag[] SAMPLE_TAG_DATA = getSampleTagData();

    public static void assertThrows(Class<? extends Throwable> expected, Runnable executable) {
        try {
            executable.run();
        } catch (Throwable actualException) {
            if (actualException.getClass().isAssignableFrom(expected)) {
                return;
            }
            String message = String.format("Expected thrown: %s, actual: %s", expected.getName(),
                    actualException.getClass().getName());
            throw new AssertionFailedError(message);
        }
        throw new AssertionFailedError(
                String.format("Expected %s to be thrown, but nothing was thrown.", expected.getName()));
    }

    //@@ author A0164032U
    private static Task[] getSamplePersonData() {
        try {
            //CHECKSTYLE.OFF: LineLength
            return new Task[]{

                new Task(new Name("study SE"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("watch movie"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("do tutorial"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("review the lesson"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("read books"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("painting"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("skiing"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("buy CD"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList()),
                new Task(new Name("go shopping"), new StartDate("09.01"), new EndDate("12.12"), new Group("learning"), new UniqueTagList())

            };
            //CHECKSTYLE.ON: LineLength
        } catch (IllegalValueException e) {
            assert false;
            // not possible
            return null;
        }
    }

    private static Tag[] getSampleTagData() {
        try {
            return new Tag[]{
                new Tag("relatives"),
                new Tag("friends")
            };
        } catch (IllegalValueException e) {
            assert false;
            return null;
            //not possible
        }
    }

    public static List<Task> generateSamplePersonData() {
        return Arrays.asList(SAMPLE_PERSON_DATA);
    }

    /**
     * Appends the file name to the sandbox folder path.
     * Creates the sandbox folder if it doesn't exist.
     * @param fileName
     * @return
     */
    public static String getFilePathInSandboxFolder(String fileName) {
        try {
            FileUtil.createDirs(new File(SANDBOX_FOLDER));
        } catch (IOException e) {
            throw new RuntimeException(e);
        }
        return SANDBOX_FOLDER + fileName;
    }

    public static void createDataFileWithSampleData(String filePath) {
        createDataFileWithData(generateSampleStorageAddressBook(), filePath);
    }

    public static <T> void createDataFileWithData(T data, String filePath) {
        try {
            File saveFileForTesting = new File(filePath);
            FileUtil.createIfMissing(saveFileForTesting);
            XmlUtil.saveDataToFile(saveFileForTesting, data);
        } catch (Exception e) {
            throw new RuntimeException(e);
        }
    }

    public static void main(String... s) {
        createDataFileWithSampleData(TestApp.SAVE_LOCATION_FOR_TESTING);
    }

    public static XmlSerializableTaskManager generateSampleStorageAddressBook() {
        return new XmlSerializableTaskManager(new YTomorrow());
    }

    /**
     * Tweaks the {@code keyCodeCombination} to resolve the {@code KeyCode.SHORTCUT} to their
     * respective platform-specific keycodes
     */
    public static KeyCode[] scrub(KeyCodeCombination keyCodeCombination) {
        List<KeyCode> keys = new ArrayList<>();
        if (keyCodeCombination.getAlt() == KeyCombination.ModifierValue.DOWN) {
            keys.add(KeyCode.ALT);
        }
        if (keyCodeCombination.getShift() == KeyCombination.ModifierValue.DOWN) {
            keys.add(KeyCode.SHIFT);
        }
        if (keyCodeCombination.getMeta() == KeyCombination.ModifierValue.DOWN) {
            keys.add(KeyCode.META);
        }
        if (keyCodeCombination.getControl() == KeyCombination.ModifierValue.DOWN) {
            keys.add(KeyCode.CONTROL);
        }
        keys.add(keyCodeCombination.getCode());
        return keys.toArray(new KeyCode[]{});
    }

    public static boolean isHeadlessEnvironment() {
        String headlessProperty = System.getProperty("testfx.headless");
        return headlessProperty != null && headlessProperty.equals("true");
    }

    public static void captureScreenShot(String fileName) {
        File file = GuiTest.captureScreenshot();
        try {
            Files.copy(file, new File(fileName + ".png"));
        } catch (IOException e) {
            e.printStackTrace();
        }
    }

