LSD

Hey Kids, Some Drugs Are Good for You

milhayser — Sun, 29 Sep 2013 12:41:55 +0000

Hey Kids, Some Drugs Are Good for You

The U.S. "war on drugs," besides failing to meet its goals, has demonstrated a stubborn ignorance of the effects that different drugs have in the human body. Granted, some drugs cause degeneration and are properly outlawed. Opiates such as heroin and stimulants such as cocaine and methamphetamine take a harsh physical toll and leave users addicted to the chemical. But classified along with these truly dangerous drugs are some of nature's most mysterious medicines. New research shows how marijuana, psychedelics, MDMA and even ketamine have positive physiological and psychological effects that can persist even after the drug has worn off.

The marijuana flower, of course, is the nearest of these drugs to public and political acceptance, and the transformation of its image over the decades is very instructive. Stuck with a Spanish name in the 1930's to excite American xenophobia, marijuana has long been demonized as causing "reefer madness." In fact, new research shows that marijuana has potent neuroprotective and neuroplastic properties, in addition to its power as a non-addictive painkiller. Marijuana contains at least 85 cannabinoid chemicals, including the well-known THC, and the lesser known CBD. New research shows that CBD, administered thirty minutes after a devastating loss of oxygen in mice brains, totally circumvented brain damage. Cannabinoids are currently being studied for a wide range of therapeutic applications, including the fight against cancer. Their potency should come as no surprise since all mammals have cannabinoid receptors in their brains. According to Salon, these receptors evolved in animals 550 million years before the marijuana plant.

Psychedelic drugs are very different; the most popular ones are psilocybin, mescaline, and LSD. Psilocybin and mescaline occur naturally, in certain mushrooms and cacti, respectively. LSD must be made in a laboratory. These drugs have differing effects, but the psychedelic experience has many features in common. A new study in PLOS ONE showed no correlation between a lifetime of psychedelic use and negative mental health outcomes. In fact, "in several cases psychedelic use was associated with lower rate of mental health problems." Ongoing research on psilocybin suggests that it can help terminally ill patients come to terms with their mortality in healthy and beneficial ways. Meanwhile mescaline, in the form of peyote, is exempt from DEA regulation when taken under certain religious circumstances. Mescaline and psilocybin have been used in tribal cultures for thousands of years as tools for understanding the self and the world. If you try them just once your life can change drastically. After marijuana, magic mushrooms and peyote cactus should be decriminalized as natural, non-addictive, safe substances. LSD on the other hand can cause psychedelic effects for up to 16 hours (about twice as long as psilocybin) and may present a bigger danger to public health.

Similar in effect to psychedelics, but also demonstrating stimulant properties, is MDMA or Ecstasy. While conflicting research suggests that long term or heavy use of MDMA may cause brain damage, a 2011 study at UCLA "found that persons with autism using the drug often report an increase in socialization and strong feelings of empathy that last even after the drug has worn off." Perhaps one day this darling of dance culture will be available for therapeutic use by prescription.

Finally, there's a drug you may not have heard of: Ketamine, best known as a horse tranquilizer and club drug. In sub-anaesthetic doses "Special K" causes very strange psychological effects unlike those of pot or psychedelics. It's a type of drug known as a dissociative, along PCP and dextromethorphan. But while these latter drugs can cause psychosis and brain damage, Ketamine turns out to be pretty gentle, and may even have a future as an antidepressant. According to Scientific American, "the enthusiasm for ketamine is such that physicians, often working out of small clinics, have already started prescribing low doses of the generic anesthetic off-label [...] and drug companies are contemplating whether to get into the act by creating new drugs based on ketamine’s biochemistry."

A word of warning: these drugs are illegal for recreational use, they often have unpleasant effects, and it's always possible to get too much of a good thing. Many drugs are truly dangerous and deserve to remain tightly regulated or illegal. One needs only to read about the emergence of krokodil, a street form of mesomorphine cooked up from codeine and toxic chemicals, to be reminded of the horrors of drug addiction.

But the prohibition of safe, non-addictive, psychologically inspiring, and medically promising substances is not the answer.

milhayser Sun, 09/29/2013 - 08:41

Weekend Diversion: Spider Webs... on drugs?

esiegel — Sat, 06 Jul 2013 12:07:34 +0000

Weekend Diversion: Spider Webs... on drugs?

"If I see a spider in my house, I put it in a cup, and then I take it outside. I save it. What is wrong with me?" -Jacqueline Emerson

There's something not only incredibly useful but also beautiful about the intricate structure of a spider web. It's such a universally admired phenomenon that it's become a metaphor for many other things, as Welbilt sings you in their song,

Spiderweb.

Dependent on the type of spider and various environmental factors, the web can take on any number of beautiful shapes.

Image credit: Darlyne Murawski, via National Geographic Society, 2007.

Image credit: public domain image.

Image credit: Jack Scheper of http://floridata.com/.

But all of that can change in a heartbeat, dependent on... how you drug the spider.

Image credit: Peter Witt.

The size and shape of the web that spiders build, as first determined by P.N. Witt in 1948, is severely affected by psychoactive drugs, including amphetamine, mescaline, strychnine, LSD and caffeine.

Wish I knew the source for this; part of the hazards of picking up an image from tumblr!

Bizarrely enough, low doses of LSD actually result in more ordered spider webs, while higher doses (and all doses of other drugs) result in more disordered webs.

