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Offlineboletusoftruth
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Psychedelic Research
    #9608614 - 01/14/09 02:27 PM (15 years, 1 month ago)

Every once in awhile I make this offer, case people missed it the last time around.

I have a subscription to a research database that has thousands of scientific journals, as well as pretty much ANYTHING else you could imagine. I've used it for final reports, research papers, as well as general curiosity into anything psychedelic.

If anyone wants to know more send me a PM...


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Offlineboletusoftruth
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Re: Psychedelic Research [Re: boletusoftruth]
    #9608680 - 01/14/09 02:35 PM (15 years, 1 month ago)

Here is a quick show of the range of information.

Currently searching  12 database(s) with 84,402,588 documents updated as recently as January 14, 2009


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Offlineboletusoftruth
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Re: Psychedelic Research [Re: boletusoftruth]
    #9608723 - 01/14/09 02:42 PM (15 years, 1 month ago)

Interesting article...

Quote:

Healing hallucinogens: psychoactive drugs are undergoing a renaissance as researchers turn to them to bring relief to patients with difficult-to-treat conditions.(News feature)(Conference notes).

Last week the third annual Clusterbusters conference finished in Atlanta, Georgia. Clusterbusters? It's an unconventional name for a patient group that espouses an unconventional treatment: using hallucinogenic drugs such as Lysergic Acid Diethylamide, better know as LSD, and psilocybin, the active ingredient in 'magic' mushrooms, to treat a type of headache so severe that many sufferers take their own lives, earning the condition--cluster headache--the gruesome name of the 'suicide headache'.

And there is much to celebrate. New unpublished research supports their use of certain psychoactive seeds and a clinical trial protocol using the hallucinogens is under review, bolstered by the presence of a world authority on headaches.

Ten years ago the future looked bleak, but thanks to a chance discovery and a combination of patient power and citizen science, treatments devised and refined by the cluster community itself are steering the research agenda.

Cluster headaches affect up to 0.4% of any population and are often misdiagnosed as migraine. Unlike migraine, they are around four times more common in men than in women and follow an unexplained annual or daily cycle.

In the episodic form, debilitating attacks occur in certain months of the year, often when the seasons change. Those with the chronic form of the condition receive no respite and are plagued by six or more attacks every day. Untreated, each attack can last for hours. The pain of a cluster headache attack is compared to expelling kidney stones or giving birth without pain relief.

Ben Khan, a lifelong chronic sufferer says the pain comes on quickly and is all-encompassing. 'I bang my head against the wall and flail my arms and body around, screaming,' he says.

Khan is one of many sufferers drawn to using hallucinogens out of desperation. One sufferer, 'Flash', posted details on a cluster community internet message board explaining how he successfully treated his headaches with magic mushrooms using small doses that did not cause the wild hallucinations and sensory distortions normally associated with psychedelic drugs.

Khan says nothing happened until he tried a second dose. 'When I woke up the next day, my headaches were pretty much gone.' He adds that he takes a small maintenance dose every six to eight weeks, which keeps the headaches away without side effects.

JPEGF

The resurgent interest in using hallucinogenic drugs in a medical context (see Box) led John Halpern from Harvard Medical School, Massachusetts and his former colleague Andrew Sewell to methodically collect the anecdotal reports. Their paper (Neurology 2006, 66, 1920) showed that hallucinogens were more effective at preventing new cycles of future attacks than conventional medicines and psilocybin was better at aborting an attack than inhaling pure oxygen, which can terminate the pain in 15 minutes if administered at the right time. However, for the oxygen to be of any use, the user needs to be near the gas cylinder and it does nothing to prevent future bouts. Around 10% of people with the condition do not respond to any treatment.

By the time the paper was published, many users, afraid of the harsh penalties for possessing LSD or psilocybin, which are Schedule I substances in the US and Class A in the UK, had graduated on to using plant seeds that contain the LSD-like compound, lysergic acid amide (LSA). In the US, LSA seeds are a Schedule III substance and, although there are penalties for ingestion, there are none for possession. In the UK, many began using the seeds when a legal loophole allowing magic mushrooms to be legally sold was closed in 2005.

This gave Andrew Sewell, now based at Yale University School of Medicine, Connecticut, and colleagues the chance to invite seed users to send their specimens of Morning Glory (Ipomoea violacea), Hawaiian Baby Woodrose (Argyreia nervosa) and Ololuiqui (Rivea corymbosa) to analyse their LSA content and interview subjects about their experiences. Only subjects who agreed to have their medical records examined were included in the total sample of 53.

More than a third of subjects said the seeds were an effective abortive treatment and aborted the attack in less than 20 minutes. Nearly half of patients with episodic cluster headache reported termination of a cycle of attacks, and a further third reported partial success. Among the chronic sufferers, just over half reported between two and 120 pain-free days. The vast majority of respondents did not report psychedelic effects, providing more evidence that sub-hallucinogenic doses can be effective.

Sewell, who presented his preliminary results at the Clusterbusters conference, says that although the results have yet to be submitted to a journal, it's strong enough evidence that a randomised clinical trial is warranted. 'The seeds appear to be effective in some patients in terminating cluster attacks, ending cluster periods and extending remission periods in doses that don't need to be hallucinogenic,' says Sewell.

The results do not match those described with psilocybin or LSD, which may be due to the highly variable LSA content of the seeds. Some seeds contained no LSA at all, and varying concentrations of alkaloids in the three species' seeds meant that the ingested dose ranged from 0-2.8mg; all users who ingested ling or less did not respond.

Bob Wold, who founded Clusterbusters to help fellow sufferers use hallucinogens as safely as possible, says people like the seeds because they are easy to get. 'We've tracked over 100 people using the seeds and the results are very similar to psilocybin and LSD, although the percentages are slightly lower at breaking cycles.' He adds that one person reported some stomach troubles, and others have reported feeling tired the next day.

This is because the chemistry of the seeds is not fully understood and ingesting them can cause nausea, vomiting and possibly other more serious side effects. Another alkaloid derived from ergot, the fungus of rye from which LSD and LSA were obtained, methysergide (Sansert), is hallucinogenic at high doses and was used to prevent migraine but is known to cause the autoimmune condition retroperitoneal fibrosis, and has now been withdrawn from the US market.

Kyle Reed, an industrial research chemist who analysed the seeds for the study, doubts whether LSA itself is hallucinogenic. 'My general feeling is that the hallucinogenic effects of the seeds are caused by the combined effects of several alkaloids acting synergistically.' He adds that it is unlikely that LSA is the only compound working to relieve the headaches. Albert Hoffman, who discovered LSD, ingested LSA but noted little more than a dreamy, sedative action.

The mechanism by which the hallucinogens ease headaches is also unclear. The hallucinogens are all tryptamine molecules and bind to the same receptors in the brain as naturally occurring neurotransmitters such as serotonin. This action is exploited by some migraine drugs, such as GSK's sumatriptan (Imitrex, Imigran). But while it is the most effective remedy for many, regular use of tryptamine drugs can lead to medicine overuse headache, and can even make episodic cluster headache sufferers go chronic.

The distressing nature of the cluster attack and the lack of viable treatments has led Peter Goadsby, a neurologist at the University of California, San Francisco, US, to work with John Halpern to try and disentangle the issues. 'There have been some important questions raised by patients in the terms of psilocybin/LSD and their possible effects in cluster headache,' he says. In the late 1990s, Goadsby used PET scans and found abnormalities in sufferers' ipsilateral posterior hypothalamus neurons, a region of the brain involved in regulating circadian rhythms and responses to light, which partly explains the strange patterns of attack.

JPEGF

Torsten Passie of Hannover Medical School, Germany, is also utilising neuro-imaging, this time combined with open label bromo-LSD, which is non-hallucinogenic, to see if the medicinal effects can be uncoupled from the hallucinogenic effects.

Clinical trials often fail to replicate the success rates of earlier studies and there are safety issues attached to using such chemicals, albeit at small, infrequent doses. However, John Halpern, who has submitted an LSD/psilocybin clinical trial protocol to Harvard University's Institutional Review Board, remains cautious but determined. 'You don't propose a study to not do it,' he says.

Outlawed drugs offer hope

Halpern's proposed LSD/psilocybin cluster headache study is just one of a clutch of new studies under way, mainly in the US, that are re-investigating the medicinal effects of banned drugs. LSD, psilocybin and MDMA ('ecstasy') are currently being used as agents to ease the anxieties associated with advanced-stage cancer; the LSD study under Peter Gasser in Switzerland being the first to use the drug in a clinical context for 35 years.

Ibogaine, a drug derived from the Iboga plant used in Central and West Africa, and the medical anaesthetic ketamine are also being explored as treatments for addiction and depression, respectively. New drugs based on cannabis and related cannabinoid compounds are being developed for conditions ranging from diabetes to obesity and neuropathic pain.

Many of the new studies, including Halpern's cluster headache trial, are part-funded by the Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit company that aims to develop illicit drugs such as MDMA into prescription medicines. MAPS founder and president Rick Doblin says the resurgence in psychedelic research is down to personnel changes at the US Food and Drug Administration in the 1990s. 'New people got there whose guiding principal was that the science should be more important than the politics,' he says. 'They started opening the doors for psychedelic and psychotherapy research.'

Doblin is excited by the 'remarkable' preliminary results of MAPS' flagship study, a trial of the effects of MDMA psychotherapy on treatment-resistant individuals with post-traumatic stress disorder (PTSD), which treated its final subject in September 2008. Lead researcher Michael Mithoefer, a psychiatrist the Medical University of South Carolina, US says 'it's too early to draw conclusions, but our results are promising at this moment.'

The MDMA/PTSD study is also underway in Israel, and similar studies are planned in Spain, France and Canada.

Arran Frood is a science journalist based in the UK




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InvisiblePenguarky Tunguin
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Re: Psychedelic Research [Re: boletusoftruth]
    #9609097 - 01/14/09 03:35 PM (15 years, 1 month ago)

Shop for:  eBay Rye Grain, Morning Glory Seeds, Hawaiian Baby Woodrose  Amazon The Doors


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Offlinejazzillion
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Re: Psychedelic Research [Re: Penguarky Tunguin]
    #9609202 - 01/14/09 03:54 PM (15 years, 1 month ago)

Cool article.


also :pm:


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When it rains, it spores :shroompick:

"Consciousness is the Universe recognizing itself." Once we perceive that everything is conscious we can then ask, "How does consciousness take all these varied forms?" - The Primacy of Consciousness by Peter Russell

All works of poster are of absolute fiction to be used for no other purpose but amusement.


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Offlinefeifen

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Re: Psychedelic Research [Re: jazzillion]
    #9609226 - 01/14/09 03:58 PM (15 years, 1 month ago)

Indeed! Interesting also :pm:


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Offlineboletusoftruth
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Re: Psychedelic Research [Re: feifen]
    #9609288 - 01/14/09 04:11 PM (15 years, 1 month ago)

Responded to all the PMs so far, quite a few interested people!!!

Here is a cool article, although extensive, on DMT!

Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis.(Original Papers).

Quote:

Full Text :COPYRIGHT 2007 Sage Publications, Inc.

Abstract

Patients with schizophrenia exhibit diminished prepulse inhibition (PPI) of the acoustic startle reflex and deficits in the attentional modulation of PPI. Pharmacological challenges with hallucinogens are used as models for psychosis in both humans and animals. Remarkably, in contrast to the findings in schizophrenic patients and in animal hallucinogen models of psychosis, previous studies with healthy volunteers demonstrated increased levels of PPI after administration of low to moderate doses of either the antiglutamatergic hallucinogen ketamine or the serotonergic hallucinogen psilocybin. The aim of the present study was to investigate the influence of moderate and high doses of the serotonergic hallucinogen N,N-dimethyltryptamine (DMT) and the N-methyl-D-aspartate antagonist S-ketamine on PPI and its attentional modulation in humans. Fifteen healthy volunteers were included in a double-blind cross-over study with two doses of DMT and S-ketamine. Effects on PPI and its attentional modulation were investigated. Nine subjects completed both experimental days with the two doses of both drugs. S-ketamine increased PPI in both dosages, whereas DMT had no significant effects on PPI. S-ketamine decreased and DMT tended to decrease startle magnitude. There were no significant effects of either drug on the attentional modulation of PPI. In human experimental hallucinogen psychoses, and even with high, clearly psychotogenic doses of DMT or S-ketamine, healthy subjects failed to exhibit the predicted attenuation of PPI. In contrast, PPI was augmented and the startle magnitude was decreased after S-ketamine. These data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and naturally occurring schizophrenia.

Keywords

startle reaction, prepulse inhibition, attention, dimethyltryptamine, S-ketamine

Introduction

Prepulse inhibition (PPI) of the acoustic startle reflex is a well established model for sensorimotor gating (Braff and Geyer, 1990). Sensorimotor gating and also habituation are considered to serve as mechanisms that protect early stimulus processing and prevent the organism from experiencing sensory overload. Habituation refers to a decrease in startle response after repeated stimulation, whereas PPI refers to the reduction of the reflex amplitude by presentation of a weak prestimulus 30-500 ms prior to the startle-eliciting stimulus. Several studies indicate that PPI does not reflect a pure preattentive (automatic) mechanism but is also influenced by controlled attentional processes (Filion et al., 1998).

Deficits in gating of cognitive and sensory information are clinically important features of schizophrenia spectrum disorders and PPI is considered a suitable measure of sensorimotor gating deficits in clinical populations. Although most studies found a diminished PPI in schizophrenic patients (Braff et al., 1992, 2001b), some recent studies failed to verify this deficit (Ford et al., 1999; Wynn et al., 2004). Variations in the experimental parameters may contribute to these inconsistencies, e.g. the Wynn et al. (2004) study measured electromyographic activity (EMG) from the left eye and did not use any background noise and the Ford et al. (1999) study also used a relatively low background noise, whereas most studies that found PPI deficits in schizophrenic patients measured startle eye blink from the right eye and used a relatively strong background noise. Remarkably, one study reported normal PPI but impaired attentional modulation of PPI in a population of patients with schizophrenia (Dawson et al., 1993).

