MAPS: Psychedelic Related Scientific Publications

[Matthew Baggott <mbagg@xxxxxxxxxxxxx>]

Here are some recent psychedelic-related scientific publications.  I am
cataloging them as part of the MAPS/Heffter Psychedelic Bibliography
Project.  This list mostly covers papers that were ostensibly
published in March.  There is a lively exchange in the Lancet
(Vol 353, Apr 10, 1999) on the apparent reduction of 5-HT
transporters in MDMA users described by Ricaurte's group which I
have not yet catalogued.  The comments are from me, of course, and
are "pending" if I haven't obtained or fully digested the paper yet.
I'll be doubling back soon and posting the earlier papers from this
year as well. Enjoy! --Matt

1-1999-3
TITLE: N-tert-butyl-alpha-phenylnitrone protects against
3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats
Author: Yeh SY 
SOURCE: Synapse, 1999 Mar 1;31(3):169-77.
ABSTRACT: The present study examined the effect of
N-tert-butyl-alpha-phenylnitrone (PBN) on 3,4-methylenedioxmathamphetamine
(MDMA)-induced depletion of serotonin in the CNS. Rats were treated with
two concurrent injections of MDMA (20 mg/kg, s.c.), PBN (50-400 mg/kg
dissolved in ethanol, 50 mg/ml of 25% ethanol, i.p.), saline or 25%
ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later.
Rectal temperature was measured prior to and hourly following the drug
injection for 5 h. Monoamine levels in the tissue were measured by HPLC.
Density of the 5-HT transporters was assayed by [3H]paroxetine binding.
Rectal temperature of rats increased after MDMA, decreased after PBN,
ethanol, PBN plus ethanol, and MDMA plus ethanol, and was not
significantly altered after MDMA plus PBN. Levels of 5-HT and 5-HIAA in
the frontal cortex, hippocampus, striatum, and brain stem of rats
decreased significantly after MDMA or MDMA plus ethanol, but not after
MDMA plus PBN, PBN plus ethanol (PBN dissolved in ethanol), or ethanol as
compared to the saline controls. Levels of 5-HT and 5-HIAA in the brain
tissues of rats treated with MDMA plus PBN were elevated as compared to
those treated with MDMA plus saline. Similar results were observed in the
density of 5-HT transporters in the frontal cortex and hippocampus. These
results indicate that scavenging of free radicals of MDMA metabolites or
reactive oxygen species by PBN and with lowering of body temperature
protected against MDMA-induced depletion of serotonin transmitter.
COMMENTS: Free radicals seem to be involved in the long-term brain changes
produced by MDMA.  This study examined whether PBN, a free radical
trapping agent with high lipid solubility, would protect against these
changes in rats.  PBN protected against depletions in serotonin and
5-HIAA as well as decreased serotonin transporter density.  However,
because PBN also produced hypothermia, it is not clear whether its
protective effects were due to the lowering of body temperature or free
radical scavenging.  In addition, the researchers examined whether ethanol
would also protect against MDMA-induced long-term brain changes.  Although
ethanol also produced lowered body temperature in rats, it did not protect
against the long-term effects of MDMA.  A previous study found that
ethanol protected against MDMA-induced depletion of dopamine in mice.  It
is not clear whether this discrepancy in results is due to the different
species studied, the dosage of ethanol used, or environmental conditions.

2-1999-3
TITLE: [Ecstasy--cool dope with long-lasting effects]?
Author: Liberg JP, Hovda KE, Nordby G, Jacobsen D
SOURCE: Tidsskr Nor Laegeforen 1998 Nov 20;118(28):4384-7 
ABSTRACT: The amphetamine derivative MDMA
(3,4-methylenedioxymethamphetamine) was first synthesised in 1914 as an
appetite suppressant, but was never used as such. MDMA is commonly known
as "ecstasy" and has become a popular recreational drug of abuse at
dance-clubs and rave parties, where it is combined with all-night dancing,
crowded conditions, poor hydration and loud sound. This combination is
probably the main reason why we have seen an upsurge in toxicity problems
at rave parties, since all these factors are thought to promote or
increase the toxicity of MDMA. The desired effects of MDMA are euphoria,
increased energy and enhanced communication with others. Adverse effects
are hyperthermia, rhabdomyolysis, acute renal failure, hepatotoxicity,
depression and psychosis. 
COMMENTS: pending.