Image credit: Rainer Foelix, in his book “Biology of Spiders”; Dr. P.N. Witt.

More recently, a group of NASA scientists studied the effects of a few different drugs on European garden spiders, where they discovered that they could use the spiders (and their webs) for quantitative drug detection tests!

Image credit: D. A. Noever, R. J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82.

Finally, a video was made lampooning this research, and it's just... well, you'll have to watch for yourself.

See you back here on Monday for some real, physical science, and hope you have a great weekend until then!

esiegel Sat, 07/06/2013 - 08:07

Weekend Diversion: Make Yourself Hallucinate (Safely)

esiegel — Sat, 24 Nov 2012 14:09:11 +0000

Weekend Diversion: Make Yourself Hallucinate (Safely)

“Life should not be a journey to the grave with the intention of arriving safely in a pretty and well preserved body, but rather to skid in broadside in a cloud of smoke, thoroughly used up, totally worn out, and loudly proclaiming, 'Wow! What a Ride!'” -Hunter S. Thompson

For those of you who've never experienced exactly what it feels like to alter your perceptions, and for those of you who have but don't want to spend hours and hours experiencing the effects, your options have traditionally been limited. Perhaps a song might provide a window into the experience for you, such as M. Ward's

Color of Water.

But thanks to the combined power of technology and our understanding of neuroscience (and perception), a simple visual pattern can induce temporary (lasting less than a minute) hallucinations, safely and temporarily.

The Strobe Illusion; screen capture from http://neave.com/strobe/.

The website Neave.com has put together a way -- simply by staring at a moving pattern on your screen -- to induce distorted, hallucinatory vision in people!

The Strobe Illusion; screen capture from http://neave.com/strobe/.

They warn you that if you are sensitive to flashing lights or suffer from photosensitive epilepsy, you should avoid this. To go experience it yourself at their site, just click here. But I couldn't resist trying to do it myself, and make a video that I could directly embed into this post.

To make it work, just full-screen it, move your face close to the screen and stare at the center. When the video ends (it's only 40 seconds long), look anyplace else and enjoy your distorted, hallucinatory vision for under a minute!

For some reason, they made this into an iPhone app, for the hallucination junkie who's on-the-go.

The Strobe Illusion; screen capture from http://neave.com/strobe/.

Once again, check out the original here, and hope you enjoyed this safe, simple (and legal) way to enjoy a little mind-bending this weekend. However you spend the rest of it, hope it's a great one!

esiegel Sat, 11/24/2012 - 09:09

The secret history of psychedelic psychiatry

neurophilosophy — Mon, 30 Aug 2010 10:45:44 +0000

The secret history of psychedelic psychiatry

This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. This article will be freely available, with registration, until September 23. See the Table of Contents for more information on this Blog Focus, and read the other blog posts:

Update: I summarize all four posts in this article for The Guardian, and there's more coverage of the Blog Focus at 3 Quarks Daily, The Atlantic (Alexis Madrigal and Andrew Sullivan), Boing Boing and The Great Beyond.

___________________________

ON August 15th, 1951, an outbreak of hallucinations, panic attacks and psychotic episodes swept through the town of Pont-Saint-Esprit in southern France, hospitalizing dozens of its inhabitants and leaving five people dead. Doctors concluded that the incident occurred because bread in one of the town's bakeries had been contaminated with ergot, a toxic fungus that grows on rye. But according to investigative journalist Hank Albarelli, the CIA had actually dosed the bread with d-lysergic acid diethylamide-25 (LSD), an extremely potent hallucinogenic drug derived from ergot, as part of a mind control research project.

Although we may never learn the truth behind the events at Pont-Saint-Esprit, it is now well known that the United States Army experimented with LSD on willing and unwilling military personnel and civilians. Less well known is the work of a group of psychiatrists working in the Canadian province of Saskatchewan, who pioneered the use of LSD as a treatment for alcoholism, and claimed that it produced unprecedented rates of recovery. Their findings were soon brushed under the carpet, however, and research into the potential therapeutic effects of psychedelics was abruptly halted in the late 1960s, leaving a promising avenue of research unexplored for some 40 years.

The secret history of psychedelic psychiatry began in the early 1950s, about 10 years after Albert Hofmann discovered the hallucinogenic properties of LSD, and lasted until 1970. It was uncovered by medical historian Erika Dyck, who examined the archives from Canadian mental health researchers and conducted interviews with some of the psychiatrists, patients and nurses involved in the early LSD trials. Dyck's work shows early LSD experimentation in a new light, as a fruitful branch of mainstream psychiatric research: it redefined alcoholism as a disease that could be cured and played a role in the psychopharmacological revolution which radically transformed psychiatry. But, despite some encouraging results, it was cut short prematurely.

At the forefront of early psychedelic research was a British psychiatrist by the name of Humphry Osmond (1917-2004), a senior registrar at St. George's Hospital in South London, who began investigating the chemical properties of mescaline, the psychoactive ingredient of the peyote cactus, during the late 1940s. After experimenting with the drug for nearly two years, Osmond and his colleagues concluded that it "caused symptoms in normal people that were similar to the symptoms of schizophrenia." Further investigation led them to believe that the chemical structure of mescaline closely resembled that of adrenaline. As a consequence, they came to regard schizophrenia as being caused by an overproduction of adrenaline. In doing so, they had formulated what Osmond believed to be the first biochemical theory of mental illness.