Pharmacological challenges with hallucinogens are used as models for psychosis in animal and human experimental studies (Geyer, 1998; Geyer et al., 2001; Gouzoulis-Mayfrank et al., 1998b, 1999). In animals, both N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine and ketamine (Swerdlow et al., 1998; Mansbach and Geyer, 1989, 1991) and serotonin agonists such as lysergic acid diethylamide or 2,5-dimethoxy-4-iodoamphetamine (Geyer et al., 2001) disrupt PPI. However, in human studies S-ketamine produced either an increase in PPI together with a decrease in startle magnitude (Duncan et al., 2001; Abel et al., 2003), or it had no significant effect on PPI (van Berckel et al., 1998; Oranje et al., 2002). Only Karper et al. (1995) reported a significant reduction in PPI with ketamine, using the simple arithmetic difference scores. However, as the reduction in PPI was no longer significant using percent scores, this effect was likely to be due to a decrease in startle amplitude.

Similarly, human studies with the serotonin receptor agonist psilocybin (Gouzoulis-Mayfrank et al., 1998a) and the serotonin reuptake inhibitor 3,4-methylenedioxymethamphetamine (Vollenweider et al., 1999) also reported an increase of PPI, in this case in the absence of any decrease in startle magnitudes. Furthermore, Riba et al. (2002) reported no distinct effects on PPI of Ayahuasca, a beverage containing the serotonergic hallucinogen N,N-dimethyltryptamine (DMT). Regarding these discrepancies between animal and human studies, one should consider that the hallucinogen doses used in animals have been higher compared to the human studies, and that the doses used in human studies have mostly induced a 'pre-psychotic' rather than a full-blown psychotic state (Gouzoulis-Mayfrank et al., 1998a). Therefore, it is conceivable that enhanced sensorimotor gating in human hallucinogen studies might be the expression of a compensatory mechanism aiming to overcome the imminent flooding of the organism with sensory overload. Hence, we expected that PPI might be disrupted in human studies with higher, truly psychotogenic doses of hallucinogenic drugs.

The aim of the present study was to investigate whether high doses of hallucinogenic drugs (NMDA receptor antagonist S-ketamine and serotonin receptor agonist DMT) disrupt PPI and its attentional modulation in humans.

Material and methods

Subjects

Fifteen healthy volunteers (nine men, six women; mean age 38.0 years, range: 28-53) with no current physical and no current or previous history of neurological or psychiatric disorder (Axis I and II according to DSM-IV criteria) were included in the study. Subjects with a positive family history of severe psychiatric disorder in first degree relatives, a personal history of current or previous drug abuse, or any regular medication were excluded. All subjects were screened with a medical history, a standardized psychiatric interview and a physical examination including a clinical test for normal hearing, electrocardiogram and a routine laboratory testing. All subjects were involved in work with psychiatric patients (physicians, psychologists and psychiatric nursing staff ). They had a scientific or clinical interest in the study and did not receive any payment for their participation. The study was carried out in accordance with the Declaration of Helsinki and was approved by the local ethics committee at the Medical Faculty of the University of Technology Aachen and the Federal Health Administration (Bundesinstitut fur Arzneimittel und Medizinprodukte, Bundesopiumstelle, Berlin). Written informed consent was obtained from all subjects after we described the experimental procedures in detail and explained that they might withdraw from the study at any time, if they wished so, without having to explain the reasons. Nine subjects completed both experimental days with the two doses of both drugs. The six dropouts (two men, four women) were due to unpleasant psychological effects (two subjects under S-ketamine, one subject under DMT), nausea (one subject under DMT), hypotonia (one subject under DMT), headache and mild orthostatic complaints (one subject on the day following an experiment with DMT).

Drugs

DMT fumarate was synthesized in the Pharmaceutical Institute, University of Tubingen (Germany) and prepared as solution for intravenous use by Wulfing Pharma (Gronau, Germany). Two different DMT dosages were used:

1 Low DMT: a bolus injection over 5 min with 0.15 or 0.2 mg/kg followed by a break of one minute, followed by continuous infusion with 0.01125 or 0.015 mg/kg*min over 84 min.

2 High DMT: bolus injection with 0.2 or 0.3 mg/kg and continuous infusion with 0.015 or 0.02 mg/kg*min.

S-Ketamine (Ketanest[R] S, Parke-Davis, Karlsruhe, Germany) was administered in the following dosages:

1 Low S-ketamine: a bolus injection over 5 min with 0.1 or 0.15 mg/kg followed by a break of 1 min, followed by continuous infusion with 0.0066 or 0.01 mg/kg*min over 54 min, followed by continuous infusion at a rate of 75% of the previous dose over 30 min.

2 High S-ketamine: bolus injection with 0.15 or 0.2 mg/kg, continuous infusion with 0.01 or 0.015 mg/kg*min over 54 min, followed by continuous infusion at a rate of 75% of the previous dose over 30 min.

The dosages for both drugs were determined in a previous open study with six subjects where we monitored psychopathology and plasma levels (unpublished data). The low dose range was determined so as to evoke relative subtle psychopathological alterations, below the threshold of psychotic symptoms (a so called 'prepsychotic' state), and the high dose range so as to evoke more profound alterations including true psychotic symptoms such as hallucinations and transient delusional misinterpretations of the experimental situation. Due to interindividual differences in the strength of psychological effects to the same drug dose, we always started with a medium dose which was on the maximum of the low, and at the same time at the minimum of the high dose range. Depending on the intensity of effects during the first infusion period we decided to go higher or lower for the second infusion period. This procedure leads to comparably strong psychological effects within each dose condition in spite of the individual responsiveness to the drug. To avoid a cumulation of plasma levels and clinical effects, the S-ketamine infusion rate was reduced after 60 min. Due to the fast elimination rate of DMT, a reduction of the DMT dosage over the 90 min administration period was not necessary. With these doses the psychological effects of both drugs developed fully within about 15 min and were kept relatively constant over the following period of 75 min from the start to the end of the infusion.

Study design

Participants had a baseline examination without drug administration. We decided to omit a placebo condition, because the effects of hallucinogens are so prominent that blinding is not really possible. Furthermore, the fact that we would have needed a third experimental day for the placebo condition would have been critical for the recruitment of volunteers for our study. Because of this, we decided that, on balance, it was reasonable and acceptable to omit the placebo condition.

After that, each subject participated in one experiment with DMT and one experiment with S-ketamine 2-4 weeks apart in a double-blind, cross-over design and pseudorandomized order. On each experimental day the same substance (DMT or S-ketamine) was administered in a low and a high dosage with a break of 2 h between. The order of administration of the two dosages was single-blind and was low-high on ten and high-low on twelve experiments.

Experiments were performed in a quiet laboratory room in the Department of Psychiatry at the University of Aachen. In the morning subjects had a light breakfast and during the break between the two dosages they received a small standardized meal. Both drugs were administered intravenously by an automatic infusion pump (Perfusor[R], B. Braun, Melsungen, Germany). Blood pressure and heart rate were monitored automatically (Dinamap[R], Critikon Tampa, FL, USA) during the whole experiment. Beside the modulation of the startle reflex we studied the psychological effects and the orienting of attention (Gouzoulis-Mayfrank et al., 2005, 2006). The startle session was always performed in the last 25 min of each of the drug infusions. After stopping the drug infusion the psychological effects of the drugs completely vanished within 10-30 min. Details on the general experimental procedures and the psychological effects of the drugs are presented in Gouzoulis-Mayfrank et al., 2005.

Startle measurement

For measurement of the acoustic startle, the EMG of the right orbicularis oculi muscle was recorded with a commercially available startle system (SR-Lab, San Diego Instruments, San Diego, CA, USA). The two miniature electrodes of the startle device were positioned below and lateral to the right eye and the ground electrode was placed behind the right ear over the mastoid. Acoustic startle stimuli were presented binaurally through headphones (TDH-39-P, Maico, Minneapolis, MN, USA).

All acoustic stimuli were bursts of broadband white noise with duration of 20 ms. Startle-eliciting stimuli were 115 dB bursts, the identical discrete prepulse and postpulse stimuli were 10 dB above the 70 dB white noise background. Starting with the onset of the startle stimulus, startle reaction was recorded in 250 1-ms epochs. The digitized electromyographic signal was bandpass filtered (100-1000 Hz) and analysed for startle responses. The criteria for reflex amplitude and latency as well as the software parameters were identical to previous reports (Braff et al., 1992, 2001a; Heekeren et al., 2004a, b). Trials were excluded when the peak amplitude occurred after 80 ms following the onset of the startle stimulus or when the baseline shifted more than 40 digital units (1 digital unit=1.72 [micro]V). If there was no detectable blink response, the amplitude was scored as zero and latency data were discarded.

The startle session consisted of 76 trials with six different trial types in three blocks: 1) pulse alone trials, 2) prepulse trials with an interval of 100 ms between onset of prepulse and onset of pulse (lead interval), 3) prepulse trials with a lead interval of 240 ms, 4) postpulse trials with a lead interval of 100 ms, 5) postpulse trials with a lead interval of 240 ms and 6) prepulse alone trials. The first and the last block consisted of only five pulse alone trials each which were presented in the relaxed condition. The 66 trials of the second block were 16 pulse alone trials, 16 prepulse trials for each lead interval, six prepulse-alone trials and six postpulse trials for each lead interval. One half of the trials were presented in the attended and the other half in the relaxed condition. The order of presentation of the trials was pseudo randomized. Before the baseline examination and again at the beginning of each experiment, subjects underwent a short training session in order to learn to discriminate 'simple' (pulse alone or prepulse alone) from 'composite' (prepulse + pulse or pulse + postpulse) stimuli. In the training session, the six different trial types were presented in a fixed order, which was known by the subjects. Each trial type was presented once. During the subsequent test session, subjects were seated comfortably in a bed with head and upper trunk supported. The instruction to attend to the pulse or to relax was presented visually trial-by-trial by means of two different slides on a computer screen in front of the subject. Subjects had to discriminate simple from composite stimuli only in the attended condition and they should respond to simple stimuli (pulse alone) by raising their hand. In the relax condition they should simply ignore all stimuli. Slides were initiated 4000 to 5000 ms before the onset of each trial (randomly) and remained on the screen until 200ms after presentation of the startle stimulus. Intertrial intervals (range 4-17 s) were used randomly. Slides were presented by Presentation software (Neurobehavioral Systems, Albany, CA, USA) which was triggered by the startle system (for details of this paradigm see Heekeren et al., 2004b).

Data analysis

Only the pulse alone and the prepulse trials entered the statistical analyses. Postpulse and prepulse alone trials were included in the task only to ensure that subjects sustained their attention to the startle stimulus until its end and to confirm that the prepulse itself was too weak to induce a startle reaction. To make sure that in the attended condtition the subjets had directed their attention to the stimuli, trials with incorrect responses were excluded from further analyses. Task performance in the attention task was assessed as percent score of trials with correct discrimination of the stimulus ('simple' versus 'composite'). Thereafter, habituation and prepulse inhibition were calculated as percentage scores for each subject. Habituation was calculated using the formula: [(mean amplitude first block--mean amplitude last block)/mean amplitude first block], and PPI using the formula: 100 - [(mean amplitude prepulse second block/pulse-alone trial second block) x 100].

Differences in task performance between the five conditions (baseline, low DMT, high DMT, low S-ketamine, high S-ketamine) were analysed by repeated measures ANOVA.

To investigate drug effects on startle reactivity, the differences between baseline condition and each drug condition were analysed by paired t-tests using the mean amplitude of the first blocks from the nine subjects who completed both experimental days with both doses of both drugs. Startle amplitudes of the second block from these nine subjects were analyzed by means of an ANOVA with the factors drug condition (baseline, low DMT, high DMT, low S-ketamine, high S-ketamine), trial type (pulse alone, prepulse 100 ms lead interval, prepulse 240 ms lead interval) and attention (attend, relax).

For the analysis of PPI, data from sessions with a mean amplitude of less than 20 digital units in the first block (pulse alone trials) were discarded. Due to the suppressing effects of both drugs (particularly S-ketamine) on startle amplitude (see results), we were able to study PPI in eleven subjects at baseline, seven subjects after DMT and only five subjects after S-ketamine. Only four subjects displayed sufficiently high amplitudes in all five conditions. Therefore, we performed separate analyses of the effects of the two drugs on PPI. For the baseline condition, PPI was analysed by means of an ANOVA with the factors attention (attend, relax) and lead interval (100ms, 240 ms) and differences between the single PPI scores (attend versus relaxed and 100 ms versus 240 ms lead interval) were analysed by subsequent t-tests.

Due to the small number of remaining subjects in the two substance groups after exclusion of data sets with low startle amplitude we used simple two-tailed t-tests (and in addition Wilcoxon matched-pairs tests) to investigate drug effects on PPI. First we focused on the passive part of the paradigm and compared the three conditions (baseline, low dose, high dose) separately for each lead interval and each substance. To analyse drug effects on attentional modulation of PPI difference scores (PPI attend-PPI relax) were calculated. The resulting difference scores were also analysed separately for each lead interval and substance.

JPEGF

Differences regarding the habituation were analysed in the nine subjects who completed both experimental days with DMT and S-ketamine by means of an ANOVA with the factor condition (baseline, low DMT, high DMT, low S-ketamine, high S-ketamine).

All analyses were performed using the SPSS software (version 11.0) Statistical significance was set at p[less than or equal to]0.05.

Results

From the 15 subjects who entered the study 12 subjects completed the experiment with both doses of DMT and 10 subjects completed the experiment with both doses of S-ketamine. So we had 13 subjects who completed at least one experimental day. From these thirteen subjects, two were nonresponders in the baseline condition; therefore, we were able to analyse the data of eleven subjects for the baseline condition. Nine of these eleven subjects completed both experimental days with the two doses of both drugs. Due to the suppressing effects of both drugs (particularly S-ketamine) on startle amplitude it was not possible to calculate PPI in all drug conditions. Therefore statistical analyses were performed with seven subjects in the DMT and only five subjects in the S-ketamine group. In all dropout cases undesirable effects were self-limited and required no additional medication. The interviews conducted 7 days and 10-12 months after the experiments revealed no aspects of psychopathology or substance abuse that might be related to participation in our study. Both drugs dose-dependently induced psychotic symptoms similar to schizophrenic manifestations. Phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia and attentional deficits were stronger after S-ketamine. The high doses of both DMT and S-ketamine induced truly psychotic symptoms such as hallucinations and transient delusional misinterpretations of the experimental situation. Details on psychopathological effects, after-effects and plasma levels are presented in Gouzoulis-Mayfrank et al. (2005).