    public static String descOnFail(Object... comparedObjects) {
        return "Comparison failed \n"
                + Arrays.asList(comparedObjects).stream()
                .map(Object::toString)
                .collect(Collectors.joining("\n"));
    }

    public static void setFinalStatic(Field field, Object newValue) throws NoSuchFieldException,
                                                                           IllegalAccessException {
        field.setAccessible(true);
        // remove final modifier from field
        Field modifiersField = Field.class.getDeclaredField("modifiers");
        modifiersField.setAccessible(true);
        // ~Modifier.FINAL is used to remove the final modifier from field so that its value is no longer
        // final and can be changed
        modifiersField.setInt(field, field.getModifiers() & ~Modifier.FINAL);
        field.set(null, newValue);
    }

    public static void initRuntime() throws TimeoutException {
        FxToolkit.registerPrimaryStage();
        FxToolkit.hideStage();
    }

    public static void tearDownRuntime() throws Exception {
        FxToolkit.cleanupStages();
    }

    /**
     * Gets private method of a class
     * Invoke the method using method.invoke(objectInstance, params...)
     *
     * Caveat: only find method declared in the current Class, not inherited from supertypes
     */
    public static Method getPrivateMethod(Class<?> objectClass, String methodName) throws NoSuchMethodException {
        Method method = objectClass.getDeclaredMethod(methodName);
        method.setAccessible(true);
        return method;
    }

    public static void renameFile(File file, String newFileName) {
        try {
            Files.copy(file, new File(newFileName));
        } catch (IOException e1) {
            e1.printStackTrace();
        }
    }

    /**
     * Gets mid point of a node relative to the screen.
     * @param node
     * @return
     */
    public static Point2D getScreenMidPoint(Node node) {
        double x = getScreenPos(node).getMinX() + node.getLayoutBounds().getWidth() / 2;
        double y = getScreenPos(node).getMinY() + node.getLayoutBounds().getHeight() / 2;
        return new Point2D(x, y);
    }

    /**
     * Gets mid point of a node relative to its scene.
     * @param node
     * @return
     */
    public static Point2D getSceneMidPoint(Node node) {
        double x = getScenePos(node).getMinX() + node.getLayoutBounds().getWidth() / 2;
        double y = getScenePos(node).getMinY() + node.getLayoutBounds().getHeight() / 2;
        return new Point2D(x, y);
    }

    /**
     * Gets the bound of the node relative to the parent scene.
     * @param node
     * @return
     */
    public static Bounds getScenePos(Node node) {
        return node.localToScene(node.getBoundsInLocal());
    }

    public static Bounds getScreenPos(Node node) {
        return node.localToScreen(node.getBoundsInLocal());
    }

    public static double getSceneMaxX(Scene scene) {
        return scene.getX() + scene.getWidth();
    }

    public static double getSceneMaxY(Scene scene) {
        return scene.getX() + scene.getHeight();
    }

    public static Object getLastElement(List<?> list) {
        return list.get(list.size() - 1);
    }

    /**
     * Removes a subset from the list of persons.
     * @param persons The list of persons
     * @param personsToRemove The subset of persons.
     * @return The modified persons after removal of the subset from persons.
     */
    public static TestPerson[] removePersonsFromList(final TestPerson[] persons, TestPerson... personsToRemove) {
        List<TestPerson> listOfPersons = asList(persons);
        listOfPersons.removeAll(asList(personsToRemove));
        return listOfPersons.toArray(new TestPerson[listOfPersons.size()]);
    }

    /**
     * Returns a copy of the list with the person at specified index removed.
     * @param list original list to copy from
     * @param targetIndexInOneIndexedFormat e.g. index 1 if the first element is to be removed
     */
    public static TestPerson[] removePersonFromList(final TestPerson[] list, int targetIndexInOneIndexedFormat) {
        return removePersonsFromList(list, list[targetIndexInOneIndexedFormat - 1]);
    }

    /**
     * Replaces persons[i] with a person.
     * @param persons The array of persons.
     * @param person The replacement person
     * @param index The index of the person to be replaced.
     * @return
     */
    public static TestPerson[] replacePersonFromList(TestPerson[] persons, TestPerson person, int index) {
        persons[index] = person;
        return persons;
    }