In 1951, Osmond moved to Canada to take the position of deputy director of psychiatry at the Weyburn Mental Hospital in Saskatchewan and, with funding from the government and the Rockefeller Foundation, established a biochemistry research program. The following year, he met another psychiatrist by the name of Abram Hoffer, and the two embarked on a long-term collaboration. Osmond expanded his research program, and started using LSD instead of mescaline, because it was readily available from the Sandoz Pharmaceutical Company's Canadian branch in Toronto.

The pair hit upon the idea of using LSD to treat alcoholism in 1953, at a conference in Ottawa. After arriving at their hotel, they were unable to sleep, and stayed up late discussing problems in psychiatry. In the small hours of the morning the conversation moved on to the similarities between the effects of LSD and the delirium tremens often experienced by alcoholics during withdrawal, and they began to wonder whether LSD could be effective in treating alcoholism. Hoffer recalls that the idea "seemed so bizarre that we laughed uproariously. But when our laughter subsided, the question seemed less comical and we formed our hypothesis: Would a controlled LSD-produced delirium help alcoholics stay sober?"

On their return to Saskatchewan, Osmond and Hoffer decided to test their hypothesis, and treated two chronic alcoholics who had been admitted to the Saskatchewan Mental Hospital with a single 200 microgram dose of LSD. Osmond knew from earlier self-experimentation that much smaller amounts were sufficient to produce profound changes in consciousness, but used very large doses for a stronger effect, the idea being that it would induce a terrifying artificial delirium that might frighten the patient into changing their drinking behaviour. One of the patients stopped drinking immediately after the treatment and remained sober for the entire six month period of the follow-up study. The other continued to drink after the experiment, but stopped after six months. Osmond and Hoffer found these results somewhat confusing, but concluded that LSD had a 50% chance of helping alcoholics.

The next Saskatchewan LSD trial was conducted several years later by Colin Smith, who treated 24 patients and reported that 12 of them were "improved" or "much improved" afterwards. Encouraged by these initial results, others began using the drug to treat alcoholics. Meanwhile, Osmond and Hoffer continued with their own research. By 1960, they had treated some 2,000 alcoholic patients with LSD, and claimed that their results were very similar to those obtained in the first experiment. Their treatment was endorsed by Bill W., a co-founder of Alcoholics Anonymous who was given several sessions of LSD therapy himself, and Jace Colder, director of Saskatchewan's Bureau on Alcoholism, who believed it to be the best treatment available for alcoholics.

Osmond also "turned on" Aldous Huxley to mescaline, by giving the novelist his first dose of the drug in 1953, which inspired him to write the classic book The Doors of Perception. The two eventually became friends, and Osmond consulted Huxley when trying to find a word to describe the effects of LSD. Huxley suggested phanerothyme, from the Greek words meaning "to show" and "spirit", telling Osmond: "To make this mundane world sublime/ Take half a gram of phanerothyme." But Osmond decided instead on the term psychedelic, from the Greek words psyche, meaning "mind", and deloun, meaning "to manifest", and countered Huxley's rhyme with his own: "To fathom Hell or soar angelic/Just take a pinch of psychedelic." The term he had coined was announced at the meeting of the New York Academy of Sciences in 1957.

LSD therapy peaked in the 1950s, during which time it was even used to treat Hollywood film stars, including luminaries such as Cary Grant. By then, two forms of therapy had emerged. Psychedelic ("mind-manifesting") therapy was practised mostly in North America and involved intensive psychotherapy followed by a single megadose of LSD. It was thought that the transcendental experiences induced by such large doses, as well as heightened self-awareness, would enable the patient to reflect on their condition with greater clarity. Psycholytic ("mind-loosening") therapy, on the other hand, was practised mostly in Europe, and involved regular low to moderate doses of the drug in conjunction with psychoanalysis, in order to release long-lost memories and reveal the unconscious mind.

The early LSD studies took place alongside trials of newly developed drugs such as the antipsychotic chlorpromazine and the tricyclic antidepressant imipramine. Together, these drug trials led to the emergence of the new field of psychopharmacology, and so caused a major paradigm shift that revolutionized psychiatry and "dragged it into the modern world". The finding that psychedelics can induce schizophrenia-like symptoms bolstered the notion that psychiatric conditions are caused by chemical imbalances in the brain. And psychiatrists, faced with new evidence that mental disorders can be effectively treated with drugs, began to abandon the psychoanalytical approach in favour of new disease models based on brain chemistry.

LSD hit the streets in the early 1960s, by which time more than 1,000 scientific research papers had been published about the drug, describing promising results in some 40,000 patients. Shortly afterwards, however, the investigations of LSD as a therapeutic agent came to an end for two reasons. Firstly, some researchers pointed at the flawed methodology of the studies. Most lacked proper controls, so that the patients involved were not randomly assigned into groups that received the real treatment or a placebo. Today, the randomized, placebo-controlled double blind study is the gold standard for clinical trials. The patient does not know whether they have been given the treatment or the placebo. The researcher should not know either, so that she does not bias the results with her expectations. Back then, though, this experimental design still had not been universally accepted as the best method for evaluating the efficacy of new drug treatments.