3-1999-3
TITLE: Thieno[3,2-b]- and Thieno[2,3-b]pyrrole bioisosteric analogues of
the hallucinogen and serotonin agonist N,N-dimethyltryptamine.
Author: Blair JB, Marona-Lewicka D, Kanthasamy A, Lucaites VL, Nelson DL,
Nichols DE
SOURCE: Journal of Medicinal Chemistry 1999 Mar 25;42(6):1106-11 
ABSTRACT: The synthesis and biological activity of 6-[2-(N,
N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N,
N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as
potential bioisosteres of N,N-dimethyltryptamine (1a), are reported.
Hallucinogen-like activity was evaluated in the two-lever drug
discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b
substituted for LSD or DOI up to doses of 50 &mgr;mol/kg. By comparison,
1a fully substituted in LSD-trained rats. However, 3a and 3b fully
substituted for the 5-HT1A agonist LY293284
((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4,
5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin
syndrome" and salivation, an indication of 5-HT1A receptor activation. At
the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At
the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice
the affinity of 3b. Therefore, thiophene lacks equivalence as a
replacement for the phenyl ring in the indole nucleus of tryptamines that
bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects.
Whereas both of the thienopyrroles had lower affinity than the
corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater
affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear
to serve as a potent bioisostere for the indole nucleus in compounds that
bind to the serotonin 5-HT1A receptor. These differences in biological
activity suggest that serotonin receptor isoforms are very sensitive to
subtle changes in the electronic character of the aromatic systems of
indole compounds.
COMMENTS: pending.

4-1999-3
TITLE: Treatment of Tourette's syndrome with delta-9-tetrahydrocannabinol.
Author: Muller-Vahl KR, Schneider U, Kolbe H, Emrich HM
SOURCE: American Journal of Psychiatry 1999 Mar;156(3):495
ABSTRACT: none
COMMENTS: This letter describes a successful treatment of Tourette's
syndrome with THC, the main psychoactive component of marijuana.  Although
earlier reports have shown that marijuana can be beneficial in Tourette's
syndrome, none of reports used purified THC. A 25 year old man had been
smoking two to three grams of marijuana per day for several years.  He
reported that he found marijuana more effective than the medication
pimozide in controlling his symptoms.  After a three-day drug free
interval, the researchers measured the effects of 10 milligrams of
Delta-9-THC on Tourette's symptoms in an uncontrolled open clinical trial.
Both motor and focal ticks improved and corprolalia (literally translated
as Rdirty mouthS) disappeared, beginning 30 minutes after THC and lasting
for about seven hours.  In addition, neuropsychological tests showed
improvements in signal detection, sustained attention, and reaction time.
The patient reported that he felt improvements in attention, impulse
control, obsessive-compulsive behavior, and premonitory feeling.

5-1999-3
TITLE: 3,4-Methylenedioxy analogues of amphetamine: defining the risks to
humans.
Author: Hegadoren KM, Baker GB, Bourin M
SOURCE: Neuroscience and Biobehavioral Reviews 1999 Mar;23(4):539-53 
ABSTRACT: The 3,4-methylenedioxy analogues of amphetamine [MDMA
("Ecstasy", "Adam"), MDA ("Love") and MDE ("Eve")] are recreational drugs
that produce feelings of euphoria and energy and a desire to socialize,
which go far to explain their current popularity as "rave drugs". In
addition to these positive effects, the drugs are relatively inexpensive
to purchase and have the reputation of being safe compared to other
recreational drugs. Yet there is mounting evidence that these drugs do not
deserve this reputation of being safe. This review examines the relevant
human and animal literature to delineate the possible risks MDMA, MDA and
MDE engender with oral consumption in humans. Following a summary of the
behavioral and cognitive effects of MDMA, MDA and MDE, risks will be
discussed in terms of toxicity, psychopathology, neurotoxicity, abuse
potential and the potential for drug-drug interactions associated with
acute and chronic use.
COMMENTS: This thorough, well balanced review article attempts to assess
the risks to humans of using MDMA, MDA, and MDE.  The authors recognize
that perhaps the most controversial issue surrounding MDMA and related
drugs is comparing the doses used in nonhuman neurotoxicity research to
those used by recreational users.  I wish they had expanded this section,
discussing methods for correcting for factors other than differences in
weight.  The authors point out that there does not seem to be a simple
relationship between acute toxic effects and dose.  Because most acute
adverse reactions present with hyperthermia, I suspect that physical
activity (such as dancing), environmental factors (such as temperature and
humidity) and hydration status are important factors in explaining the
acute toxicity of MDMA.  Toxicity research with rats supports the
importance of these factors, although we must keep in mind that
thermoregulation in rats is very different from in humans.  The authors
call for more systematic follow-up of individuals who experience acute
toxicity as well as animal studies which use dosing regimens that more
closely follow patterns of human use.