    /**
     * Appends persons to the array of persons.
     * @param persons A array of persons.
     * @param personsToAdd The persons that are to be appended behind the original array.
     * @return The modified array of persons.
     */
    public static TestPerson[] addPersonsToList(final TestPerson[] persons, TestPerson... personsToAdd) {
        List<TestPerson> listOfPersons = asList(persons);
        listOfPersons.addAll(asList(personsToAdd));
        return listOfPersons.toArray(new TestPerson[listOfPersons.size()]);
    }

    private static <T> List<T> asList(T[] objs) {
        List<T> list = new ArrayList<>();
        for (T obj : objs) {
            list.add(obj);
        }
        return list;
    }

    public static boolean compareCardAndPerson(PersonCardHandle card, ReadOnlyTask person) {
        return card.isSamePerson(person);
    }

    public static Tag[] getTagList(String tags) {
        if ("".equals(tags)) {
            return new Tag[]{};
        }

        final String[] split = tags.split(", ");

        final List<Tag> collect = Arrays.asList(split).stream().map(e -> {
            try {
                return new Tag(e.replaceFirst("Tag: ", ""));
            } catch (IllegalValueException e1) {
                //not possible
                assert false;
                return null;
            }
        }).collect(Collectors.toList());

        return collect.toArray(new Tag[split.length]);
    }

}

redpajama_set_name: RedPajamaGithub


text:
TJ Cox declares victory in the last undecided House race
The 116th U.S. Congress will include 20 AAPI members -- the most ever.
More than three weeks after election day, we have a winner.
In California's 21st Congressional District, TJ Cox defeated three-term Republican Rep. David Valadao on Wednesday, giving Democrats a gain of seven House seats in the state and 40 nationwide.
Cox is only one of two Filipino Americans currently elected to the House of Representatives. Meanwhile, in New Jersey's 3rd District, Andy Kim became only the second ever Korean American elected to the House. Their victories, along with Michael San Nicolas' victory for Guam's delegate representative, solidifies a historic number of AAPI members in Congress.
The 116th United States Congress will include 20 AAPI members -- the most ever.
BREAKING: We have won!
This campaign succeeded because of the tireless efforts of thousands of people. Our communities came together and made this possible.
Thank you for your support #CA21, I am truly honored to be your next Representative. See my statement below: pic.twitter.com/VGpzrbBkW5
— TJ Cox (@TJCoxCongress) November 28, 2018
The Central Valley race was the country's last remaining undecided congressional contest. Cox trailed Valadao by nearly 44,000 votes on election night. But with every mail-in vote and other ballots finally counted, updated results from Fresno and Kings counties pushed Cox's lead over Valadao to 529.
Don't tell me your vote doesn't count. Every vote counts.
More here: TJ Cox beats Republican Rep. David Valadao to give Democrats gain of 40 House seats, seven in California
FILE UNDER: california, congress, election, filipino american, politics, tj cox