The second - and more important - reason was the cultural and political climate of the time. By the mid-1960s, LSD had became a popular recreational drug, and was closely linked to the hippie counterculture and related phenomena - student riots and anti-war demonstrations, non-conformity and social disobedience. The mass media increasingly portrayed LSD as a dangerous drug of abuse that could cause, among other things, chromosomal damage and foetal abnormalities. Sandoz voluntarily stopped making and supplying the drug in 1966, and the American, British and Canadian governments first placed severe restrictions on its use in research, then banned its use altogether in 1970. The documents pertaining to the Saskatchewan LSD trials were locked away, and gathered dust in the archives until they were re-discovered by Dyck five years ago.

The mid-1990s saw renewed interest in the potential therapeutic benefits of psychedelics, a key figure being Franz Vollenweider, who co-authored the new Nature Reviews Neuroscience paper. As the article explains, the new research confirms that psychedelics are indeed effective therapeutic agents, at least when given in combination with behavioural therapy, and can alleviate the symptoms of various psychiatric disorders. Sophisticated new techniques such as functional magnetic resonance imaging (fMRI) are providing fresh insights into how they affect the brain, and revealing the brain mechanisms that might underly their therapeutic effects.

We now know, for example, that the classical hallucinogens (LSD, psilocybin and mescaline) exert their effects by activating the 5-HT2A serotonin receptor subtype expressed by pyramidal cells in the deep layers of the prefrontal cortex. Serotonin is involved in signalling within a widely distributed neural circuit that is implicated in mood and affective disorders. Activation of the serotonin receptors in turn alters signalling mediated by glutamate and dopamine, and may also induce synaptic plasticity, modifying the strength of the long-range connections between the circuit components. The therapeutic effects of psychedelics may therefore be due to their ability to modulate the neuronal activity within these circuits.

Other new research shows that ketamine, a dissociative anaesthetic with hallucinogenic properties that acts primarily on the glutamatergic transmitter system, can effectively alleviate depression, and can also reduce the frequency of suicidal thoughts in depressed patients. A recent clinical trial showed MDMA ('Ecstasy') is beneficial for patients suffering from post-traumatic stress disorder. And some of Vollenwieder's own research shows that psilocybin can alleviate anxiety and pain in terminally ill cancer patients. Remarkably, this recent work shows that some psychedelics are effective after just one dose; this has obvious advantages over other drug treatments, which can take many months or even years. But despite these advances, much remains to be discovered about how the psychedelics act on the brain and why they are of therapeutic value.

The history of LSD experimentation could be of use to those who make decisions about drug policy, too. The criminalization of LSD in 1970 was evidently a knee-jerk reaction by governments to the sensationalist media reports about the dangers of the drug that occurred without proper debate. A similar situation arose earlier this year, when the British government banned mephedrone. Examination of the reasons why the early LSD trials were brought to an end so abruptly could therefore provide valuable lessons about how controversial drugs could be effectively incorporated into modern medicine.

References:

Vollenweider F. X. & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat. Rev. Neurosci. 11: 642-651. doi: 10.1038/nrn2884

Dyck, E. (2006). 'Hitting Highs at Rock Bottom': LSD Treatment for Alcoholism, 1950-1970. Soc. Hist. Med. 19: 313-219. [PDF]

Dyck, E. (2005). Flashback: Psychiatric Experimentation With LSD in Historical Perspective.

Can.

J. Psychiatry 50: 381-388. [PDF]

Smart, R. G. & Storm, T. (1966). The Efficacy of LSD in the Treatment of Alcoholism. Quart. J. Stud. Alcohol 25: 333-338. [PDF]

neurophilosophy Mon, 08/30/2010 - 06:45

Categories

Medicine

http://muarchives.missouri.edu/c-rg14-s24.html#2

You can try to practice nirvana in yoga.It is much better solution than hallucinogenic drugs.

To what extent are hallucinogens thought to act in mood disorders similar to other drugs with putative antidepressant effects? One current hypothesis seems to be that alteration of neurotransmitters via medications such as SSRIs has a secondary effect stimulating BDNF.
(Yes there have been problems seeing enough of a effect from supposed antidepressants beyond placebo in clinical studies. This assumes they really do have an antidepressant effect.)
I wonder whether hallucinogens act by a similar mechanism, or is it a broader "what is the meaning of the universe" higher-order cognition effect that shocks the individual out of a rut?

let's talk about Jolly West...

"...some psychedelics are effective after just one dose;"

And therein lies the primary reason, in our capitalist economy, why these drugs will never be accepted. What capitalist will invest the money to develop and show the efficacy of a drug when they can only sell one dose per patient?

"concluded that LSD had a 50% chance of helping alcoholics."

on an 'n' of 2?

@Eskimo: The molecular mechanisms and cognitive effects are linked, and the aim of neuroscience is to bridge the gap between the two.

@Sven: Here it is - West's classic 1962 paper, Lysergic acid diethylamide: Its effects on a male Asiatic elephant. (Acid probably was not the cause of death.)

@Joe D: As I said, flawed terminology.

As someone who is familiar with the legitimate research in this field, I'm very happy to see it resuming without a lot of media hype and political nonsense.

I'd like to suggest an approach that I have so far not seen in the literature: subclinical doses used over an extended period of time.

For example:

The standard clinical dose of LSD (to produce all of the well-known effects) is approx. 100 - 200 micrograms for a person of average body weight. The threshold dose for detectable changes in cognition is in the range of 15 - 25 micrograms for a person of average mental abilities and no particular training in mental disciplines such as meditation.

However: what happens if we give someone a dose on the order of 1 - 5 micrograms daily? At that level there will be no detectable altered state, though arguably, someone trained in mindfulness meditation might notice a very slight change at 5 micrograms. Yet, the drug will have subtle effects on the brain, that may become cumulative over time.