Task performance

Data are reported for the nine subjects who completed both experiments with both doses of DMT and S-ketamine. Subjects responded correctly in 94.6% of the trials at baseline, 90.7% at low DMT, 94.5% at high DMT, 91.3% at low S-ketamine and 89.3% at high S-ketamine. The ANOVA revealed no significant difference between the five conditions (p = 0.174). Only the data from correct trials entered further analyses.

Amplitude

The descriptive statistics for startle amplitudes of the first block of the nine subjects with available data for all five drug conditions are presented in Fig. 1. The mean amplitude of the first block was significantly lower in the high S-ketamine condition compared to the baseline condition (t = 2.52, df = 8, p = 0.036) and there were also trends for lower amplitudes in the low S-ketamine (t = 2.20, df = 8, p = 0.059) and the high DMT condition (t = 1.87, df = 8, p = 0.098). Because of the small sample we calculated additional Wilcoxon matched-pairs tests. With this nonparametric test, the mean amplitude of the first block was significantly smaller in both S-ketamine conditions (low dosage p = 0.021, high dosage p = 0.008).

JPEGF

The complete descriptive statistics for startle amplitudes of the second block are presented in Fig. 2. There was a significant main effect of trial type (F = 6.42, df = 2,7, p = 0.026) indicating that the pulse-alone trials had the highest and the prepulse with 100 ms lead interval had the lowest amplitudes. The main effect of drug condition approached but did not reach significance (F = 4.65, df = 4,5, p = 0.061). Attentional modulation had no significant effect on startle amplitude (p = 0.171).

PPI

Percent PPI scores in the baseline condition are presented in Fig. 3. There was a significant effect of the factor lead interval (F = 19.05, df = 1,10, p < 0.001), indicating a stronger PPI with the 100 ms than with the 240 ms lead interval. The factor attention just failed significance (F = 4.69, df = 1,10, p = 0.056) and there was a trend towards a lead interval x attention interaction (F = 3.49, df = 1,10, p = 0.091). Subsequent t-tests confirmed previous observations (Heekeren et al., 2004b) of a significant influence of attention only in prepulse trials with a 240 ms lead interval (t = 2.28, df = 10, p = 0.046) and a significant influence of lead interval only in the relaxed condition (t = 4.89, df = 10, p < 0.001).

JPEGF

The PPI scores for DMT and S-ketamine are presented in Figs. 4 and 5. After both S-ketamine doses PPI was marginally or significantly increased compared to baseline at the 100 ms (t = -2.61, df = 4, p = 0.059 and t = -4.47, df = 4, p = 0.011), but not at the 240 ms lead interval. Because the S-ketamine sample was very small we performed additional non-parametric analyses by means of Wilcoxon tests. In these analyses, PPI after S-ketamine was significantly higher than baseline for both doses at the 100 ms and for the high dose at the 240 ms lead interval (all p < 0.05). There was no significant difference in PPI between baseline and DMT (t- and Wilcoxon-tests).

In order to investigate the influence of the drugs on attentional modulation of PPI, difference scores (PPI attend-PPI relax) were calculated (data not shown). Although descriptive statistics suggest an impaired attentional modulation of PPI under both drugs and dosages (Fig. 2), this effect was not confirmed by statistical analyses using either parametric or nonparametric procedures.

Habituation

We found no significant effects of drug condition on habituation (data not shown).

Discussion

The present investigation studied the influence of DMT and S-ketamine on PPI and its attentional modulation in humans. Contrary to findings with schizophrenia patients and animal studies of hallucinogens (Braff et al., 2001b; Geyer, 1998; Geyer et al., 2001), previous investigations with healthy volunteers reported increases of PPI after low to moderate doses of both the antiglutamatergic hallucinogen S-ketamine and the serotonergic hallucinogen psilocybin (Gouzoulis-Mayfrank et al., 1998a; Duncan et al., 2001; Abel et al., 2003). We speculated that this effect might be related to the relatively low doses given in human studies resulting in a 'pre-psychotic' rather than a full-blown psychotic state (Gouzoulis-Mayfrank et al., 1998a). Based on this hypothesis, we expected to find an increase of PPI after moderate, but a decrease of PPI after high, truly psychotogenic doses of both substances. In addition, we expected to find a dose-dependent impairment of the attentional modulation of PPI. This second hypothesis was based on data demonstrating disturbed attentional modulation of the PPI in schizophrenia patients even in the presence of normal PPI in a passive paradigm (Dawson et al., 1993).

JPEGF

At baseline, we found stronger PPI with the 100 ms lead interval and stronger attentional modulation of PPI with the 240 ms lead interval. These findings corroborate our previous report from a larger sample (Heekeren et al., 2004b). Both drugs elicited schizophrenia-like psychopathology, although full-blown psychotic symptoms such as hallucinations and paranoid ideation occurred only after the high doses of either DMT or S-ketamine (Gouzoulis-Mayfrank et al., 2005). After S-ketamine, startle reactivity was diminished, which is consistent with previous findings (Abel et al., 2003, Karper et al., 1995). To our surprise, however, DMT had no detectable effect on PPI and S-ketamine increased PPI after both doses. Clearly, these results are not in line with our hypothesis, that a possible compensatory mechanism during prepsychotic states after low hallucinogen doses should break down after high doses that produce truly psychotic symptoms and result in deficits of sensorimotor gating (Gouzoulis-Mayfrank et al., 1998a).

One alternative explanation for our unexpected observation of an apparent increase in PPI after the high dose of S-ketamine is that the assessment of PPI is confounded by the marked decrease in startle magnitudes produced by this drug in our study and in previous studies showing increases in PPI after ketamine (Abel et al., 2003). In both mice and rats, ketamine can reduce PPI without having any effect on startle magnitudes (Brody et al., 2003; Mansbach and Geyer, 1991). As discussed elsewhere (Swerdlow et al., 2000), it is difficult to be certain that a dramatic change in startle such as produced by ketamine in humans has not contributed to an apparent change in PPI despite the use of percentage scores. Indeed, in the case of high dose DMT, the robust psychotomimetic effects of the drug did not lead to significant changes in either percent PPI or startle magnitudes. Thus, PPI was only increased by a drug treatment when startle was decreased simultaneously. Another alternative explanation of our findings with S-ketamine derives from the demonstration by Moghaddam et al. (1997) that low doses of ketamine cause an increase of glutamatergic outflow from prefrontal cortex in rats. Abel et al. (2003) referred to this study and argued that if low dose NMDA antagonists (e.g. S-ketamine) act paradoxically as glutamate releasers, then this effect might result in an enhancement of sensorimotor gating. However, we found enhancement of sensorimotor gating after both a moderate and a high, psychotogenic dose of S-ketamine.

JPEGF

Nevertheless, we should acknowledge that our study has methodological limitations mainly due to the very small remaining sample sizes resulting after exclusion of nonresponders and drop outs. Also the order of the drug and gender distribution was not balanced in the remaining sample. Because of the small sample size we did not adjust for the alpha level in our analyses. Due to the firm restrictions in our permissions to conduct this study with a scheduled drug (DMT) we were not able to increase the sample in order to replace the drop outs. Therefore, these findings should be regarded as preliminary.

In summary, our data do not support the hypothesis of sensorimotor gating deficits in human experimental psychoses with hallucinogens and they are not in line with experimental studies in animals. Similarly, we found no clear deficits in the attentional modulation of PPI after either hallucinogen. Finally, neither drug influenced habituation of the startle reflex. This finding is in accordance with the findings from other studies with S-ketamine (Abel et al., 2003) and Ayahuasca, a beverage containing DMT (Riba et al., 2002).

In conclusion, even after high doses of the serotonergic hallucinogen DMT or the antiglutamatergic hallucinogen S-ketamine, both of which elicited clear psychosis-like psychopathological alterations, healthy subjects did not show any attenuation of PPI. Rather, PPI was augmented and startle was decreased after S-ketamine, in contrast to the decreases in PPI produced by ketamine in animals. In our view there is no indication that the conflicting PPI findings between naturally occurring and experimental psychoses are related to any limitations of the startle PPI paradigm. Rather, because PPI is reduced in patients with schizophrenia, these data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and schizophrenia.

Acknowledgements

This work was supported by a grant of the German Research Foundation (Deutsche Forschungsgemeinschaft = DFG) to the last author (Project No. 6 of a DFG clinical researcher group KFO 112/1/-1, Go 717/5-1). Some of the results of this article form part of a doctoral thesis of the fourth author (M.S.) at the Medical Faculty of the RWTH Aachen. M.A. Geyer holds an equity interest in San Diego Instruments, Inc.

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Gouzoulis-Mayfrank E, Hermle L, Thelen B, Sass H (1998b) History, rationale and potential of human experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry 31 (Suppl 2): 63-68

Gouzoulis-Mayfrank E, Thelen B, Habermeyer E, Kunert H J, Kovar K A, Lindenblatt H, Hermle L, Spitzer M, Sass H (1999) Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers. Results of an experimental double-blind placebo-controlled study. Psychopharmacology 142: 41-50

Gouzoulis-Mayfrank E, Heekeren K, Timmerbeil A, Stoll M, Stock C, Obradovic M, Kovar K A (2005) Psychological effects of S-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry 38: 301-311

Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C, Daumann J, Obradovic M, Kovar K A (2006) Inhibition of return (IOR) in the human 5HT2A agonist and NMDA antagonist model of psychosis. Neuropsychopharmacology 31: 431-441

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Riba J, Rodriguez-Fornells A, Barbanoj M J (2002) Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively. Psychopharmacology 165: 18-28

Swerdlow N R, Bakshi V, Waikar M, Taaid N, Geyer M A (1998) Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats. Psychopharmacology 140: 75-80

Swerdlow N R, Martinez Z A, Hanlon F, Platten A, Farid M, Auerbach P, Braff D L, Geyer M A (2000) Towards understanding the biology of a complex phenotype: Rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists. J Neurosci 20: 4325-4336

van Berckel B N, Oranje B, van Ree J M, Verbaten M N, Kahn R S (1998) The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects. Psychopharmacology 137: 271-281

Vollenweider F X, Remensberger S, Hell D, Geyer M A (1999) Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans. Psychopharmacology 143: 365-372

Wynn J K, Dawson M E, Schell A M, McGee M, Salveson D, Green M F (2004) Prepulse facilitation and prepulse inhibition in schizophrenia patients and their unaffected siblings. Biol Psychiatry 55: 518-523

K. Heekeren, A. Neukirch, J. Daumann, Department of Psychiatry and Psychotherapy, University of Technology Aachen (RWTH), Aachen, Germany and Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.

M. Stoll Department of Psychiatry and Psychotherapy, University of Technology Aachen (RWTH), Aachen, Germany.

M. Obradovic, K.-A. Kovar Institute of Pharmacy, University of Tubingen, Tubingen, Germany.

M. A. Geyer Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

E. Gouzoulis-Mayfrank Department of Psychiatry and Psychotherapy, University of Technology Aachen (RWTH), Aachen, Germany and Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.

Corresponding author: Professor E. Gouzoulis-Mayfrank, Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany. Email: e.gouzoulis@uni-koeln.de




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Re: Psychedelic Research [Re: boletusoftruth]
    #9609294 - 01/14/09 04:13 PM (15 years, 1 month ago)

Hahahaha here is another great article on time perception...

Title:Effects of psilocybin on time perception and temporal control of behaviour in humans.(Original Papers).

Quote:

Full Text :COPYRIGHT 2007 Sage Publications, Inc.

Abstract

Hallucinogenic psilocybin is known to alter the subjective experience of time. However, there is no study that systematically investigated objective measures of time perception under psilocybin. Therefore, we studied dose-dependent effects of the serotonin (5-HT)[.sub.2A/1A] receptor agonist psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) on temporal processing, employing tasks of temporal reproduction, sensorimotor synchronization and tapping tempo. To control for cognitive and subjective changes, we assessed spatial working memory and conscious experience. Twelve healthy human volunteers were tested under placebo, medium (115 [micro]g/kg), and high (250 [micro]g/kg) dose conditions, in a double-blind experimental design. Psilocybin was found to significantly impair subjects' ability to (1) reproduce interval durations longer than 2.5 sec, (2) to synchronize to inter-beat intervals longer than 2 sec and (3) caused subjects to be slower in their preferred tapping rate. These objective effects on timing performance were accompanied by working-memory deficits and subjective changes in conscious state, namely increased reports of 'depersonalization' and 'derealization' phenomena including disturbances in subjective 'time sense.' Our study is the first to systematically assess the impact of psilocybin on timing performance on standardized measures of temporal processing. Results indicate that the serotonin system is selectively involved in duration processing of intervals longer than 2 to 3 seconds and in the voluntary control of the speed of movement. We speculate that psilocybin's selective disruption of longer intervals is likely to be a product of interactions with cognitive dimensions of temporal processing--presumably via 5-HT2A receptor stimulation.