text:
Robinson honored with Gerald and Emily Leischuck Endowed Presidential Award for Excellence in Teaching
Robinson honored with Leischuck Endowed Presidential Award for Excellence in Teaching
Neal Reid | AU Office of Communications and Marketing | 11/18/2021
The right educator, offering the right guidance at the right time, can be a transformative figure in the lives of college students, and Jennifer Robinson has committed herself to being that type of difference-maker at Auburn University.
The Alumni professor from the Department of Psychological Sciences in the College of Liberal Arts is adored by her students, whom she provides with knowledge through top-flight instruction, experience-driven advice from a caring heart and the foundation for successful careers after graduation. For her commitment to her students, her dedication to life-changing research and service to military veterans, Robinson has been selected to receive the Gerald and Emily Leischuck Endowed Presidential Awards for Excellence in Teaching.
Gerald and the late Emily Leischuck, 1964 graduates and retired Auburn University administrators, created the Endowed Presidential Awards for Excellence in Teaching in 2005 to recognize two full-time, tenured faculty members who have demonstrated effective and innovative teaching methods, along with a continuing commitment to student success through advising and mentoring. Robinson was selected for this year's distinction and a $10,000 prize along with Paul Holley, professor and director of the Center for Construction Innovation and Collaboration in the College of Architecture, Design and Construction's McWhorter School of Building Science.
The special honor has been motivational for Robinson, not only personally, but to urge other professors to put themselves out there for similar distinctions.
"I think it's an incredibly special honor when your students feel that strongly and highly of your investment in them," said Robinson, an Auburn professor since 2012. "It's also nice to get recognition as a faculty member. I hope that some day I'll be able to provide that same kind of recognition or a similar mechanism for faculty, because I think it's really important. I'm so grateful to the Leischucks for providing such a distinguished award.
"You feel a sense of responsibility to usher forward the same mission that got you where you are and to also just encourage other faculty who are doing amazing things to apply for Auburn's faculty awards. I do feel like there is a responsibility that comes with this type of recognition to continue teaching at the highest level and try to be both inspirational and motivational. I think in the last year, we've really been tested to keep the 'classroom,' which can sometimes be a computer screen, engaging."
Robinson–who earned master's and doctoral degrees in experimental psychology from Case Western Reserve University in Cleveland–teaches both undergraduate and graduate students. Her classes range from cognitive neuroscience and introduction to psychology to research methods in psychology, and she is heavily involved with the Auburn University MRI Research Center.
An inherent passion for the work, as well as a love for the students, is what drives Robinson.
"Auburn is just such a special place," said Robinson, who holds appointments in the School of Kinesiology and Department of Electrical and Computer Engineering. "I love what I do, so, that is very helpful. I think when you are doing things that you love, it intertwines with your regular life. So, I'm sure my work-life balance is a little off, but I also find a lot of joy in what I'm doing, so, it's soul-filling.
"It really is a pleasure, and honestly, my students are phenomenal. My graduate students make life a lot easier on me, and they pick up that it takes a village to accomplish anything. They are kind, brilliant and hard-working team players, and I've found that when you surround yourself with really great people, great things happen."
Mentoring as a methodology
Robinson remembers what it's like to be a college student, including one who may not be sure about where their path may lead.
"I thought for sure I knew what I wanted to do until I was a year away from graduating and found something else I was way more interested in," she said. "I was like, 'Oh, shoot, now what?'"
Helping her students not only learn the material, but also have the "light bulb moment" is a thrill for Robinson.
"I think that's the beauty of this career, that you get to see those moments regularly, and not many people have a career where you get that constant reinforcement," said Robinson, the 2017 Psi Chi International Honor Society Teacher of the Year. "There's nothing really like it to see that light bulb go off or even see them go off into a field because they found inspiration in your class. Helping them find their passion is pretty special."
Robinson is no stranger to lofty honors, winning the 2020 College of Liberal Arts Teaching Excellence Award and the 2019 Alumni Excellence in Teaching Award. She takes her role as a mentor seriously and thinks about the emotions of students' parents who may be trepidatious about their children leaving the nest for college life.
"I have these young adults who are at such an awesome time in their life, and they're very vulnerable and malleable, and they're trying to figure things out," said Robinson, who serves on the Auburn Graduation Committee, the College of Liberal Arts Budget Committee and the Auburn Institutional Review Board. "It's such an honor to be a part of that journey, and to get to share that time with them.
"Then I think from the parent side, the parents are letting go of their kids for the first time into a new environment where they're trying to figure out life. We have the honor of taking that position to a degree and being mentors and trying to help them navigate that next step which sets the foundation for the rest of their life. To me, that is such a tremendous honor."
Robinson has spearheaded the Auburn University Brain Camp, or AUBC, for high school students since 2013 and provides opportunities for students to learn about functional magnetic resonance imaging, or fMRI, and psychophysiology as part of their curriculum. She promotes an engaging and welcoming atmosphere in class and the laboratory, committing herself to four key qualities of emphasis–commitment, enthusiasm, respect and scholarship.
Her students know Robinson cares about them and has their best interests at heart.