I tend to believe that LSD on that kind of dosing schedule will alleviate some of the symptoms of normal age-related cognitive decline. (And a formulation of LSD compounded with other drugs may also be patentable, thereby giving Big Pharma an incentive:-)

The item about ketamine and depression is new to me and very interesting: it also lends itself to this approach. For example, administer a clinical dose of ketamine on day 1, for rapid recovery from a suicidal depression; and then follow up with a threshold dose the next day, and subclinical doses each day thereafter. The prospect of an antidepressant without the nasty side effects of even the current crop of SSRIs, is certainly worth pursuing.

Similarly, could daily subclinical doses of entactogens such as MDMA, administered to children who have symptoms of antisocial personality disorder, prevent them turning into adult sociopaths? A medical treatment for sociopathy would be an absolute breakthrough in this area.

The going hypothesis here is that the neurochemical action of these drugs is important in and of itself, as an entirely separate and distinct issue from their subjective effects such as "deep personal sense of meaning."

Subclinical dosages are a way to test that hypothesis, and perhaps lead to new treatment modalities for difficult psychiatric conditions.

I'm going to email Vollenweider and see what he thinks about this.

Wondefully written!
I know an individual that swears ketamine works better than anything for him for his lyme disease as well.

A few details...
1. How is a succesful double-blind study of psychedelics possible? These substances have such an effect that even a completely drug-naive patient will know whether he or she has received "the real thing" or a placebo. Surely there were attempts to find a placebo, but all failed. Pahnke (study on mystical experiences occasioned by psilocybin, 1964) gave the control group nicotinic acid, so they would experience slight somatic distress and think they actually received psilocybin. But when the real psilocybin effects started, everyone - the subjects and the researchers - clearly knew who had received what.
Another proposition is to use some stimulant. But I think in this case too the patient would soon know whether he or she had received the psychedelic or the placebo. If you test, let's say, eye drops versus saline solution, the patient can't notice any effects at once. But the effects of psychedelics are of such a kind that it's not possible not to be aware of them. Perhaps some kind of single-blind study would be possible - just the results being evaluated by someone who hasn't witnessed the sessions. But it's impossible not to let the patient know what was in the pill.
2. In my opinion it's important to clearly say that the connection of LSD to chromosomal damage was completely ungrounded. This is just false. It was an in vitro experiment on the effects of an LSD solution on a cell sample. In such concentration even milk would lead to chromosomal abnormalities. There is absolutely no proof of LSD or any other serotonergic psychedelic leading to chromosome damage in vivo. And still the meme caught on, this belief can still be found. An acquaintance said something along the lines of: "I wouldn't take it because it damages the genes and I would like to have children someday" ("because I'm a NORMAL WOMAN, unlike you, you feminist and wannabe psychonaut"? - this is, of course, just my reconstruction of a possible motivation).
3. And generally it's incredible that such promising research was completely crushed because of the late 60s moral panic around psychedelics. And even if there are much less obstacles to research, even if psychedelic psychotherapy is somewhat accepted again - it's still a long way to lat people try these substances if they want. And if we have a constitutional right to privacy, we also have a right to use psychedelics.

I want to throw in some skepticism. I don't believe that psychiatric problems can be cured *completely* by chemicals. For two reasons.

First, a close relative of mine had a psychotic episode, and after that, she mixed up imagined events, real events and memories. Drugs didn't work, they mostly just put her to sleep.

Two, I have a hard time understanding how changing chemical levels *across* the brain *randomly* could fix such a mix-up of events, particularly if this mix-up has been happening for a while.

My mental model of pharmacological intervention goes like this: a program in your computer has crashed, and your solution is to sprinkle some Germanium, or some other doping element, on the computer's chip.

This is a caricature, of course, but the essential approach of pharmacology is similar. It is totally unclear to me how sprinkling LSD or L-Dopa across the whole brain could lead to, for instance, a disentanglement of memories, actions and imaginings. It may lower further entanglements, but chances are, the patient will also lose some other functions in the process -- kinda like what would happen if you sprinkle Germanium on the chip.

@SC: The interesting thing about LSD is that it isn't equivalent to "sprinkling" a chemical on the brain. You will have to experience it to understand how it can be helpful, as it isn't simply a chemical reaction. It is a mystically profound experience that can reconnect a consciousness / universe. It is this profound religious experience and the ability to reflect on your existence at a higher level (again, must be experienced to be understood) that helps people. Also, you can remember many of your profound realizations afterward and can use these going forward in your life.

I have a friend (now 88) who used LSD to treat anorexics in South Africa during the '60s, with, he claimed, excellent results. Then the research was shut down towards the end of the decade and never mentioned again.

Another friend was the Sandoz rep - and he schlepped around Cape Town in the 1960s with a brief-case full of LSD, trying with some success to interest the medical community (and turning his friends on).

Re. NowhereGirl #8:

Good point about the difficulty of running double-blind controlled experiments, and good to hear that you know about Pahnke's study. There was a follow-up study on mystical experience a couple of years ago by Roland Griffiths, that in my opinion did a darn good job on this point.

First, he worked with drug-naive subjects, which is a necessary starting point in many studies of this type.