Keywords

psilocybin, 5-HT[.sub.2A] receptor, temporal processing, sensorimotor synchronization, altered states of consciousness, working memory, human study

Introduction

Events are perceived over time, and motor actions evolve over time. The brain, therefore, has to process temporal information adequately for the control of perception and action. Evidence to date suggests that different temporal-processing mechanisms are implemented in distinct circumscribed neural circuitries that can be affected by brain injury and pharmacological treatments (Harrington and Haaland, 1998; Rammsayer, 1999; Wittmann, 1999). Accuracy and precision of time estimation and the exact timing of motor behaviour are intimately linked to overall cognitive functioning. Basic timing processes (internal clocks) are an integral part of the whole cognitive system (Steinbuchel and Poppel, 1993; Wearden, 2004). Patients with structural damage to the brain such as with right-hemispheric focal brain lesions following a stroke (Kagerer et al., 2002) or with traumatic brain injury dominantly affecting frontal areas (Pouthas and Perbal, 2004), patients with dysfunctions related to the dopaminergic system of the brain such as in Parkinson's disease (Pastor et al., 1992) or in schizophrenia (Elvevag et al., 2003), but also healthy older adults (Block et al., 1998) can show substantial impairments in temporal processing. Specifically, these populations show more variability and deviate more strongly from target durations during tasks involving time estimates and the timing of motor acts. These findings are discussed in relation to alterations on several information-processing stages related to time processing, specifically a clock, memory and decision stage (Wearden, 2004) as well to attentional mechanisms (Zakay and Block, 1996). Specifically, recent studies report that schizophrenic patients show deficits in discriminating temporal durations (Volz et al., 2001; Davalos et al., 2002; 2003; Elvevag et al., 2003) as well as recognizing the temporal order of visual and acoustic stimuli (Braus, 2002; Tenckhoff et al., 2002).

Recent research into the pharmacological mechanism of hallucinogens (LSD, psilocybin) and dissociative anesthetics (PCP, ketamine) suggests that a dysbalance between serotonin, glutamate and dopamine neurotransmitter systems may be critical to psychotic symptom formation (Vollenweider, 1998). Specifically, there is increasing evidence that the serotonin 5-H[T.sub.1A/2A] receptor systems are involved in psychotic symptom formation as well as the cognitive and behavioural deficits of schizophrenia (Mita et al., 1986; Arora and Meltzer, 1991; Ngan et al., 2000; Bantick et al., 2001; Roth and Hanizavareh, 2004). Receptor binding studies in rats have shown that psilocin (4-Hydroxy-N, N-dimethyltryptamine), the pharmacologically active metabolite of psilocybin (Hasler et al., 1997), primarily binds to 5-HT[.sub.2A] receptors (Ki = 6 nM) and with a lower affinity also to the 5-HT[.sub.1A] sites (Ki = 190 nM) (McKenna et al., 1990). Psilocybin induces a model psychosis which mimics certain aspects of acute and incipient stages of schizophrenia (Gouzoulis-Mayfrank et al., 1998; Klosterkotter et al., 2001; Vollenweider, 2001; Vollenweider and Geyer, 2001) and causes deficits in sustained and spatial attention (Gouzoulis-Mayfrank et al., 2002; Umbricht et al., 2003; Hasler et al., 2004). In addition, it is well established, based on early phenomenological and psychological studies, that psilocybin and related serotonergic hallucinogens produce a strongly altered experience of time (reviewed in Heimann, 1994), notably a feeling of slowing down of the passage of time and a subjective overestimation of time intervals expressed in reports that 'minutes appear to be hours' or even that 'time is standing still' (Kenna and Sedman, 1964; Fischer et al., 1966).

To date, alterations in time perception and performance in humans have been linked primarily to the dopamine system (O'Boyle et al., 1996; Rammsayer, 1999), specifically to the cortico-basal ganglia-thalamic-cortical loop representing the neuronal clock (Meck, 1996). Pharmacological studies on animals and humans also support the general hypothesis that fronto-striatal circuits are critical for temporal processing. Dopaminergic antagonists (like haloperidol) that affect the meso-striatal dopamine system disrupt temporal processing in healthy subjects (Rammsayer, 1999). Moreover, animal studies indicate that both dopaminergic agonists and antagonists influence timing processes, presumably by increasing and decreasing clock speed, respectively (Meck, 1996). Patients with Parkinson's disease, who have decreased dopaminergic function in the basal ganglia, and particularly depleting input to the putamen, not only show deficits in motor timing but also in the discrimination of temporal intervals (O'Boyle et al., 1996; Hellstrom et al., 1997). Thus, intact dopamine neurotransmission within striatal and fronto-cortical sites is important for temporal processing, which is consistent with the notion that a cortico (SMA)-striato-thalamo-cortical system is involved in sensorimotor timing (Harrington et al., 2004). The basic idea in these models is that a pacemaker generates pulses and that the number of pulses represents the subjective estimate of an elapsed interval. The higher the clock rate (presumed to be dependent on the effective dopamine level) the better the temporal resolution will be and the longer subjective estimates of duration (Church, 1984; Matell and Meck, 2004; Harrington et al., 2004; but see Ivry, 1996, who proposes the dominant role of cerebellar mechanisms). Recently, the association of dopaminergic gene loci with endophenotypes of cognitive functioning such as attention and the speed in motor timing was shown (Reuter et al., 2005). Pharmacological manipulations of the serotonin system, applying 5-HT agonists and antagonists, however, have also been shown to affect duration discrimination abilities in humans. Duration discrimination of small intervals with a base duration of 50 ms even improved slightly (Rammsayer, 1989). Given the impairments of patients with schizophrenia in timing tasks, the alterations in subjective time perception in psilocybin model psychosis, and the rather unknown role of the serotonin system in modulating basic timing mechanisms, we designed the present study to elucidate the contribution of the serotonin system to time perception and temporal behaviour. Indications exist that intervals below a time unit of approximately 2 to 3 seconds are processed differently from longer intervals (e.g. Woodrow, 1951; Fraisse, 1984; Poppel, 1997; Wittmann, 1999). Typically, intervals up to 2 to 3 sec are reproduced accurately, whereas longer intervals tend to be underestimated (Kagerer et al., 2002). Subjects can accurately synchronize their motor actions to a sequence of tones presented with a frequency of approximately 1 to 2 Hz. The ability to synchronize these tones becomes more difficult with increasing inter-tone intervals and finally breaks down when intervals exceed durations of about 2 sec (Mates et al., 1994). Therefore, in the present study we aimed to investigate dose-dependent effects of psilocybin on temporal control of motor performance in sensorimotor tasks on time ranges below and above 2 to 3 seconds. We hypothesized that psilocybin would affect performance on the longer time ranges given the known elicited deficits in attention and working memory and the importance of working memory in longer duration temporal behaviour. Given the lack of any previous data on the phenomena in question, we did not know what to expect regarding possible decrements of timing performance at shorter time ranges which would indicate fundamental influence on the more basic proposed central pacemaker/accumulator mechanism.

For this double-blind, placebo-controlled experimental study of healthy volunteers, sensorimotor tasks were selected that are standard experimental tools in timing research and have proven to be sensitive measures of behavioural differences between brain-injured patient groups and controls. We employed the tasks of sensorimotor synchronization (Mates et al., 1994), temporal reproduction of time intervals (Kagerer et al., 2002), and personal and maximum tapping speed (Wittmann et al., 2001). Concerning the latter tapping tasks, neuropsychological studies point to a specialization of distinct brain networks associated with either voluntarily-chosen speed or with movements at maximum pace (Wittmann et al., 1999, 2001). This is the first systematic study of timing tasks performed in pharmacological models of psychoses in healthy human subjects. Former studies on time perception in LSD- or psilocybin-induced states in humans reporting the subjective experience of the passage of time (Kenna and Sedman, 1964), each used a single temporal-processing task to assess time-related psychomotor performance. In the study conducted by Fischer et al. (1966) self-paced tapping rate during an 8-minute recording period increased in the two subjects exposed to 115 [micro]g/kg psilocybin as compared to the performance of the same subjects on the next day without the drug. Significantly shortened pause durations between the articulations of words were recorded in 12 volunteers who were under the influence of 123 to 174 [micro]g/kg psilocybin. This result was interpreted as evidence for an increase in the speed of a physiological clock (Tosi et al., 1968). However, in a duration identification task with a time range between 300 and 1000 ms, LSD did not affect performance of four subjects (Mitrani et al., 1977). Distinct from these limited measures of timing used previously, our study aims to systematically assess timing performance by investigating the impact of psilocybin on standardized measures of temporal processing. Following from this approach, basic neuropharmacological mechanisms of time perception in the normal brain as well as in psychotic disorders may be elucidated.

Methods and Materials

Subjects

Subjects were students from the University of Zurich and a technical college. Volunteers were supplied with oral and written information about the aim of the study and the effects and possible risks of psilocybin administration. All provided written informed consent. Eligible subjects had to have normal or corrected-to-normal vision, no hearing problems, were healthy according to medical history, physical examination, clinical-chemical blood analysis and electrocardiogram. Participants were right handed and instructed to use their dominant hand in all experimental tasks. They were also deemed by psychiatric interview to have no personal or family (first-degree relatives) history of a major psychiatric disorder or evidence of regular alcohol or substance abuse. Subjects were also diagnosed according to the DIA-X computerized diagnostic expert system (Wittchen and Pfister, 1997). Administration of psilocybin to healthy subjects was authorized by the Swiss Federal Office of Public Health, Bern. The study protocol was approved by the Ethics Committee of the University Hospital Zurich. Twelve young volunteers (six men and six women; mean age 26.8 years, SD 3.6) were recruited. Six of these participants reported having had previous experience with psilocybin through the ingestion of psilocybe mushrooms (no more than three times) and seven had used cannabis sporadically. All subjects were reimbursed for their time and were informed that they were free to withdraw from the study at any time without reprisal.

Time measures

Temporal reproduction Subjects were instructed to reproduce the duration of a sound at 500 Hz that was presented at comfortable loudness via earphones. Six different standard intervals of 1500ms, 2000ms, 2500ms (short intervals), and 4000 ms, 4500 ms, 5000 ms (long intervals) were used. Each interval was presented randomly eight times, resulting in 48 trials per subject. A trial started with the presentation of a randomly-selected standard interval. After the tone had ended, a fixed-pause interval of 2000 ms duration followed. Then the tone was presented again. Subjects were instructed to reproduce this duration by pressing a key to switch off the stimulus when they believed that the duration corresponded to the previously presented standard interval. After completion of the reproduction phase, a new standard interval was presented. Thus, presentation phases always alternated with reproduction phases. Mean reproduced intervals and the standard deviation of reproduction were calculated over the eight trials per standard interval.

Sensorimotor synchronization Through headphones subjects heard a regular sequence of tonal stimuli that had to be synchronized precisely by tapping the index finger on a key. The intervals between tone onsets were constant. Four different durations of inter-onset intervals were presented in different trials: 700 ms, 1000 ms, 2000 ms and 4000 ms. The number of tones in each trial was varied to achieve a constant trial duration of 56 sec: 80 (700 ms), 56 (1000 ms), 28 (2000 ms), and 14 (4000 ms). Tones had a frequency of 500 Hz and duration of 100 ms. A software program (Mates, 1990) controlled the stimulus presentation and the registration of the inter-tap intervals, as well as recording the asynchrony between the tone onset and the tap onset. As a measure of accuracy of synchronization, the mean asynchrony between tap and tone onset per trial was registered. As a measure of impaired synchronization ability the number of reactions to the tones per trial was calculated. A reaction to a tone or 'missed synchronization' was defined as a tap onset following a tone with an interval of at least 120 ms. If recorded human reaction times to acoustic stimuli occur less than approximately120 ms after a stimulus has been presented, they are considered as 'false start', e.g., they were initiated before the stimulus actually occurred (Najenson et al., 1989). Therefore, we defined positive asynchronies (taps occurring after the tone) of more than 120 ms as reactions to the stimulus, that is, as failed attempts to anticipate and synchronize with the repeatedly occurring tone.

Tapping speed Subjects were instructed to tap constantly on a key with the index finger in a personally chosen constant tempo that was neither too fast nor too slow (personal tapping tempo). Then, in a second task, subjects had to tap at maximum speed (maximum tapping tempo). The program by Mates (1990) registered every single inter-tap interval and terminated the program after 20 taps in each task. The median inter-tap interval per trial is calculated as the measure of tapping speed and a coefficient of variance (Interquartile/Median x 100) per trial is taken as a measure of stability of the tapping performance for each person and tapping task.

Cognitive test

Spatial Span test Spatial working memory was assessed using the spatial span (SSP) test taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Robbins et al., 1994). The spatial span test is a computerized version of Corsi's block tapping task measuring the spatial working memory span. For this test, up to nine white boxes arranged irregularly on a black background were presented on a touch screen. During each trial a set number of the boxes were sequentially highlighted by a change in their colour, before returning back to white. Each box was highlighted for the duration of 3 sec. The period between each subsequent box highlighting was 0.5 sec. For each trial the subject was instructed to remember the order in which the boxes were highlighted and then reproduce these changes at the end of the trial by touching the respective boxes in the appropriate sequence. Subjects were initially presented with a sequence of two boxes. After this trial one additional box was added to the sequence after every correct response, up to a maximum of nine boxes. When the subject made a mistake the following trial would repeat the previous number of boxes in a different sequence. After three incorrect responses on any number of boxes, the test was terminated. The final number of boxes that the subject was able to accurately reproduce (Span Length) was recorded.

Psychometric measures

The Altered State of Consciousness rating scale (5D-ASC) (Dittrich, 1998) and the Adjective Mood Rating Scale (AMRS) (Janke and Debus, 1978) were used to assess the subjective effects under placebo and psilocybin. Both the AMRS and 5D-ASC have previously been shown to be sensitive to the psychological effects of psilocybin in humans (Vollenweider et al., 1997, 1998, 1999; Hasler et al., 2004).

5D-ASC The Altered States of Consciousness rating scale 5D-ASC (Dittrich, 1998; Dittrich et al., 1999) consists of 94 items that are visual-analogue scales of 10 cm length. These items measure alterations in mood, perception, experience of self in relation to environment, and thought disorder. Scores of each item range between zero ('No, not more than usually') and ten ('Yes, much more than usually'). The ASC items are grouped into five main factors comprising several items. (1) 'oceanic boundlessness' (OB) measures derealization and depersonalization accompanied by changes in affect ranging from heightened mood to euphoria and/or exaltation as well as alterations in the sense of time. The corresponding item clusters are 'positive derealization', 'positive depersonalization', 'altered time sense', 'positive mood', and 'mania-like experience'. (2) 'anxious ego dissolution' (AED) measures ego disintegration associated with loss of self-control, thought disorder, arousal, and anxiety. The item clusters are 'anxious derealization', 'thought disorder', 'delusion', 'fear of loss of thought control', and 'fear of loss of body control'. (3) 'visionary restructuralization' (VR) includes the item clusters 'elementary hallucinations', 'visual (pseudo-) hallucinations', 'synesthesia', 'changed meaning of percepts', 'facilitated recollection', and 'facilitated imagination'. (4) 'auditory alterations' (AA) refers to acoustic hallucinations and distortions in auditory experiences and (5) the dimension 'reduction of vigilance' (RV) relates to states of drowsiness, reduced alertness, and related impairment of cognitive function.