"In the classroom, Dr. Robinson epitomizes what is expected of educators at the collegiate level," wrote Kate Conkey, an Auburn doctoral candidate and colonel in the military police who was a student of Robinson's, in a recommendation letter. "Intelligent, informed and personable, Dr. Robinson connects easily with students and creates a classroom where students are engaged and enjoy learning. Her passion for education and dedication to student development is an undeniable asset to Auburn University."
Cutting-edge research changing lives
Robinson runs the Cognitive and Affective Neuroscience, or CAN Lab, participates in the Human Brain Mapping Mentor Program and directs the Cognitive and Behavioral Sciences, or CaBS, doctoral program. She uses those endeavors to further research about the brain, examining how different regions are interconnected and relating her findings to topics like post-traumatic stress disorder, or PTSD.
Robinson's research uses fMRI and psychophysiological techniques to investigate the interplay of emotions and cognitive thought, and her lab is one of the only labs in the world to combine these technologies.
"I don't know of any university I've been at that makes imaging and scanners so accessible to students," said Robinson, who has published more than 50 peer-reviewed articles and contributed to two books. "Auburn is very unique in that the Auburn University MRI Research Center, housed in the [Ginn] College of Engineering under the direction of Tom Denney, is so gracious and generous about allowing us to use the scanner for teaching, and obviously, for research. Having the opportunity to show students the magnificence of their own brain is a powerful teaching and learning tool.
"To be able to say, 'Every thought that you've had, every memory, every personality trait is housed in this small organ in your head.' And we can take a picture of that in a couple of minutes, and we can see how it works.'"
Robinson, who serves as associate editor of Frontiers' "Brain Imaging Methods" journal and has been a grant reviewer for the National Institutes of Health and the National Science Foundation, has long been fascinated by the brain.
"Everything comes from that command center," said Robinson, who won the 2016 President's Outstanding Collaborative Units Award for a neuroscience partnership with seven other professors. "I think giving students an appreciation for just how important that is and how unique that organ is compared to all the others is important. It's fascinating how impressive our brains are.
"I've always been interested in the mind-body connection, and just how much of our mental health can affect our physical health. So, I was always interested in medicine and making people's lives better. I have a servant's heart, and helping others brings me a lot of joy."
Through her research, Robinson hopes to advance science and learn more about the brain.
"We don't know enough about the brain, so I think inspiring the future generations of neuroscientists and getting folks interested in the brain is crucial," said Robinson, who has been awarded more than $300,000 in grants the last five years. "We don't have a cure for almost all neurological or psychiatric conditions. We have treatments that can slow progression, but we really don't have cures. So, I'm hoping that this new generation will be able to usher in a new age of medicine."
A service to those who serve
Her servant's heart has carried over into the military realm. Robinson works routinely with the Veterans Resource Center, from obtaining grants to helping veterans deal with PTSD.
"There's always been a very special place in my heart for folks who have fought for our country and given me opportunities that most don't get," said Robinson, the 2019 Veteran's Advocate Award recipient from the Auburn Student Veterans Association. "Unfortunately, women don't get opportunities to go and get Ph.D.s everywhere in the world. I think sometimes we forget just how privileged we are to live in the United States, and I don't think we have done a terribly awesome job of taking care of veterans when they come back home from war.
"Post-traumatic stress disorder is just tough to deal with in general because it's so complex and so different. I never wore a uniform, but I feel like this is the way I can give back in that capacity, to try and help on the back end of things. I guess the goal of most research is to learn so you can apply it to practical things to make people's lives better."
An environment in which to thrive
Robinson is invigorated by being part of a team of elite faculty in the Department of Psychological Sciences.
"Psychological Sciences has some pretty phenomenal educators who balance everything really, really well," she said. "I think being surrounded by faculty who have figured out how to be successful educators and researchers who are willing to mentor junior colleagues creates a culture of excellence."
An Auburn resident for nearly a decade, the Ohio native has a special place in her heart for the Plains.
"It's been a dream come true and so fun," Robinson said. "It's not just that I'm blessed to be in a career that I love, but the Auburn community is extraordinary.
"It's a vibrant community, really. I love my hometown of Lakewood, Ohio. It set the bar very high, but Auburn does a really good job of making me feel at home. I love it here."
Tags: Faculty Research Psychological Sciences
Hale receives Lifetime Achievement Award from Election Center
Kathleen Hale, a professor of political science, was recognized at the Election Center's 36th Annual National Conference in Phoenix, AZ.
Auburn Alumni Association honors inaugural 20 Under 40 class
Seven College of Liberal Arts alumni were named to the Auburn Alumni Association's first 20 under 40 class.
Aviation faculty awarded Delta Air Lines professorships
James Witte and James Birdsong are the first recipients of the professorship established by Delta to support outstanding faculty dedicated to high quality aviation instruction, research and service.
Shelley named American Society for Aesthetics vice president
Professor James Shelley will serve a two-year term as VP for one of the nation's premier philosophical societies.
Milford discusses things you didn't know about organizations and social change
On this podcast, Mike Milford, an expert in pop culture, sports and political messaging, breaks down things you didn't know you didn't know about organizations and social change.
Franco-Watkins named dean of Kentucky's College of Arts and Sciences
Ana Franco-Watkins, professor and interim dean, has been named dean of the College of Arts and Sciences at the University of Kentucky, effective July 1.