Second, he used a number of active controls: various stimulants and depressants that are ordinarily prescription drugs. Thus, drug-naive subjects would feel subjective effects and experience altered states of some kind, which in combination with expectation effects, would heighten the probability that they too would have mystical or quasi-mystical experiences. The point here being to raise the control scores as far as possible, thereby maximizing the probability that the effect shown for the test compound (psilocybin) was *not* significant. In other words, per normal scientific method, take steps to attempt to falsify your own hypothesis.

Third, subjects were given eyeshades and headphones, with which to lie down on a couch and quietly listen to classical music. With all the subjects lying there quietly, the possibility of overt behavioral cues to the session observers was minimized, in contrast to the Pahnke study where subjects interacted verbally with the session observers.

As well, the procedure of lying down wearing eyeshades and listening to classical music over headphones, is likely to induce subjective effects in many subjects, including visual imagery that might be interpreted as a drug effect. This would heighten the effects of the placebos, once again increasing the probability of falsifying the hypothesis that psilocybin's effects were unique.

There were some other details that impressed me about Griffiths' study, that I don't recall at the moment (I'm writing this quickly while at work), but that had to do with the strength of his protocol and the steps taken to attempt to falsify the psilocybin/mystical experience hypothesis.

That said, a standard clinical dose of any psychedelic does produce certain unmistakable effects such as vivid imagery, that can become confounds unless carefully controlled per Griffiths: and thereby narrowing the range of controlled experimentation that can be performed under double-blind conditions.

This can be a problem with any procedure used in consciousness research, whether psychoactive drugs, meditation, hypnosis, or whatever. How can you tell if someone is doing a meditation procedure correctly, other than by their subjective reports? And merely doing the procedure does not guarantee an outcome: a standard hypnotic induction may not produce a trance state reliably in all subjects (this is well known in clinical hypnosis: different clients require different induction procedures, per Milton Erickson's work in this field).

These types of considerations led Charles Tart to develop the idea of state-specific sciences, as a research paradigm that could potentially offer entirely new methodologies that would be intrinsic to the states being studied. His paper was originally published in _Science_ in 1972, but can be found here:

http://www.paradigm-sys.com/ctt_articles2.cfm?id=53

Tart was decades ahead of his time with this, and anyone who is interested in this field should read his paper.

Re. SC, #9: No one today would reasonably suggest that psychedelic drugs in and of themselves are some kind of psychiatric panacea. They are useful under certain limited conditions, when used with appropriate counseling: for example in coming to terms with events that led to PTSD, or in dealing with the psychological issues in life-threatening illness.

My suggested subclinical dosage protocol is not the same thing, since it is not geared toward producing an altered state and addressing psychodynamic issues. And here also, only a limited range of application, as with other psych meds: for example one wouldn't prescribe an antidepressant to treat anxiety, or an antianxietal to treat depression.

There is a broader issue here, having to do with the way health care is handled in the US, where financial considerations often work against providing adequate counseling in cases where medication can at least get someone well enough to get back to work. For example antidepressants can treat the biological factors that produce depression, but counseling is still necessary to address the psychological factors such as learned behaviors and attitudes that arise when a person has been depressed for a period of time. Yet very often, the counseling is neglected or minimized in the interests of economics, and this is an issue that needs to be addressed. (This forum is not the place to get into the larger health-care debate.)

Re. Jim #10: For some people, psychedelics produce mystical experiences, but that is not a foregone conclusion, and for some people psychedelics can be harmful to their psychological wellbeing. We have to be careful here to not become advocates in a manner that could result in media controversies and in people misusing these drugs as occurred decades ago. This is especially important now that the FDA is taking a more reasonable approach in authorizing human subject studies.

Also let's not forget that the traditional means of access to mystical experience, notably meditation, are not only safe for virtually everyone, but also immediately accessible to anyone who wishes to pursue them. Forty or fifty years ago, access to meditation was far more difficult, and required finding a credible teacher (these were few and far-between, and outnumbered by self-made gurus of varying qualifications). Today, the information is literally at our fingertips via the internet.

My father, Dr. Bennett Braun, who wrote the DSM III-R definition of multiple personality disorder, also supervised the testing of LSD and other substances for the army at Edgewood Arsenal.

President Bush Sr. shredded all info regarding these and other MK-ULTRA projects when he was CIA Director.

Good fun, knowing your tax dollars are hard at work!

Here's an interview with another pioneer of psychedelic psychiatry, Ronald Sandison.

Interesting - do you have a reference for the MDMA/PTSD info? ("A recent clinical trial showed MDMA ('Ecstasy') is beneficial for patients suffering from post-traumatic stress disorder".)

@Marc: The paper's just been published in the Journal of Psychophsarmacology: The safety and efficacy of 3,4-methylenedioxymethamphetamine-assisted
psychotherapy in subjects with chronic, treatment-resistant posttraumatic
stress disorder: the first randomized controlled pilot study [PDF].

Enjoy!

@Nowhere Girl, Problems with maintaining the blind of clinician and patient are not unique to psychedelic research - the same issues arise in studies of psychotherapy, surgery, and many medications. As you mention, more important than maintaining a strict double-blind is to randomize the subjects and to have independent, blinded assessment of baseline and outcome measures. Another possible method for clinical studies with psychedelics is to have a range of doses and look for a dose-response relationship.

@g725, Do you know of anyone who has tried your suggested daily subtreshold LSD regime? Also, you say that meditation is "safe for virtually everyone" - this is an exaggeration, there have been reports of adverse effects from mediation.