AMRS The Adjective Mood Rating Scale (AMRS) (Janke and Debus, 1978) consists of 60 adjectives representing different mood states. Subjects were instructed to rate the extent to which each adjective was applicable to their current mood from the options: 'not at all' (1), 'a little' (2), 'quite' (3) and 'strongly' (4). The AMRS consists of the following main factors: 'concentration', 'inactivation,' 'tiredness,' 'dazed state', 'introversion', 'heightened mood', 'emotional excitability', 'anxiety,' 'depressiveness,' and 'dreaminess.'

Experimental procedure

Substance and dosing Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) was obtained through the Swiss Federal Office of Public Health, Bern. Psilocybin capsules (1 mg and 5 mg) were prepared at the Pharmacy of the Cantonal Hospital of Aarau, Switzerland. Quality control comprised tests for identity, purity and uniformity of content. Psilocybin and lactose placebo were administered in gelatine capsules of identical appearance. After oral uptake, psilocybin is rapidly transformed to the pharmacologically active metabolite psilocin (Hasler et al., 1997; Lindenblatt et al., 1998). Usually, first subjective effects of psilocybin are perceived 20 to 40 min after oral administration and peak at about 60 to 90 min to last for another 60 to 120 min. All psilocybin-induced symptoms usually wear off 6 to 8 hours after drug administration (Vollenweider et al., 1997; Hasler et al., 2004).

Study design

We conducted a double-blind, placebo-controlled, within-subject design with three experimental arms: placebo, medium and high doses of psilocybin were administered with a counterbalanced order of administration. Subjects were tested on 3 days separated by at least 14 days to avoid carry-over effects. The medium dose (MD) psilocybin (115 [micro]g/kg; mean body weight of subjects 70.3 [+ or -] 12.5 kg; absolute doses 8.2 [+ or -] 1.4 mg psilocybin) and the high dose (HD) psilocybin (250 [micro]g/kg; absolute doses 17.6 [+ or -] 3.2mg psilocybin) were selected for this study due to observations from a previous investigation (Hasler et al., 2004). These selected doses produced perceptual alterations without producing profound thought disturbances or complete loss of ego control. One week ahead of the first experiment, subjects underwent a somatic and psychiatric examination and were familiarized with the sensorimotor tasks. Subjects arrived at the research unit of the University Hospital of Psychiatry at 8.30 AM on each experimental day, and psilocybin or placebo capsules were administered at 10.00 AM.

Performance on the sensorimotor tasks was assessed just prior to administration of drug/placebo ([t.sub.0]; baseline measures), at 90 minutes during the anticipated peak effects ([t.sub.1]), and 240 minutes after drug intake ([t.sub.2]), when effects had decreased substantially. Subjects also underwent psychometric measurements using the AMRS (at 0, 80 and 280 min after drug/placebo administration) and the 5D-ASC (at 110 min). The SSP of the CANTAB battery was accomplished at 0, 100 and 360 min after drug/placebo intake. Subjects were examined by the principal investigator approximately 7 to 8 hours after drug intake and released from the hospital only when the psychotropic effects had completely subsided. The presented results are part of a study that also comprised tests of binocular rivalry (sampled at 100 min, 180, 270 and 360 min), these results are reported separately (Carter et al., 2005).

Statistical analysis

Psychometric data were analysed using a one-, two-or three-way repeated measures ANOVA. Analysed factors were (1) treatment (placebo, MD psilocybin, HD psilocybin), (2) time of measurement ([t.sub.0], [t.sub.1], [t.sub.2]) and--where applicable-(3) measures or subscales (different temporal intervals in a timing task or subscales on a questionnaire). The interaction of treatment x time of measurement was considered as the main source of information since the effect of psilocybin should occur at [t.sub.1] and to a lesser degree at [t.sub.2], in contrast to the placebo condition. In cases where a significant interaction effect was observed, simple a priori contrasts compared differences between placebo and both MD and HD psilocybin. These drug dose effects were considered in respect to changes over time from both [t.sub.0] to [t.sub.1] and [t.sub.0] to [t.sub.2] (four contrasts). In some cases we looked at the three treatment conditions separately. Then, time of measurement ([t.sub.0], [t.sub.1], [t.sub.2]) was the main factor in three drug conditions followed by two contrasts each ([t.sub.0] to [t.sub.1] and [t.sub.0] to [t.sub.2]). Pearson's correlation analysis was used to compare relative change in performance on the temporal-processing tasks, the spatial span working memory test and the 5D-ASC rating scale. Only those correlations found to be significant at both medium and high doses were considered. For these cases, the low and high dose data were pooled to calculate a single Pearson's r value for that measure.

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To minimize the possible effects of non-normal distribution in the data sets, we transformed all data prior to analysis by applying a natural log transform. In the case that negative values had to be transformed, a constant was added to the variable to make sure that all values were positive. Additionally, Greenhouse-Geisser adjustment of degrees of freedom was applied to the data set when, according to the Mauchly test, sphericity of the sample distributions could not be assumed. Significance levels were set to values of p < 0.05. However, since multiple comparisons were planned for each measure, the risk of Type I error increases (incorrect rejection of null hypothesis). To ensure overall protection level, only those planned contrasts associated with the decisive interaction for hypothesis testing (e.g. time of measurement X treatment) on each measure are reported. Nevertheless, we adjusted the alpha level for each measure to the amount of contrasts that were applied (e.g. two contrasts: p < 0.025, four contrasts: p < 0.0125) as well as for the number of ANOVAs that were calculated for different subscales of a task.

Results

Temporal reproduction

To test for an effect of psilocybin on temporal reproduction, three-way repeated measure ANOVAs were calculated separately for the short (1500 ms, 2000 ms, 2500 ms) and the long intervals (4000 ms, 4500 ms, 5000 ms). The three main factors included were interval duration (three intervals for the short and the long intervals, respectively), measurement time ([t.sub.0], [t.sub.1], [t.sub.2]) and treatment (placebo, MD and HD psilocybin). For the short intervals, interval duration was the only factor to show a significant effect [F(2, 16) = 600.2, p < 0.001], reflecting a linear increase in reproduction intervals as a function of the presented interval duration (see Figs 1a-1c). No other main factors or interactions showed significant differences. For the long intervals, significant main effects of interval duration [F(2, 16) = 130.0, p < 0.001] and measurement time [F(2, 16) = 6.9, p = 0.007] were revealed. The interaction treatment X measurement time, the decisive interaction to reveal differential drug effects between peak and baseline, proved to be significant [F(4, 32) = 3.2, p = 0.025]. No other interaction revealed a significant effect.

To discern the treatment X measurement-time interaction at the long intervals, we looked separately at the three treatment conditions that were tested at the three measurement times. For every treatment condition, a two-way ANOVA with the interval duration (4000 ms, 4500 ms, 5000 ms) and measurement time ([t.sub.0], [t.sub.1], [t.sub.2]) was calculated. In the placebo condition (Fig. 1a), we found a significant difference for the factor interval [F(1, 8) = 98.1, p < 0.0001], but no significant effect of measurement time and no significant interaction of measurement time X interval duration. A similar result was obtained for MD psilocybin (Fig. 1b): a significant difference was only revealed for the factor interval [F(2, 20) = 122.7, p < 0.0001] and measurement time did not reach the significance level (p < 0.1). The interaction between interval duration and measurement time also revealed no significant effect. In the treatment condition HD psilocybin (Fig. 1c), however, the ANOVA revealed significant effects for both main factors, interval duration [F(2, 22) = 49.5, p < 0.001] and measurement time [F(2, 22) = 7.0, p = 0.004]; no significant interaction effect was found. As depicted in Fig. 1c, temporal reproductions at the long intervals showed a stronger tendency toward underestimation at peak time of HD psilocybin as compared with baseline. Contrasts for the effect of measurement time in the HD-psilocybin condition showed significant differences for the contrast between [t.sub.1] and [t.sub.0] [F(1, 11) = 13.0, p = 0.004] but no significant difference between [t.sub.2] and [t.sub.0] [F(1, 11) = 0.36, p = 0.561]. Thus, HD psilocybin leads to a significant under-reproduction of time intervals of 4 seconds and longer.

To assess the stability of performance, we compared the standard deviation of the reproduced interval for the three factors: interval, measurement time and treatment. A three-way ANOVA for the short intervals did not reveal any significant effects. For the long intervals, measurement time showed a significant effect. However, for both, the long and short interval durations, the treatment X measurement time interaction failed to reach the significance level.

Sensorimotor synchronization

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Asynchrony (Mean) To assess the subjects' ability to temporally synchronize to a regularly occurring external stimulus, a three-way ANOVA with the main factors: treatment, measurement time and interval (700 ms, 1000 ms, 2000 ms, 4000 ms) was calculated for the dependent variable asynchrony. Whereas the effect of treatment failed to reach significance [F(2, 22) = 3.0, p = 0.069], measurement time [F(2, 22) = 10.1, p = 0.001] and interval [F(1.2, 13.5) = 16.7, p < 0.001; Greenhouse-Geisser adjusted] showed significant differences. Moreover, the measurement time X treatment interaction was found to be significant [F(4, 44) = 3.9, p = 0.009]. The interaction between interval and measurement time failed to reach significance [Greenhouse-Geisser adjusted]. The interaction of interest (measurement time X treatment) only tended towards significance for the contrast between HD psilocybin and placebo between [t.sub.1] and [t.sub.0] [F(1, 11) = 4.5, p = 0.057] but a significant difference was observed for the contrast between MD psilocybin and placebo between [t.sub.1] and [t.sub.0] [F(1, 11) = 14.5, p = 0.003].

To take a closer look at the treatment X measurement-time interaction, we calculated two-way ANOVAs separately for the three treatment conditions with the two main factors: measurement time and interval. In the placebo condition, only the main factor interval [F(1.2, 13.2) = 13.6, p = 0.01; Greenhouse-Geisser adjusted] proved to be significant. No significant differences were found for either measurement time or the interval X measurementtime interaction (Fig. 2a). In the MD-psilocybin condition both factors interval [F(1.27, 33) = 12.4, p = 0.002; Greenhouse-Geisser adjusted] and measurement time [F(2, 22) = 10.2, p < 0.001] revealed significant differences, but not the interaction of the two. Contrasts for the effect of measurement time in the MD-psilocybin condition showed a significant difference for the contrast between [t.sub.1] and [t.sub.0] [F(1, 11) = 16.9, p = 0.002] but no significant difference between [t.sub.2] and [t.sub.0] [F(1, 11) = 0.669, p = 0.431] (Fig. 2b). In the HD psilocybin condition, interval [F(1.4, 15.9) = 9.9, p = 0.003; Greenhouse-Geisser adjusted] and measurement time [F(2, 22) = 8.1, p = 0.002] as well as the interval X measurement-time interaction [F(2.5, 27.7) = 4.7, p = 0.012; Greenhouse-Geisser adjusted] reached the significance level. Contrasts for the effect of measurement time in the HD-psilocybin condition revealed only a marginally significant difference (adjusted p value) for the contrast between [t.sub.1] and [t.sub.0] [F(1, 11) = 5.5, p = 0.039] and no significant difference between [t.sub.2] and [t.sub.0] [F(1, 11) = 1.844, p = 0.202] (Fig. 2c). It is to note that the smaller mean asynchrony between tap and tone onset does not reflect a more precise synchronization ability but instead an increase in reaction times, that is, more missed synchronizations (see below).

Asynchrony (standard deviation) To measure the stability of synchronization performance, the standard deviation of the asynchrony between the tap and the tone was taken as the dependent variable in a three-way ANOVA with the main factors: treatment, measurement time and interval. Treatment [F(2, 22) = 1.4, p = 0.874] and time of measurement [F(2, 22) = 1.6, p = 0.229] showed no effect on performance. The length of the inter-beat interval had a significant influence on tapping variability [F(3, 33) = 227.5, p < 0.001]-the standard deviation getting bigger with increasing intervals. However, the important interaction measurement time X treatment [F(4, 44) = 1.4, p = 0.268] was not significant.

Per cent missed synchronization As can be seen in Fig. 3a-c, it was only for the 2- and 4-seconds intervals that a considerable amount of reaction time asynchronies (> 120 ms) were detectable. Therefore, only these two intervals were taken for further calculations. A three-way ANOVA comparing the per cent missed synchronization for the factors--treatment, measurement time and interval (2000 ms, 4000 ms)--showed a significant main effect only for treatment [F(2, 22) = 4.9, p = 0.018] and interval [F(1, 11) = 16.5, p = 0.002]. The interaction in focus of our hypotheses treatment X measurement time showed not to be significant [F(4, 44) = 1.1, p = 0.37] although--descriptively--subjects show more reaction times under psilocybin at peak-time than at baseline or at post peak (see Fig. 3a-c).

Personal tapping speed

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A two-way ANOVA (treatment and measurement time) revealed that psilocybin significantly slowed tapping tempo. There was a main effect of measurement time [F(2, 20) = 3.5, p = 0.05], treatment [F(2, 20) = 4.9, p = 0.019], and the measurement time X treatment interaction [F(4,40) = 3.1, p = 0.026]. Subjects tapped slower during peak effects of HD psilocybin (949.0 ms, SD: 390.0) than at baseline (692.2 ms, SD: 274.6) and post-peak effects of drug (772.1 ms, SD: 280.7). Following a one-way ANOVA with the factor measurement time in the HD condition [F(2,20) = 8.7, p = 0.002], subsequent contrasts reveal a significant difference between [t.sub.1] and [t.sub.0] [F(1,10) = 13.6, p = 0.004] but no significant difference between [t.sub.2] and [t.sub.0] [F(1,10) = 2.7, p = 0.133]. No effect of measurement time was seen in the MD condition [F(2,20) = 1.5, p = 0.247]. The coefficient of variance, the measure for tapping stability in the personal tempo, revealed a significant main effect of measurement time [F(2,20) = 5.7, p = 0.01], but no effect for treatment or the interaction of the two main factors.