Calling it a "national emergency," some 2020 Democratic hopefuls have personal experience with big loans that are hard to pay back.
Harris, Booker, Warren and Gillibrand have since signed on to Sen. Brian Schatz's Debt-Free College Act, which also addresses costs beyond tuition, such as books and living expenses. The Hawaiian Democrat's more ambitious plan carries an even larger price tag — an estimated $90 billion.
College debt in the United States has roughly tripled since 2006 and now exceeds $1.5 trillion, second only to mortgage debt. There are about 43 million student loan borrowers nationwide.
Sen. Cory Booker, D-N.J., is offering what he's said could be a long-term solution to the problem — establishing a savings account with $1,000 in it for every baby born in the U.S. Depending on family income, up to another $2,000 a year would be added to the account, which could be accessed for higher education payments or home ownership after the child turns 18. Booker's also co-sponsoring the Schatz bill, and has pushed for tuition-free community colleges, simplifying the student loan process and refinancing existing loans.
Sen. Elizabeth Warren, D-Mass.,calls the student debt problem a "national emergency." She's signed onto Schatz's Debt-Free College for All Act, and has sought to enable borrowers to refinance their loans, introducing the Reduce Student Debt Act in 2016. A long-time law professor, the Massachusetts senator also introduced a bill to cap student loan interest rates in 2013. On the 2020 campaign trail, she introduced a plan that would offer free public college for future students while cancelling up to $50,000 in student debt for over 40 million Americans. The $1.25 trillion plan would be paid for in part by a tax on the super-rich.
Rep. Eric Swalwell, D-Calif., is another candidate with experience in student loan debt. "I have two kids under two. I'm paying off just under $100,000 of student loan debt," he told MSNBC in March. In Congress, he's introduced legislation to enhance student forgiveness for teachers, police officers and other public servants, as well as another bill that would allow student loans to be discharged in bankruptcy proceedings.
Andrew Yang, the New York entrepreneur, has said he wants to focus on bringing college costs down, in part by "a gradual phase-in of a desired ratio of administrators to students of 1 to 30" instead of the current 1 to 21. He noted that ratio was 1 to 50 in the 1970s. He also wants to require universities with endowments of over $30 billion to contribute 1 percent of their total endowment to establish a new university in Ohio.
Mayor Wayne Messam, of Miramar, Florida, who announced he was running for president this week, says he will push for "national student loan forgiveness." "It is time for the federal government to cancel all federal and private student loans," he said in prepared remarks for his campaign launch speech Saturday. He proposes having the government take over responsibility for the loans, which he'd pay off in part by repealing the Trump tax cuts.