6-1999-3
TITLE: The anxiogenic-like and anxiolytic-like effects of MDMA on mice in
the elevated plus-maze: a comparison with amphetamine.
Author: Lin HQ, Burden PM, Christie MJ, Johnston GA
SOURCE: Pharmacology Biochemistry and Behavior 1999 Mar;62(3):403-8 
ABSTRACT: Many abused substances have been found to possess
anxiogenic-like or/and anxiolytic-like properties. Discrepancies about the
effects of MDMA, one of the most popular recreational drugs in recent
years, on anxiety have been seen in the literature, and almost all of the
data in this respect were derived from retrospective studies. The present
study was thus designed to examine the drug's actions by using an animal
model of anxiety, the elevated plus-maze test in male mice.
Intraperitoneal MDMA at 1 mg/kg was ineffective, at 4 mg/kg decreased the
percent of open arm entries (p < 0.01), and increased enclosed entries (p
< 0.05), at 12 mg/kg had no significant effect, and at 20 mg/kg induced an
increase of percent of open time (p < 0.01). As control drugs, amphetamine
(0.5-4 mg/kg, i.p.) produced a dose-dependent, anxiogenic-like effect and
diazepam (1 mg/kg, i.p.) induced an anxiolytic-like effect in the test.
The results indicate that MDMA has anxiogenic-like properties at lower
doses and anxiolytic-like at higher doses. The effects of MDMA and
amphetamine on the mouse's responses to the plus-maze are compared. These
findings provide a possible explanation for the controversies over MDMA's
effects on anxiety in the literature.
COMMENTS: This study used an elevated plus-maze to measure the effects of
MDMA and amphetamine on anxiety in mice.  The elevated plus-maze has two
opposing open arms and two opposing closed arms.  Because rodents have a
natural fear open space, the time spent in the open arms of the maze and
ratio of entries and the percent of entries into the closed arms can be
used as measures of anxiety.  This study found that MDMA was "ineffective
at 1 mg/kg IP, appeared to increase anxiety at 4 mg/kg, had no effect at
12 mg/kg, and seemed to decrease anxiety at 20 mg/kg."  Amphetamine (given
for purposes of comparison) appeared only anxiogenic, which the authors
feel supports the theory that MDMA belongs to a separate pharmacological
class of compounds. Although MDMA-induced anxiety has been reported,
decreased anxiety appears to be a more typical effect of MDMA in humans.
Therefore, I found it surprising that MDMA appeared anxiogenic in this and
a previous study.  One possible explanation is that the measurements of
rodent behavior in this experimental paradigm are insensitive to
serotonergic drugs which affect anxiety. While this experimental paradigm
is well established for classical anxiolytics and anxiogenics, it seems to
produce less consistent results with serotonergic drugs.  It may be that
additional behavioral measures such as "risk assessment" and "scanning"
would produce more consistent results.  A second possibility is that
differences between species make mice much less sensitive to the effects
of MDMA than humans and that 20 mg/kg are required in mice produced the
characteristic MDMA effect.  If this is the case, then the increased
anxiety noted at 4 mg/kg could reflect the disturbing effects of a dose
which makes one feel "off baseline" but not actually "high."

7-1999-3
TITLE: Effects of stimulants of abuse on extrapyramidal and limbic
neuropeptide Y systems.
Author: Westwood SC, Hanson GR
SOURCE: Journal of Pharmacology and Experimental Therapeutics 1999
Mar;288(3):1160-6 
ABSTRACT: Neuropeptide Y (NPY), an apparent neuromodulating neuropeptide,
has been linked to dopamine systems and dopamine-related psychotic
disorders. Because of this association, we determined and compared the
effects of psychotomimetic drugs on extrapyramidal and limbic NPY systems.
We observed that phencyclidine, methamphetamine (METH),
(+)methylenedioxymethamphetamine (MDMA), and cocaine, but not (-)MDMA,
similarly reduced the striatal content of NPY-like immunoreactivity from
54% (phencyclidine) to 74% [(+) MDMA] of control. The effects of METH on
NPY levels in the nucleus accumbens, caudate nucleus, globus pallidus, and
substantia nigra were characterized in greater detail. We observed that
METH decreased NPY levels in specific regions of the nucleus accumbens and
the caudate, but had no effect on NPY in the globus pallidus or the
substantia nigra. The dopamine D1 receptor antagonist SCH-23390 blocked
these effects of METH, suggesting that NPY levels throughout the nucleus
accumbens and the caudate are regulated through D1 pathways. The D2
receptor antagonist eticlopride did not appear to alter the METH effect,
but this was difficult to determine because eticlopride decreased NPY
levels by itself. A single dose of METH was sufficient to lower NPY
levels, in some, but not all, regions examined. The effects on NPY levels
after multiple METH administrations were substantially greater and
persisted up to 48 h after treatment; this suggests that synthesis of this
neuropeptide may be suppressed even after the drug is gone. These findings
suggest that NPY systems may contribute to the D1 receptor-mediated
effects of the psychostimulants.
COMMENTS: This study examined the effects of the two isomers of MDMA
(administered separately) as well as methamphetamine, cocaine, and PCP on
extrapyramidal and limbic Neuropeptide Y systems.  Neuropeptide Y seems to
act as a neural modulator and interacts with the dopamine system.  It may
also be involved in psychiatric conditions such as schizophrenia in which
the dopamine system is altered.  The researchers found that all of the
studied drugs except the less active minus isomers MDMA decreased
Neuropeptide Y-like immunoreactivity.  The researchers speculate that such
changes in neuropeptide activity may play a role in the expression of
naturally occurring or drug-related psychoses.