Wasn't LSD outlawed for any purpose in 1965, not 1970? I think it was the Drug Abuse Control Amendments that criminalized it throughtout the USA...

http://www.druglibrary.org/special/king/dhu/dhu26.htm

Odd -- For many years I took an ergotamine derivative for the treatment of migraine, before the "advancement" of the triptans (one of which is the therapeutic agent I use currently). I was not formally diagnosed and adequately treated for migraine until I was in college, though the headaches manifested around puberty (about 12 years old in my case). I had a rather miserable adolescence.

I vividly remember the incredible relief of taking my first Cafergot tablet, the mild nausea it caused, and the hallucinations. They were different from the prodromal hallucinations that I suffer in that they weren't ominous, warning me to go to a dark place Right Soon Now or there would be Consequences... they were just things that I saw that I knew weren't really there. I could even talk to some of them, if they were people, still knowing it was just my imagination and the chemical. Good thing my roommate wasn't there for most of them.

Don't get me wrong, the triptans work as well if not better (with the exception of the first one, Imitrex, which gives me chest pain and scares the stuffing out of me), but I have to say that I almost miss the little creatures. With few exceptions, they were benign, and almost amusing. I never was a user of illicit drugs, so that's the closest I've come to anything of the sort. That being said, I'd be willing to volunteer for a study on say, ketamine or a hallucinogen for the relief of depression with the proper guidance and help; I am no longer of childbearing age and few medications have proven effective in the long term. Perhaps it's a habit to break with a literal "brain reset".

Hey. Just a detail : the name of the city is "Pont-Saint-Esprit".

@S. Danori: I'm not sure exactly when it was banned.

@Julien: Thanks - it's fixed now.

While I was hospitalized in the psychiatric ward of a mental hospital, my roommate, a married 21 year old woman with a 1 1/2 year old little girl, was brought into that same psycho ward on a four point restraint board because she was in the middle of a psychotic break caused by an overdose of LSD. Very powerful stuff.

@Mermaid. You can overdose on water with neurotoxic effects too. A touch anecdotal for the discussion maybe?

Personally, LSD & psychedelics has raised my awareness regarding the wonders & mysteries of life. I hope one day the propaganda surrounding these spiritual molecules will wither away, and it begins with those who have benefited spiritually & mentally by taking a stand and speaking up when one speaks ill of it due to prejudice & ignorance.

Peace all

Heya,
Just landed on your blog through a bit of surfing. Interesting article, I never do drugs but I do sometimes hang around people who take them, and sometimes also hallucegenic drugs.

I don't see or understand the fun in seeing all sorts of fairies and goblins and whatever else, it messes you up so bad!

Cheers
Diggy

From my old reminescence of my neuropharmacology exam, I remember that my professor insisted on the fact that LSD was not connected to neurotoxic effects, at least on the nervous system of the fruitor and therefore it shouldn't kill the "neuronal cell". At the same time, the professor stressed the concept that LSD was associated with the revelation of hidden psychoses, or, in other words, that this drug might increase the chances of developing skyzophrenia in subjects that show a degree of predisposition. I don't know exactly how research on this subject has evolved, but I always considered this fact as interesting from a psychiatric perspective.

What do you think about.

Hi, I have just read your post and it's very interesting. Can I translate it in my italian blog about psychotherapy and neuroscience? I would cite your blog, of course.

Growing up in the 60's I had an opportunity to ingest some LSD before it became illegal. I believe that it was Owsely's product which to my understanding had a high level of purity and that the dosage was high by today's standards. My recollection is that my friends and I split one small purple pill 4 ways and still got very "stoned" to the point where none of us could not drive a car during the peak of the experience. Another recollection was that we were able to experience ESP (from what I can remember???). This always fascinated me as I never took LSD again after it became illegal. I'm curious if studies have been done around this property of the drug. It was quite amazing. I would be interested in hearing from anyone who had this experience. Might make a good scientific study? clarkewinz@hotmail.com

This is a very important topic in relation to psychology counseling for anyone to read about. The topics that licensed psychologists need to learn about is never ending.

@Buffalo:

Here's an entertaining yet quite un-scientific study into the ESP properties of what I expect to be psilocybin: http://www.youtube.com/watch?v=fz7k00544PA
("One Step Beyond - the sacred mushroom" 1961)

Hey Mr. Science Blog Guy: Where have you been? We miss you.

But according to investigative journalist Hank Albarelli, the CIA had actually dosed the bread with d-lysergic acid diethylamide-25 (LSD), an extremely potent hallucinogenic drug derived from ergot, as part of a mind control research project.

WHAT? In a European town? If that is true then the American government is in grave legal, moral and diplomatic trouble. It doesn't really matter how long time ago it is... there are most likely plenty of victims, and relatives to victims (both dead and psychotic victims), to raise lawsuits.

Ergotism -- the symptoms that struck Pont-Saint-Esprit -- had been observed, on occasion, for hundreds of years. It's much more plausible that the town was struck by another ergot outbreak than that the US government was involved.

On another note, how can you write a whole post about psychedelic psychotherapy without mentioning Stanislav Grof??? His book LSD Psychotherapy is the distillation of many years of careful observation of the effects of LSD on his patients. It's a must-study for anyone interested in this area.

Entheogen and hallucinogen, N,N'-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors

terrasig — Mon, 23 Feb 2009 11:02:01 +0000

Entheogen and hallucinogen, N,N'-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors

Welcome 4 March readers of The Daily Grail - please be sure to also click on the original post about the DMT article by my colleague, Laura Mariani.