text:
Many Trips, Diminishing Returns: Cross-Tolerance Between LSD and DOI
Psychedelic drugs like LSD powerfully alter consciousness and promote neural plasticity, but drug tolerance occurs rapidly following the first dose. Although the mechanisms that underlie psychedelic tolerance may overlap with those that confer a therapeutic effect, until recently these mechanisms were unknown.
November 29, 2022 - By Daniel Lustberg, PhD
Sangoiri / Shutterstock
One and Done: Rapid Therapeutic Effects of Psychedelics
Clinical interest in the use of psychedelic drugs for the treatment of psychiatric disorders has recently exploded, with researchers testing the effects of compounds like LSD and psilocybin on patient populations that are resistant to traditional pharmacotherapies.1-4 The profound alterations in consciousness, sensory perception, and emotional state elicited by psychedelics depends on the ability of these drugs to bind to and activate the 5-HT2Areceptor.4-6 Further, activation of this receptor with specific research chemical agonists like DOI confers therapeutic effects in animal models relevant to human disorders like depression, anxiety, and addiction.7-9
The hallucinogenic properties of naturally-occurring psychedelics and their synthetic analogs can be modeled in mice using the head-twitch response (HTR), which reliably correlates with 5-HT2A activation and serves as a behavioral proxy of the "psychedelic trip" experienced by humans.10-12 Pharmacological blockade of 5-HT2A receptors reduces the psychedelic-induced HTR response in rodents and suppresses the subjective effects of psychedelics in human participants.10-13 Although not established indisputably, 5-HT2A receptor activation and downstream neural plasticity may be necessary for many of the therapeutic effects of psychedelics as well.9,13
Losing Reception: Mechanisms of Drug Tolerance
The 5-HT2A receptor, the primary target of psychedelics, is a G-protein coupled receptor (GPCR).4,13 This family of receptors includes the targets of many other psychoactive drugs, including stimulants and opioids.14,15 As with other GPCRs, 5-HT2A receptors are subject to processes like upregulation and downregulation in response to drug exposure or experience.15-26 The process of receptor downregulation following repeated drug exposure engenders a state of drug tolerance, characterized by an attenuated response to the same amount of drug.14,24-26
Opioid tolerance is perhaps the best studied form of drug tolerance, and develops after repeated exposure to commonly used opioids.14,15 Opioid tolerance reduces both the analgesic and euphoric effects of opioids, limiting their therapeutic or recreational effects at the same dose and thus requiring dose escalation to achieve the desired effects.15 Opioids target a GPCR known as the μ opioid receptor (μOR), which are internalized after repeated activation through signaling pathways that occur inside cells and involve proteins called arrestins.14,15 Because most commonly used opioids target the μOR, chronic exposure to an opioid like oxycodone would also produce "cross-tolerance" to other opioids like morphine, even if the person had never taken morphine before.14,15
There is some evidence of tolerance and cross-tolerance to psychedelics, but many of these studies did not meet present day methodological standards and questions remain about the mechanisms that might be involved.16-26 Moreover, while arrestins are typically conceptualized as simple "chaperones" that internalize GPCRs to bring them offline after prolonged activation, their intracellular signaling capacity is in fact much more complex.14,15 For instance, arrestins like ꞵ-arrestin-2 (ꞵArr2) can act as a "scaffold" for a broad range of proteins that control transcriptional and translational programs important for neural plasticity.14 Further study of how psychedelics alter 5-HT2A receptor expression and initiate 5-HT2A-dependent adaptations in neurons may be clinically important, as these same changes may underlie the therapeutic effects of these drugs.9,13,24-26
Question and Approach
In a new study, de la Fuente Revenga and colleagues set out to investigate the development of tolerance and cross-tolerance to multiple chemical classes of psychedelics by using the phenethylamine DOI and the ergoline LSD in mice with the HTR model of drug effects.27 For comparison, they also tested the effects of the non-psychedelic 5-HT2A agonist lisuride on tolerance and cross-tolerance to DOI and LSD.27 In addition, the researchers examined the effects of 5-HT2A receptor blockade with the specific antagonist M100907 on the development of psychedelic tolerance, as well as the effect of genetic of ꞵArr2 using special ꞵArr2 knockout (ꞵArr2 KO) mice.27,28
Tolerance to DOI and LSD as assessed by the HTR in mice revealed diminished responses to both drugs following repeated once-daily exposure (both 24 hours and 4 days after), suggesting that psychedelic drugs induce rapid drug tolerance. This phenomenon was accompanied by a ~50% downregulation of 5-HT2A receptors in the frontal cortex of mice 24 hr after DOI exposure, as measured by a binding assay of receptor density.