Maximum tapping speed

Over the different experimental conditions, subjects' maximum tapping speed was registered with mean inter-tap intervals of approximately 150ms. Two-way ANOVA for the factors measurement time [F(2,22) = 10.9, p = 0.001] and treatment [F(2,22) = 4.3, p = 0.026] showed significant main effects. However, the important measurement time X treatment interaction was not significant. Since the main effect of treatment includes the [t.sub.0] and [t.sub.2] measurement times in addition to the [t.sub.1] measurement time, the treatment effect was probably due to by chance different performance on the psilocybin administration day. Furthermore, a two-way ANOVA on the coefficients of variance for the inter-tap interval showed no significant main effects or interaction, suggesting that tapping stability at maximum speed is unaffected by psilocybin.

Spatial span task

Two-way ANOVAs (factors treatment and measurement time) were calculated to elucidate the effects of psilocybin on the spatial span length. We found no overall effect for treatment [F(2,22) = 1.33, n.s.], a significant effect to measurement time [F(2,22) = 4.05, p = 0.032], and-decisive for the question of concern--a significant interaction effect [F(2,22) = 4.66, p = 0.003]. A priori contrasts (alpha level adjusted to p < 0.0125 for four contrasts) revealed a significant difference only for the contrast between placebo and HD psilocybin between [t.sub.1] and [t.sub.0] (p < 0.011). Thus, at the peak of effects, HD psilocybin (and not MD psilocybin) impaired spatial span task (SSP) performance as indexed by span length (see Fig. 5).

Altered States of Consciousness rating scale (5D-ASC)

As shown in Fig. 4, psilocybin increased the scores of the 5DASC dimensions (as assessed at peak time) in a dose-dependent manner. There was a main effect of treatment [F(2,22) = 14.2, p < 0.001]. The main effect for subscale did not reach the significance level [F(2.22,24.2) = 4.38; p = 0.064; Greenhouse-Geisser adjusted] but the treatment X subscale interaction did [F(8,88) = 2.53, p = 0.016]. Subsequent one-way repeated measures ANOVAs comparing the three treatment conditions at peak time were performed for each of the five subscales (adjusted alpha level for five comparisons is p < 0.01). A significant effect of treatment could be seen in all five subscales: OB [F(2,22) = 13.54; p < 0.001; contrast for MD psilocybin vs placebo: p = 0.01; contrast for HD psilocybin vs. placebo: p < 0.001], AED [F(2,22) = 7.08; p = 0.004; MD psilocybin vs. placebo: p = 0.046 (n.s.); HD psilocybin vs placebo: p = 0.005], VR [F(2,22) = 11.2; p < 0.001; MD psilocybin vs placebo: p = 0.006; HD psilocybin vs placebo: p = 0.003], AA [F(1.368,15.05) = 9.79; p = 0.004; Greenhouse-Geisser adjusted; MD psilocybin vs placebo: p < 0.167 (n.s); HD psilocybin vs placebo: p = 0.007], RV [F(2, 22) = 7.67; p = 0.003; MD psilocybin vs placebo: p = 0.004; HD psilocybin vs placebo: p = 0.003].

A subsequent exploration of the ASC item clusters in each subscale revealed that the increase in OB after high-dose psilocybin was mainly due to moderate increases in (positive) 'derealization phenomena' (30.8 [+ or -] 18.7% of scale maximum), 'heightened mood' (30.1 [+ or -] 18.9%) and 'mania-like symptoms' (26.0 [+ or -] 18.5%). The item of special interest, 'altered time sense', also showed a significant effect of psilocybin [F(1.33,14.61) = 7.9; p = 0.009; contrast for MD psilocybin vs placebo: p = 0.083 (n.s.); contrast for HD psilocybin vs placebo: p = 0.017]. The increase in AED was attributable to moderate 'thought disturbances' (45.0 [+ or -] 29.8% of scale maximum) followed by slight increases in 'loss of body control' (20.1 [+ or -] 21.0%), 'loss of thought control' (15.9 [+ or -] 28.5%) and 'anxious derealization' (15.0 [+ or -] 23.4%). Furthermore, the analysis of the VR item-cluster revealed that only the high dose, but not the medium dose of psilocybin significantly produced 'Complex hallucinations' and increased 'facilitated recollection and imagination,' and that increase in VR after medium dose of psilocybin was mainly due to visual illusions and elementary hallucinations, such as light flashes or geometric figures.

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Adjective Mood Rating Scale (AMRS)

Two-way repeated measures ANOVAs were performed for each of the ten subscales (adjusted alpha level: p < 0.005). A significant interaction between treatment and measurement time, was found for the subscales of inactivation [F(4,44) = 7.89, p = 0.001; significant contrast for MD psilocybin vs placebo between [t.sub.0] and [t.sub.1] (p < 0.001) as well as between HD psilocybin and placebo between [t.sub.0] and [t.sub.1] (p = 0.019)], tiredness [F(4,44) = 6.6, p < 0.001; MD psilocybin vs placebo between [t.sub.0] and [t.sub.1] (p < 0.001)], dazed state [F(4,44) = 6.51, p < 0.001; MD psilocybin vs placebo between [t.sub.0] and [t.sub.2] (p < 0.001)], introversion [F(4,44) = 9.84, p < 0.001; MD psilocybin vs placebo between [t.sub.0] and [t.sub.2] (p < 0.001)], emotional excitability [F(4,44) = 5.36, p < 0.001; MD psilocybin vs placebo between [t.sub.0] and [t.sub.1] (p = 0.015)], and dreaminess [F(4,44) = 12.4, p < 0.001; MD psilocybin vs placebo between [t.sub.0] and [t.sub.1] (p = 0.009) as well as [t.sub.0] and [t.sub.2] (p < 0.001)]. A tendency for a treatment X measurement-time interaction was found for the subscale of 'Concentration' [F(4,44) = 4.12, p = 0.006]. No significant interaction effect appeared for the subscales of heightened mood, anxiety and depressiveness. The effects of psilocybin on the AMRS mood scales during peak time, comparing the three treatment conditions, are presented in Fig. 6.

Correlations between working-memory performance, time measures and psychometric scores

Correlational analyses revealed no significant correlation between spatial span length and temporal reproduction for the longer intervals (4000, 4500, 5000 ms; where significant drug effects were found) (r ranged from -0.17 to 0.16). However, there was a strong negative correlation between spatial span length and the OB subscore (r = -0.73, p < 0.001). Further multiple regression analysis revealed that the two OB items 'depersonalization' and 'altered time sense' contributed most to this effect (r = -0.83, p < 0.0001 and r = -0.69, p < 0.001, respectively). Importantly, the other factors on the 5D-ASC did not show significant correlations with spatial span length, indicating that this effect was specific and not a generalized association between the drug-induced altered state of consciousness and working-memory decrement. There were no significant correlations between any of the temporal-processing measures and the 5D-ASC subscales, however a trend towards correlation between the OB subscore and the time reproduction underestimation at longer time intervals was found. Specifically, the item 'altered time sense' showed moderate correlation coefficients with the longer time intervals in temporal reproduction at peak time under the influence of MD and HD psilocybin: the larger the underestimation of the 4500 and 5000ms interval, the higher the score on the 'altered time sense' item (r between 0.4 and 0.6). However, these associations failed to reach the significance level.

Discussion

Our investigation clearly revealed that the 5-H[T.sub.2A]/5-H[T.sub.1A] mixed agonist psilocybin alters time perception and temporal control of behaviour in humans. These results confirm self-reports that hallucinogens cause strong alterations in spatial and temporal perception (Vollenweider et al., 1997; Hasler et al., 2004) and extend these psychometric findings by showing the specific ways in which objective measures of temporal processing can be affected. Psilocybin was found to affect an individual's capacity to accurately reproduce interval lengths longer than 3 seconds, synchronize a motor response (finger tap) to regular auditory beats with intervals longer than 2 seconds, and to slow down the personal tapping tempo (preferred tapping rate). No impairment of performance was observed for shorter lengths on the sensorimotor synchronization and the reproduction task. This indicates that the effects found at the longer intervals were likely a product of interactions with cognitive dimensions of temporal processing instead of interactions with the proposed basic pacemaker/accumulator mechanisms of the brain (Rammsayer, 1999; Wearden, 2004).

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Several studies on timing point to a temporal-integration interval of approximately 2 to 3 sec that can be found in perception and motor performance (for reviews, see Fraisse, 1984; Poppel, 1997; Wittmann, 1999). Durations of temporal intervals in the temporal-reproduction task are estimated precisely with intervals up to approximately 2 to 3 sec, whereas longer intervals are substantially underestimated (Kagerer et al., 2002). A temporal limitation of anticipatory planning is also observed in the sensorimotor synchronization task. The ability to synchronize accurately becomes substantially weaker when the inter-stimulus interval is longer than 2 sec (Mates et al., 1994). Our pharmacological approach contributes to these findings, as psilocybin mildly affects only those intervals of longer duration in each task. One of the few time perception studies under LSD in humans adds to our results (Mitrani et al., 1977): subjects did not show distortions in the ability to identify durations of visual stimuli in the range between 300 ms and 1 sec although they reported changes in the subjective passage of time.

In respect to the current model of timing with multiple processing stages (Wearden, 2004), the disturbed timing abilities for sensorimotor synchronization and duration reproduction we show here could reflect impairments of short-term memory, attention or decision-making mechanisms (Zakay and Block, 1996; Pouthas and Perbal, 2004), rather than the alteration of the pacemaker-accumulator clock (the basic internal timing mechanism). This is especially supported by the concurrent deficits observed in working memory in the present study. Converging evidence exists for the involvement of working memory in temporal reproduction. Processing of a secondary task that influences working-memory capacity interferes with the encoding and reproducing of durations in the domain of seconds (Fortin and Rousseau, 1998). Miyake et al. (2004) showed that a secondary working-memory task affected the accuracy of synchronization only with inter-stimulus intervals above 2 seconds. With inter-stimulus intervals below 2 seconds the memory task had no influence on performance. In a group of elderly subjects, working memory capacity correlated with performance in a temporal reproduction task with durations of 5 and 14 seconds (Baudouin et al., 2006). Frontal regions known to be closely linked with working-memory function, particularly dorsolateral and frontomedial cortices (Postle et al., 2000; Cabeza and Nyberg, 2000; Owen, 2000) are active during temporal reproductions of time intervals of a few seconds (Elbert et al., 1991; Volz et al., 2001; Monfort and Pouthas, 2003). Given the selective effect of psilocybin on the longer duration intervals in both the temporal reproduction and sensory synchronization tasks it seems that the temporal disturbance observed is induced through interference with cognitive processes like attention and working memory. The fact that no correlations were found between performance on the working-memory and temporal-processing tasks, should not be considered as evidence against this hypothesized role of working memory in the observed timing impairments. Rather it is likely to reflect the small sample size combined with the relatively small effect sizes seen in both the timing measurements and the working memory. In fact, the small impairments observed for the timing measures may reflect a relative insensitivity of working memory performance to psilocybin, a claim supported by the finding that psilocybin had no significant effect on working memory at either the median dose used in this study (115 [micro]g/kg) or a higher dose (215 [micro]g/kg) used in a separate study (Carter et al., in press). However, further studies are warranted to corroborate this interpretation. Moreover, it is also possible that other working-memory functions such as verbal working memory might be more significantly associated with the timing tasks.

JPEGF

Whereas the maximum-tapping speed was unaffected by psilocybin, the tapping tempo in a voluntarily chosen tempo was significantly slower during peak effects of HD psilocybin as compared to baseline and post-peak time of that condition. This finding is consistent with several lines of evidence showing that the control of motor speed can basically be characterized by two distinct sensorimotor processes functioning with different frequencies. For example, movements with a frequency of 1 to 2 Hz are under voluntary control and allow the collection of somatosensory information (feedback control), while movements at maximum speed with frequencies of 5 Hz and above require only coarse pre-attentive control (feed-forward control) (Peters, 1989; Kunesch et al., 1989; Wittmann et al., 1999). These two sensorimotor modes appear to be controlled by distinct neural networks. Injury of the cerebellum can lead to dysdiadochokinesia, the inability to alternate agonist and antagonist muscles with maximum speed (Dichgans, 1984). In contrast, metabolic dysfunction of the basal ganglia such as in Parkinson's disease can lead to the inability to tap at a slower pace, patients showing the so-called hastening phenomenon (Nakamura et al., 1978). In another study, tapping in a self-paced tempo was slowed down in patients with left-hemispheric lesions to the brain, whereas maximum-tapping speed was not influenced by lesions in either side of the cortex (Wittmann et al., 2001). The effect of HD psilocybin on personal tapping tempo, leading to a slower pace of the regular finger taps at peak time, could be the result of the drug influencing cortical sites of the brain, including those of the left hemisphere. In partial support of such a hypothesis we have previously found that psilocybin caused left-over-right sided dorsolateral overactivation that significantly correlated with depersonalization phenomena using FDG-PET imaging (Vollenweider et al., 1997; Vollenweider, 2001).

Psilocybin-induced dose-dependent changes to subjective measures of conscious state, i.e. the loosening of ego boundaries, changes in affect and perceptual distortions as previously reported in detail (Vollenweider et al., 1997; Hasler et al., 2004), included the expected changes in time perception as indexed by the 5DASC item 'altered time sense'. Although we found no correlation between working-memory deficits and the objective timing measures used, we did find significant correlations between working-memory impairment and subjective measures of altered time sense and depersonalization experiences measured by the OB subscale of the 5D-ASC. The trend towards correlations for the duration underestimation above 3 seconds and the OB item 'altered time sense' merits further studies seeking to investigate the relationship between alterations in temporal processing and experiences of self.