Thanks to Dave Munger & Co's ResearchBlogging.org, I just found a fabulous neuroscience grad student blogger from Emory University: Laura E Mariani at Neurotypical?

Doctor-to-be Mariani blogged last Monday about a paper in Science where the endogenous ligand of the orphan sigma-1 receptor was identified as the hallucinogen, N,N'-dimethyltryptamine, or DMT. The work originated with the group of Arnold Ruoho and colleagues at the University of Wisconsin's Depts of Pharmacology and Physiology, together with a collaborator at the Isfahan University of Technology in Iran.

As an aside, what blows me away is that the first author on this publication, Dominique Fontanilla, is a graduate student in the UW Molecular and Cellular Pharmacology training program. The funding acknowledgment suggests that she was on an NIH institutional training grant and then scored her own individual predoctoral NRSA from the National Institute on Drug Abuse. It appears that she also has a background in synthetic chemistry that extends back to her Sigma Xi-recognized undergraduate work at Carleton College in Minnesota. If anyone is looking for a stellar postdoc candidate in this field (*cough* DrugMonkey), you'd better get in line now.

Anyway, as a neuroscientist, Laura tells the story far better than I can so you should go to her post to read the details.

Where a natural products cancer pharmacologist gets interested in this story is its intersection with plant-derived medicines - 25% of today's pharmaceuticals can be traced to natural sources, I recognize that the history of my discipline lies in the ethnobotany of indigenous cultures and their religious and ritual use of plant compounds with hallucinogenic effects of other activities in modulating the central nervous system. Hallucinogens used culturally in religious rituals are often called entheogens (loosely translated as "creating god within").

DMT is a naturally-occurring analog of serotonin, or 5-hydroxytryptamine, the neurotransmitter we try to manipulate with many antidepressant therapies. Many serotonin-like molecules, the most famous being LSD, have the potential to more dramatically influence our perception of reality than the neurotransmitter itself. Interestingly, we make very small but detectable amounts of DMT.

Where DMT is most famous, however, is as part of plant-derived hallucinogen cocktail called ayahuasca or hoasca used by the religious group, the União do Vegetal (more precisely the Centro Espírita Beneficente União do Vegetal or UDV.). I wrote awhile back about New Mexico-based UDV community that won the right to use their traditional plant brew containing DMT in a 21 Feb 2006 US Supreme Court decision citing protection of the group's activities under the 1993 Religious Freedom Restoration Act.

Here was my description at the time of the Ayahuasca tea:

The Hoasca hallucinogenic tea, more appropriately called Ayahuasca, is made from stems of the vine Banisteriopsis caapi together with the leaves of Psychotropia viridis (in Brazil, Peru, and Ecuador) or Diplopterys cabrerana (in Ecuador and Colombia). The latter two plants contain the hallucinogen, DMT, a serotonin analog that stimulates 5-HT_2A receptors similar to LSD. However, DMT alone would normally be very quickly metabolized in the liver by monoamine oxidase A (MAO-A) such that little of the compound, if any, could get to the brain.

The key plant is B. caapi which is not hallucinogenic on its own. Instead, B. caapi contains beta-carboline compounds that inhibit the liver's ability to destroy the DMT. Most important among these is a compound called harmine, a well-characterized MAO inhibitor. In pharmacology, one would say that harmine potentiates the hallucinogenic effect of DMT. As a scientist, I am in awe of the South American cultures that discovered this concoction long before we had HPLCs and mass spectrometers.

The reader will note that I cited DMT's effect at serotonin 5-HT_2A receptors. In other recent work, DMT has also been found to act on trace amine-associated receptors, or TAARs. However, it appears that a combination of in vitro and in vivo results, particularly behaviorial hypermobility studies in sigma-1 receptor knockout mice, is suggestive that DMT acts primarily on sigma-1 receptors.

I'm not qualified to delve too much into the therapeutic potential of these discoveries but the sigma-1 receptor may represent a unique opportunity to develop new drugs for schizophrenia and other debilitating psychotic disorders. For example, it was news to me from the Ruoho paper that the antipsychotic drug haloperidol (Haldol^®) binds with very high affinity to sigma-1 receptors even though its therapeutic activity has long been attributed to its antagonism of dopamine at central dopamine D₂ receptors.

Finally, Fontanilla et al. hypothesize that other dimethylated serotonin-like compounds may also exert their effects at sigma-1 receptors. For example, N,N'-dimethylserotonin, or bufotenine, is another compound with hallucinogenic activity that has been also been observed at elevated concentrations in the urine of patients with schizophrenia.

If the prefix "bufo" rings a bell to you, you'll think of the genus name for toads: bufotenine (and 5-methoxy-DMT) is secreted from the skin of many toads (Cane, Colorado River, Sonoran Desert toads). Toad licking or smoking of toad skin is a favorite hallucinogenic pastime of individuals in the desert southwest US, Mexico, and Australia.

I'll leave a scholarly treatment of toad licking and toad smoking for another day.

The fact that we are now finding a common mechanism for entheogens and hallucinogens reveals once again the awesome power of natural products in the discovery of the pathophysiology and pharmacotherapeutics of human diseases.

D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, A. E. Ruoho (2009). The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science, 323 (5916), 934-937 DOI: 10.1126/science.1166127

terrasig Mon, 02/23/2009 - 06:02