Diminished responses to DOI following repeated LSD exposure, but not lisuride, indicate that cross-tolerance develops only for the psychedelic 5-HT2A agonists.
Blockade of the 5-HT2A receptor with the antagonist M100907 predictably reduced the initial HTR response elicited by DOI, but also reduced the development of tolerance after repeated exposures. However, in the absence of the antagonist, tolerance to DOI in the HTR assay could be overcome by doubling the dose on test day.
Development of drug tolerance to DOI was unchanged in ꞵArr2 KO mice, indicating that downregulation of 5-HT2A receptors and reduced sensitivity to DOI do not depend on ꞵArr2 signaling.
Psychedelic Tolerance: Big Picture and Clinical Implications
This elegant, detailed study by de la Fuente Revenga and colleagues establishes that psychedelic 5-HT2A agonists produce tolerance and cross-tolerance after repeated exposures, and sheds light on biological targets that are required or dispensable for this phenomenon. The finding that lisuride, a 5-HT2A agonist devoid of hallucinogenic potential, does not elicit cross-tolerance is fascinating, but further studies are necessary to clearly delineate the molecular differences in drug binding and 5-HT2A receptor dynamics responsible for this difference.3,9,13,28
Downregulation of 5-HT2A receptors in the frontal cortex after DOI exposure, observed in this study as well as in previous studies, corroborates that reduced availability of this receptor likely contributes to psychedelic tolerance as part of a homeostatic response.24-27 Second-generation antipsychotic drugs like clozapine and quetiapine block the 5-HT2A receptor as antagonists but still reduce the availability of this receptor.29 Thus, homeostatic downregulation of 5-HT2A receptors elicited by psychedelics (agonists) or antipsychotics (antagonists) could indicate partially overlapping common therapeutic mechanisms between these disparate drug classes.4,9,13,29 Lastly, the finding that psychedelic tolerance is independent of ꞵArr2 signaling raises interesting questions about novel, atypical signaling pathways that regulate the expression of the 5-HT2A receptor.14,30 Future studies aimed at answering these questions will be important to establish a clear model of the mechanism of action of psychedelics in the context of treating psychiatric disease.1-4
Daniel Lustberg, PhD
Danny Lustberg received his PhD in Molecular & Systems Pharmacology from Emory University in 2022. He is currently a postdoctoral researcher at Emory University, studying the role of the central noradrenergic system in stress-related psychiatric diseases, including anxiety disorders and OCD.
sian olsen
Short & sweet summary.
Big Thx Daniel.
Come visit the Big Isle, and we'll take you out on the water. Boat, SUP, etc.
Tolerance, Tachyphylaxis, and Psychedelic Drug Action
DO-Why? The Story of DOI
The Structure and Function of the Serotonin 5-HT2A Receptor
Acid for Anxiety: Fast and Lasting Anxiolytic Effects of LSD
Psychedelic or Not: Of Mice, 5-HT2A Agonists, and Head Shakes
Ketanserin's Contributions to Psychedelic Research
From Dendrites to Drug Discovery: An Interview with Dr. Alex Kwan
G Protein-Coupled Receptors: What Are They and How Do They Work?
Cellular Receptors and Their Role in the Psychedelic Effect
Pharmacological Testing in Psychedelic Research
Variants in 5-HT2A Receptor Gene Alter Psychedelic Pharmacology
Genetic Determinants of the LSD Response
Related Compounds
More articles about Scientific Research
Gut Feeling: Links Between LSD, Endocannabinoids, and the Microbiome
Abuse Potential: Considerations for Rescheduling MDMA and Psychedelics
How To Stop A Psychedelic Trip: The Promise of Ketanserin
Psychedelic Brains In A Dish
← How To Stop A Psychedelic Trip: The Promise of Ketanserin
Abuse Potential: Considerations for Rescheduling MDMA and Psychedelics →
Carhart-Harris RL, Goodwin GM. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology. 2017;42(11):2105-2113. doi:10.1038/npp.2017.84
Nutt D. Psychedelic drugs-a new era in psychiatry?. Dialogues Clin Neurosci. 2019;21(2):139-147. doi:10.31887/DCNS.2019.21.2/dnutt
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Joe Acosta, Guitar, Voice, and Percussion Instructor
Joe Acosta was born in 1982 in Daytona beach Florida. Starting singing in elementary school chorus and began learning to play the guitar at age eleven. In middle and high school he joined symphonic and marching band as a percussionist making superiors in all competitions but one. In 1998 he co founded a band called Cid Brown and co-wrote original songs one of which got radio play on the local rock radio station. In 2009 he co founded the band Jamocracy and played in the local Gainesville music scene until the band decided to split in 2016. He then joined the band Southern Burn and is currently still performing in and around the Gainesville area.