The pharmacological basis of the experience of time and temporal processing is only vaguely understood. Pharmacological manipulations in animal and human studies indicate that dopaminergic agonists and antagonists influence timing processes--supposedly by increasing and decreasing (respectively) clock speed (Rammsayer, 1989; Cevik, 2003). The detrimental effect of the DA antagonist haloperidol on duration discrimination with base intervals of 50 ms has been interpreted as resulting from a slowing down of the clock rate (Rammsayer, 1989). Studies in patients with Parkinson's disease show that dopaminergic agonists can improve motor timing (O'Boyle et al., 1996). It appears that dopaminergic neurotransmission within striatal and cortical sites is strongly connected to temporal processing, leading to the postulation of a cortico-striato-thalamo-cortical system involved in sensorimotor timing (Matell and Meck, 2004). The present results indicate that the serotonin system is also involved in temporal processing, either directly as a component of one of the basic processing stages in the model of timing or indirectly by influencing dopaminergic or glutaminergic transmission as we have previously shown in PET studies of psilocybin model psychosis (Vollenweider et al., 1999). When taking into account the different levels of the timing model that are an integrative part of the cognitive system (Pouthas and Perbal, 2004), several neurotransmitter systems play a decisive role in temporal processing in the range of seconds. Rammsayer (1999), for example, discovered that the dopamine receptor antagonist haloperidol as well as benzodiazepine midazolam had detrimental effects on duration discrimination of intervals ranging around 1 second whereas processing of 50-ms intervals was only affected by haloperidol. These results were discussed as influences via disruption of transmitter-guided cognitive processes such as attention and working memory. The author concluded that any pharmacological treatment that affected working-memory capacity would interfere with temporal processing of intervals in the longer time range. It has to be noted that we did not find effects of psilocybin on durations below 2 seconds. This discrepancy can only be resolved in future studies that consider task-specific and pharmacological factors. In addition to comparing possible task-related differences between the duration discrimination task and the sensorimotor tasks used in our study, selective effects of individual pharmacological substances will probably be accounted for by the inconsistencies found over different studies. In the study presented here, the 5-H[T.sub.2A/1A] receptor agonist psilocybin affected time intervals in sensorimotor synchronization and temporal reproduction only above 2 to 3 seconds and only self-paced tapping (and not maximum tapping). These effects can also be interpreted as following the disruption of cognitively mediated temporal-processing stages. Moreover, as we are reporting the specific effects of the drug concerning the time domain, we can rule out the possibility that a generally decreased capacity of subjects to interact with the environment or a decreased interest for the experimental task produced the effects shown.

Our main goal was to elucidate whether psilocybin induced specific effects on temporal control of behaviour and, if so, whether these would be a function of the duration of the processed time interval--an effect we did find. In future studies the possible relationship between duration processing and underlying cognitive functions including different aspects of working memory--for example, taking into account differences between spatial and verbal working memory--needs to be further investigated by concurrently probing other dimensions of attention and working memory. Further studies with specific 5-H[T.sub.1A], 5-H[T.sub.2A] and dopamine receptor antagonists are needed to tease out the relative contribution of each of these receptor systems to the observed effects. In respect to the use of psilocybin in modelling endogenous psychosis, temporal processing deficits have been observed in chronic medicated schizophrenics at both short and long intervals (Davalos et al., 2002, Davalos et al., 2003, Elvevag et al., 2003) whereas our current findings indicate that only longer interval processing is affected by psilocybin. It would be of interest to see whether the use of the same paradigm in healthy subjects with psilocybin and unmedicated acute schizophrenic subjects would show the same disparity of effects. Moreover, as some effects could be seen on a descriptive level but differences failed to reach the significance level it would be interesting to investigate whether increasing the number of participating subjects may yield further effects of the psilocybin intervention.

Acknowledgments

This study was supported by the Heffter Research Institute, Santa Fe, NM, USA, and the Swiss Federal Office of Public Health (BAG contract No. 00.001023) through grants to FXV. The authors especially thank G. Greer, MD, for critical comments on the manuscript.





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Re: Psychedelic Research [Re: boletusoftruth]
    #9609312 - 01/14/09 04:17 PM (15 years, 1 month ago)

An interview with Terrence McKenna!!!

Title:Terence McKenna. (botanist) (Interview).

Quote:

Abstract:

Ethnobotanist McKenna's radical ideas include the theory that prehistoric humans ingested hallucinogenic plants that prompted evolution. He believes enlightenment can be achieved through drugs such as dimethyltryptamine (DMT) and psilocybin.

Full Text :COPYRIGHT Omni Publications International Ltd. 1993

My life is like a James Joyce scratch pad," declares Terence McKenna. "I have a lot of fun, a kind of reverse paranoia. I think reality is a plot for my own amusement and advancement--which it seems to be. It's absolutely eerie." Ethnobotanist, radical historian, and co-steward of a botanical garden in Hawaii where he collects endangered plant species and their lore, McKenna is, as well, a world-class psychedelic researcher.

In the Sixties, it was not uncommon for friends or colleagues to leave for awhile, then return. These travelers, however, had not made round trips to such identifiable exotic stops as Tibet or China, or even Mexico. Rather, they had tripped on acid or mushrooms: new territory. Upon reentry they would be asked the usual questions one asks a traveler: "What did you see? Who did you meet? How long were you gone?" And they'd show their slides, as it were.

In those years, taking psychedelic drugs was viewed as self-experimentation. One's goal was informational--to learn and explore. And taking drugs carried an unstated mandate: It was incumbent upon you to contribute to the unofficial databank--report the efficacy of various doses, the effect of varying settings, elapsed duration, potential uses, and so forth. It was not uncommon to ask, "Why did you take it?"--truly a statement of inquiry. Terence McKenna comes from this tradition.

Born in 1946 in western Colorado, McKenna moved to Los Altos, California, when he was in high school. He graduated from the University of California at Berkeley with a major in shamanism and the conservation of natural resources. Collecting Asian art in the East, for years he also made his living as a professional butterfly collector. In his 1992 book Food of the Gods, McKenna delineates a radical history of drugs and human evolution, chronicling our descent from "stoned apes" and extolling the virtues of psilocybin mushrooms and DMT (dimethyltryptamine), a potent psychedelic compound. Eve achieves top billing in our collective history as "the mistress of magical plants."

Heralded by some as the "New Scientist," McKenna admits that "defenders of orthodox science find me a pain." When he was younger, this so bothered him that he sought the counsel of Gunther Stent, the pioneering Swedish genetic biochemist. McKenna sat in front of his hero and earnestly laid out his research, theories, and ideas of science. "What I am interested to know is," McKenna concluded, "are these ideas fallacious?" Rising from behind his desk, Stent crossed the room, placed his hands on McKenna's shoulders, and delivered the following: "My dear young friend." they aren't even fallacious!" Although crushed and shattered by the encounter, McKenna persevered to become a high-voltage speaker, storehouse of remarkable information, and prolific writer of worldwide repute.

Before this interview, McKenna offered friend and interrogator Sukie Miller the following tip: "Being able to pun, sing, or riddle will usually get you through fairy checkpoints. To deal with real fairies is to enter a realm of riddles and puzzle settings where what they punish is stupidity and what they love is intellectual cleverness." Editor's note: Sukie Miller, Ph.D., is a practicing psychotherapist in New York City, a former director of Esalen, and the Director of the Death and Dying II Project.)

Omni: You've been called a prophet, madman, the most important visionary scholar in America, a bard of our psychedelic birthright, and more. How did you grow up? Was there something in the water at your house? McKenna: I was born in a Colorado cattle and coal-mining town of 1,500 people called Paonia. They wanted to name it Peony but didn't know how to spell it. In your last year of high school, you got your girlfriend pregnant, married her, and went to work in the coal mines. An intellectual was someone who read Time. My mother went to secretarial school and had a very large vocabulary. She was aware of classical music and writing and was my grandfather's favorite daughter.

His metier was language. He frequently used the phrase "the fustilerian fizgigs from Zimmerman!" I reconstructed it. It means "a shrewish fishwife from a town named Zimmerman." Whenever he got excited, he'd yell, "~Great God!' said the woodcock when the hawk struck him." A nut, a poet is what he was.

Omni: How early in your life were you into altered states? McKenna: Until I was three, we lived in my grandfather's house. I've had regression-hallucinations where I see myself in my child body playing with my trains alone in that living room. Then something catches my attention and I turn and look: A DMT hallucination is pouring out of the air, into this house, into the room. This is not supposed to be happening. This is not permitted! It was as if an invisible teapot were beginning to pour some heavy, colored liquid swimming with objects and shapes, a flowering geometry. It was as if reality got broken, like a window could get broken, and the outside--poured through the teapot--came rushing in. I go to find my mother to show her. Then, of course, it's not there. Omni: And now? Toward what end is your research directed? McKenna: I can't stomach the human tragedy of somebody going to the grave ignorant of what is possible. I make the analogy to sex. Few people can avoid some kind of experience with sex-sex informs the experience of humanness; sex is a great joy and travail. I don't like to think about someone going to the grave without ever having contacted it. This work is that big. It's ours. It makes available an entire domain of being that somehow got lost, to our detriment.

Omni: What is DMT's effect?

McKenna: My best guess is that it mediates attention so that when you hear a noise coming from someplace within your peripheral vision, you turn and focus on what the noise might be. Somehow this very rapid focusing of mental functioning is driven by DMT It is also a Schedule I drug. So technically, we are all bustible all the time! The paradox is that DMT is the safest and quickest hallucinogen to leave your system-safest, that is, in terms of any accumulated detriment to the organism.

Omni: Food of the Gods relates DMT to psilocybin. What's the connection?

McKenna: Psilocybin and DMT are chemically near relatives. My book is about the history of drugs; it tries to show drugs' cultural and personality-shaping impact. People have attempted-unsuccessfully--to answer the question of how our minds and consciousness evolved from the ape. They've tried all kinds of things to account for this evolution, but to my mind, the key unlocking this great mystery is the presence of psychoactive plants in the diet of early man.

Omni: What led you to this startling conclusion? McKenna: Orthodox evolutionary theory tells us that small adaptive advantages eventually become genetically scripted into a species. The species builds upon this minute change to further its adaptive advantage until ultimately it outbreeds all of its competitors for a particular niche or environment.

Omni: So prehistoric humans got a leg up on the apes by ingesting a drug? McKenna: Yes. Lab work shows that psilocybin eaten in amounts so small that it can't be detected, as an experience, increases visual acuity In the Sixties, Roland Fisher at the National Institute of Mental Health gave graduate students psilocybin and then a battery of eye tests. His results indicated that edges were visually detected more readily if a bit of psilocybin was present in the student's body Well, edge detection is exactly what hunting animals in the grassland environments use to observe distant prey! So here you have this chemical factor; when added to the diet, it results in greater success in hunting. That, in turn, results in greater success in child rearing and so increases the size of the next generation.

As we descended from the trees and into the grasslands, began to experiment with bipedal gait and omnivorous diet, we encountered mushrooms. At low doses, they increase visual acuity; at midrange, they cause general central-nervous-system arousal, which in a highly sexed primate means a lot of horsing around, which means there is more pregnancy among females associated with psilocybin-using behavior. Higher dosages of psilocybin leads to group sexuality and dissolved boundaries between individuals. The ego dissolves and you experience boundary ecstasy. We can assume that as the level of ingestion became high enough, egoless states were quite common.

The way I analyze the modern predicament-pollution, male dominance, there are a million ways to say it--the overriding problems are brought on by the existence of the ego, a maladaptive behavioral complex in the psyche that gets going like a tumor. If it's not treated--if there's not pharmacological intervention--it becomes the dominant constellation of the personality.

Omni: How did all this play out? McKenna: From 75,000 to about 15,000 years ago, there was a kind of human paradise on Earth. People danced, sang, had poetry, jokes, riddles, intrigue, and weapons, but they didn't possess the notion of ego as we've allowed it to crystallize in Western societies. The reason for this lack of ego was a social style of mushroom taking and an orgiastic sexual style that was probably lunar in its timing. Nobody went more than three or four weeks before they were redissolved into pure feeling and boundary dissolution. Community, loyalty, altruism, self-sacrifice--all these values that we take to be the basis of humanness--arose at that time in a situation in which the ego was absent.

Omni: If this was all so wonderful, why did it end?

McKenna: The most elegant explanation is that the very force that created the original breakthrough swept away its conditions. The climatological drying of Africa forced us out of the forest canopy, onto the grasslands, and into bipedalism and omnivorous diets. We lived in that paradisaical grasslands situation, but the climate was slowly getting drier. Mushrooms began to be less available. There could've been many strategies for obtaining mushrooms, all detrimental. The first would be to do it only at great holidays, and only a certain class of people--shamans, for example. Eventually the mushroom only existed around water holes in the rain shadows of certain mountains; finally, the mushroom was gone. At that moment, under great pressure from the drying climate, agriculture was invented. Agriculture represents an intellectual understanding of how cause and effect can be separated in time. You return to last year's camp, look where you discarded the trash, and there all in one place are the food plants you so carefully gathered. Women, the gatherers, put this together: Wow! Bury food, come back a year later, and it's there. This was a watershed in the development of abstract thought.

At the same time, men were understanding that the sex act, previously associated with this group orgiastic stuff, was the equivalent of burying food and coming back a year later! Male paternity is recognized as a phenomenon. The road to hell is paved-eight lanes!--from that point on. The man thinks my--my children, not our children--and therefore, animals I kill are food for my women and my children. Women are seen as property. The ego is rampant and in full force. Omni: How does data on psilocybin support your theory? McKenna: Well, here's the problem: Psilocybin, discovered in 1953, not chemically characterized until 1957, became illegal in 1966. The window of opportunity to study this drug in humans was only nine years. People working with psilocybin never dreamed they'd be forbidden by law to work in this area. When LSD was first released into the psychotherapeutic community, it swept through with the same impact that the news of the splitting of the atom touched the physics community. People thought, "Ah-ha! Now we're going to understand mental illness, trauma, and obsession, this being only the first of a family of drugs that will lead to an operational understanding of the genesis and curing of neuroses!"

When the scientific establishment was informed that there would be no government-grant support for psychedelic research, they just bowed their fuzzy heads and went along with it. The consequences of their failure to stand up to that decision is a mangled society and a science that hasn't fulfilled it's agenda. In no other instance has science laid down so gutlessly and allowed the state to tell it how to do its business.

I'm not trying to make a revolution in primate archaeology or theories of human emergence. My scenario, if true, has enormous implications. For 10,000 years, with the language and social skills of angels, we've pursued an agenda of beasts and demons. Human beings created an altruistic communal society; then, by withdrawing the psilocybin or having it become unavailable, we've had nothing to fall back upon except old primate behaviors, all tooth-and-claw dominance.

Omni: You're giving an enormous amount of power to a drug. What can you tell me about psilocybin? McKenna: We don't know what DMT means. It's like Columbus sighting land, and somebody says, "So you saw land; is that a big deal?" And Columbus says, "You don't understand; it is the New World."

For the last 500 years, Western culture has suppressed the idea of disembodied intelligences--of the presence and reality of spirit. Thirty seconds into the DMT flash, and that's a dead issue. The drug shows us that culture is an artifact. You can be a New York psychotherapist or a Yoruba shaman, but these are just provisional realities you're committed to out of conventional or local customs.

Omni: Well, it gives one something to do, Terence.

McKenna: Yes, but most people think it's what's happening. Psilocybin shows you everything you know is wrong. The world is not a single, one-dimensional, forward-moving, causal, connected thing, but some kind of interdimensional nexus.

Omni: If everything I know is wrong, then what?

McKenna: You have to reconstruct. It's immediately a tremendous permission for the imagination. I don't have to follow Sartre, Jesus, or anybody else. Everything melts away, and you say, "It's just me, my mind, and Mother Nature." This drug shows us that what's waiting on the other side is a terrifyingly real self-consistent modality, a world that stays constant every time you visit it.

Omni: What is waiting? Who? McKenna: You burst into a space. Somehow, you can tell it's underground or an immense weight is above it. There's a feeling of enclosure, yet the space itself is open, warm, comfortable, upholstered in some very sensual material. Entities there are completely formed. There's no ambiguity about the fact that these entities are there.

Omni: What are they like, Terence?

McKenna: Trying to describe them isn't easy. On one level I call them self-transforming machine elves: half machine, half elf. They are also like self-dribbling jeweled basketballs, about half that volume, and they move very quickly and change. And they are, somehow, awaiting. When you burst into this space, there's a cheer! Pink Floyd has a song, "The Gnomes Have Learned a New Way to Say Hooray." Then they come forward and tell you, "Do not give way to amazement. Do not abandon yourself." You're amazingly astonished. The most conservative explanation for these elves, since these things are speaking English and are intelligent, is that they're some kind of human beings. They're obviously not like you and me, so they're either the prenatal or postmortal phase of human existence, or maybe both, if you follow Indian thinking. You're saying, "Heart beat? Normal. Pulse? Normal." But your mind is saying, "No, no. I must be dead. It's too radical, too fucking radical. It's not the drug; drugs don't do stuff like this." Meanwhile, what you're seeing is not going away.

Omni: What are these elves, these creatures about?

McKenna: They are teaching something. Theirs is a higher dimensional language that condenses as a visible syntax. For us, syntax is the structure of meaning; meaning is something heard or felt. In this world, syntax is something you see. There, the boundless meanings of language cause it to overflow the normal audio channels and enter the visual channels. They come bouncing, hopping toward you, and then it's like--all this is metaphor; they don't have arms--it's as though they reach into their intestines and offer you something. They offer you an object so beautiful, so intricately wrought, so something else that cannot be said in English, that just gazing on this thing, you realize such an object is impossible. The best comparison is Faberge eggs. The object generates other objects, and it's all happening in a scene of wild merriment and confusion.

Ordinarily language creates a system of conventional meanings based on pathways determined by experience. DMT drops you into a place where the stress is on a transcending language. Language is a tool for communicating, but it fails at its own game because it's context-dependent. Everything is a system of referential metaphors. We say, "The skyline of New York is like the Himalayas, the Himalayas are like the stock market's recent performance, and that's like my moods"--a set of interlocking mnetaphors.

We have either foreground or background, either object or being. If something doesn't fall into these categories, we go into a kind of loop of cognitive dissonance. If you get something from outside the metaphorical system, it doesn't compute. That's why we need astonishment. Astonishment is the reaction of the body to the ineffectiveness of its descriptive machinery. You project your description, and it keeps coming back. Rejected. Astonishment breaks the loop.

Omni: What other experiences can you liken to the DMT trip?

McKenna: The archetype of DMT is the three-ring circus. The circus is all bright lights, ladies in spangled costumes, and wild animals. But right underneath, it's some fairly dark expression of Eros and freaks and unrootedness and mystery. DMT is the quintessence of that archetype. The drug is trying to tell us the true nature of the game: Reality is a theatrical illusion. So you want to find your way to the impresario who produces this and then discuss his next picture with him.

Omni: So the circus is really just a doorway. How does it end?

McKenna: This crazy stuff goes on for 90 seconds; then you fall away from it. They bid you farewell. In one case they said to me: "Deja vu, deja vu!"

Omni: You've devoted a good part of your life to mapping the DMT and psilocybin terrain. How would you interpret all of it?

McKenna: These drugs can dissolve in a single lightning stroke all our provisional programming. The drugs carry you back to the truth of the organism that language, conditioning, and behavior are entirely designed to mask. Once on the substance, you are reborn outside the envelope of culture and of language. You literally come naked into this new domain.

Omni: What do you say to doubters? McKenna: DMT is utterly defeating of the drug phobia. We could get rid of all drugs but DMT and psilocybin and have thrown out nothing. The fact that DMT is so brief and intense makes it look as if it's designed for doubters. Someone will say, "I can't risk five hours on a drug. It's nuts." The unspoken thing they're saying is, "My career, my life, will be ruined, so keep it away from me." But if you say to these people, "Look, you're making these statements about drugs. Can you invest ten minutes? . . ."

DMT is inhaled. The entire trip lasts that long with no after-feelings. They, fools that they are, with a naive version of linear time, think, "Well, ten minutes. How bad can that be?" Then you have them. If they won't join after that, they'll at least shut up.

Omni: Do you think there is such a thing as a bad trip?

McKenna: A trip that causes you to learn faster than you want is what most people call a bad trip. Most people try to hold back on the learning inherent in drugs. But sometimes the drug releases the information and says, "Here's what you need to know." The information may be, "You treat people wrong!" and nobody wants to hear that or, "You need a divorce!" and that can be scary or, "You have some habits you need to think seriously about," and who wants to do that?

Omni: How can you advocate drugs so strongly when such pain, disruption, and chaos may be associated with taking them?

McKenna: We should talk about the word ecstasy. In our world, ruled by Madison Avenue, ecstasy has come to mean the way you feel when you buy a Mercedes and can afford it. This is not the real meaning. Ecstasy is a complex emotion containing elements of joy, fear, terror, triumph, surrender, and empathy. What has replaced our prehistoric understanding of this complex of ecstasy now is the word comfort, a tremendously bloodless notion. Drugs are not comfortable, and anyone who thinks they are comfortable or even escapist should not toy with drugs unless they're willing to get their noses rubbed in their own stuff.

Omni: What people specifically should not take them?

McKenna: People who are mentally unstable, under enormous pressure, or operating equipment that the lives of hundreds of people depend on. Or the fragile ones among us--those to whom you wouldn't give a weekend airline ticket to Paris, those you wouldn't expect to guide you out of the Yukon. Some people have been so damaged by life that boundary dissolution is not helpful to them. These people are trying to maintain boundaries, their functionality. They should be honored and supported and not encouraged to take drugs. If because of genetic or cultural or psychological factors it's not for you, then it's not for you.

We're not asking everybody to feel that they must take drugs, but rather, just as a woman should be free to control her body, for heaven's sake, a person should also be free to control his or her mind. Everyone should be free to do it and be well informed of the option. Drug information isn't that much different from sex information. We make a gesture toward sex education in schools. And we've come a long way: We no longer make adulterers stitch large letters on the fronts of their clothing. But the issues of drugs are more complicated because there's a vast spectrum, from aspirin to heroin, and each has to be evaluated on its own strengths and weaknesses.

Omni: Would you want education on the joys of drugs in high schools?

McKenna: Absolutely, because these kids are already self-educating and informing each other through an underground body of unsanctioned, scientifically unexamined knowledge. We stand with the issues of drugs where we were with sex in the Twenties and Thirties. You learn by rumor. So people have funny ideas, knowing far more about crack than they know about mescaline or psilocybin.

Animal life has been transfused with something either willfully descended into matter or trapped by some cosmic drama. Something in an unseen dimension is acting as an attractor for our forward movement in understanding.

Omni: Attractor?

McKenna: It's a point in the future that affects us in the present. For example, if you were to do your Christmas shopping in July, then Christmas is an attractor for your summer shopping habits. Our model that everything is pushed by the past into the future, by the necessity of causality, is wrong. There are actual attractors ahead of us in timelike the gravitational field of a planet. Once you fall under an attractor's influence, your trajectory is diverted.

Omni: Does the attractor have a kind of intelligence?

McKenna: I think so. It's what we have naively built our religion around: God, totem. It's an extradimensional source of immense caring and reflection for the human enterprise.

Omni: How will science explore the after-death state?

McKenna: By sending enough people into this other dimension to satisfy themselves that this is eternity. Here the analogy of the New World holds: A few lost sailors and shipwreck victims like myself are coming back, saying, "There was no edge of the world. There was this other thing. Not death and dissolution, not sea monsters and catastrophe, but valleys, rivers, cities of gold, highways." It will be a hard thing to swallow, but then the scientists can go back to doing science on after-death states. They don't have to throw out their method.

Omni: Where is your hope?

McKenna: With psychology and young people. They have what we never had: older people who went through a psychedelic phase. I'm meeting old freaks in Berlin, London, who are mentoring this thing and trying to keep it away from what we perceive as our mistakes, mainly political confrontationalism. LSD was a direct frontal assault on society. An inspirited undergraduate in biochemistry with his roommate's $20,000 trust fund can turn out 5 to 10 million hits of this drug in a long weekend. This immediately created pyramids of criminal activity of such size and potential earning power that the government reacted as though a gun had been pointed at its head. Which it had. The proper strategy is stealth, subversion, and boring from within.

Omni: Terence, my friend, does anything scare you?

McKenna: Madness. People always ask, "Will I die on drug A, B, or C?" That's the wrong question. Of course you can die, but what is at risk is your sanity, because it seems as though the deconstruction of reality has no bottom, and you can just move out into these places. I worry about not being able to contextualize these things, losing the thread allowing me to return to the human community. We're trying to build bridges here, not just sail off.

Omni: How do you see the future?

McKenna: If history goes off endlessly into the future, it will be about scarcity, preservation of privilege, forced control of populations, the ever-more-sophisticated use of ideology to enchain and delude people. We are at the breakpoint. It's like when a woman comes to term. At a certain point, if the child is not severed from the mother and launched into its own separate existence, toxemia will set in and create a huge medical crisis.

The mushrooms said clearly, "When a species prepares to depart for the stars, the planet will be shaken to its core." All evolution has pushed for this moment, and there is no going back. What lies ahead is a dimension of such freedom and transcendence, that once in place, the idea of returning to the womb will be preposterous. We will live in the imagination. We will quickly become unrecognizable to our former selves because we're now defined by our limitations: the laws of gravity; the need to eat, excrete, and make money. We have the will to expand infinitely into pleasure, caring, attention, and connectedness. If nothing more--and it's a lot more--it's permission to hope.

WHAT IS DMT?

Dimethyltryptamine is chemically related to the LSD, psilocybin class of hallucinogenic drugs. It is a serotonin agonist; that is, it mimics the neurotransmitter serotonin, but interferes with its normal action. This class of drugs enhances the brain's sensitivity to many kinds of incoming information. As an agonist, DMT locks into receptors of neurons usually available to serotonin and competes with--often "winning out" over--serotonin at the receptor site. To find out more about DMT's mechanism of action, we consulted leading neurobiologist and serotonin investigator, Dr. George Aghajanian of the Yale University School of Medicine.

Aghajanian: I'm finding that except for the fact that it has a very short duration of action--30 to 45 minutes--DMT has the same effects on various receptors, particularly the serotonin-2 (5-HT2) receptor, as the other hallucinogens--LSD or mescaline--that can have effects for up to eight hours. Omni: Is 5-HT2 a postsynaptic receptor? Aghajanian: Yes. DMT also works on a presynaptic receptor, but that is not the action responsible for its hallucinogenic effects. Omni: Since DMT binds at these receptors, does that mean it is found naturally in the brain? Aghajanian: Enzymes able to synthesize DMT exist in certain tissues, such as in the lungs. But there's no evidence that more than a trace of DMT exists in the body, not enough to have any pharmacological effect.

Omni: What's the difference between DMT and LSD, psilocybin, and so forth?

Aghajanian: All the other psychedelic hallucinogens I've looked at in tissue--brain slice--shave a remarkable prolonged effect. So it's interesting that in the same preparation, DMT has a short-lived effect corresponding to its brief action clinically.

Omni: Why do the other psychedelics have more prolonged effects? Aghajanian: I think the other hallucinogens are taken up in lipid [fat] compartments of the brain, cell membranes, and elsewhere and that the drug is released slowly from these compartments. The persistence of effects depends on the continued presence of the drug. DMT is not very lipid soluble, so it's not stored in the lipid compartments and thus washes out rapidly.





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Offlineskatealex2
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Registered: 07/04/08
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Re: Psychedelic Research [Re: boletusoftruth]
    #9609329 - 01/14/09 04:22 PM (15 years, 1 month ago)

any marijuana research in there?


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Offlineboletusoftruth
Psychedelic Funk
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Registered: 10/03/07
Posts: 1,133
Loc: MASS
Last seen: 11 years, 1 month
Re: Psychedelic Research [Re: skatealex2]
    #9609332 - 01/14/09 04:23 PM (15 years, 1 month ago)

Buttloads full.... PM for more info


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