8-1999-3
TITLE: Comparative epidemiology of initial drug opportunities and
transitions to first use: marijuana, cocaine, hallucinogens and heroin
Author: Van Etten ML, Anthony JC
SOURCE: Drug and Alcohol Dependence 1999 54: 117-125
ABSTRACT: The earliest stages of involvement with illicit drugs have been
understudied. In a recent report, we examined initial opportunities to try
marijuana and transitions from first opportunity to first use of that
drug. This report extends that work by investigating early involvement
with cocaine, heroin, and hallucinogens as well. We examine sex and
race-ethnicity differences in estimates of having a drug opportunity, and
in the probability of progressing from having an opportunity to try a drug
to actually using the drug. Self-report interview data collected for the
National Household Surveys on Drug Abuse (NHSDA) from 1979 to 1994 were
analyzed. Results showed that an estimated 51% of US residents have had an
opportunity to try marijuana; comparative estimates for with cocaine,
hallucinogens, and heroin are 23, 14, and 5% respectively. Among those who
eventually used each drug, the vast majority made the transition from
first opportunity to first use within one year.  Males were more likely
than females to have opportunites to try these drugs, but were not more
likely than females to progress to actual use once an opportunity
occurred. Time trends indicate recent increases form 1990 to 1994 in the
estimated probability of using an illicit drug once an opportunity occurs,
particularly for hallucinogens. Exploratory analyses on race-ethnicity
yielded some interesting leads for future research. This study sheds light
on the epidemiology of the earliest stages of drug involvement in the USA.
Implications for prevention efforts and for our understanding of sex
differences in drug involvement are discussed.
COMMENTS: This study used data from the National Household Surveys on Drug
Abuse from 1979 to 1994 2 examined the initial opportunities to try
selected drugs and the transitions from first opportunity to first use of
these drugs.  Although data on hallucinogens is presented, these data are
limited because the category 'hallucinogens' includes PCP as well as more
classical hallucinogens.  Overall, an estimated 14 percent of U.S.
adolescents and adult household residents have had an opportunity to use
hallucinogens. (Approximately 64 percent of individuals given the
opportunity actually go on the use hallucinogens.) The researchers found
that, for persons given an opportunity to use hallucinogens, the
likelihood of actually using hallucinogens has progressively increased
from 1979 to the mid 1990s.  This pattern was not seen with the other
drugs studied (marijuana, cocaine, and heroin).  The researchers also
found that male-female differences in drug use are due to differences in
the opportunity to try the drugs not to differences in the probability of
trying them once the opportunity has occurred.

9-1999-3
TITLE: 5-HT modulation of dopamine release in basal ganglia in
psilocybin-induced psychosis in man--A PET study with [11C]raclopride
AUTHOR: Vollenweider FX; Vontobel P; Hell D; Leenders KL
SOURCE: Neuropsychopharmacology 1999 May;20(5):424-33
ABSTRACT: The modulating effects of serotonin on dopamine
neurotransmission are not well understood, particularly in acute psychotic
states. Positron emission tomography was used to examine the effect of
psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine
receptors in the striatum in healthy volunteers after placebo and a
psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent
indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist.
Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood,
disturbances in thinking, illusions, elementary and complex visual
hallucinations and impaired ego-functioning. Psilocybin significantly
decreased [11C]raclopride receptor binding potential (BP) bilaterally in
the caudate nucleus (19%) and putamen (20%) consistent with an increase in
endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum
correlated with depersonalization associated with euphoria. Together with
previous reports of 5-HT receptor involvement in striatal dopamine
release, it is concluded that stimulation of both 5-HT2A and 5- HT1A
receptors may be important for the modulation of striatal dopamine release
in acute psychoses. The present results indirectly support the hypothesis
of a serotonin-dopamine dysbalance in schizophrenia and suggest that
psilocybin is a valuable tool in the analysis of serotonin- dopamine
interactions in acute psychotic states.
COMMENTS: pending.

10-1999-3
TITLE: Ibogaine blocked methamphetamine-induced hyperthermia and induction
of heat shock protein in mice.
AUTHOR: Yu X; Imam SZ; Newport GD; Slikker W Jr; Ali SF
SOURCE: Brain Research 1999 Mar 27;823(1-2):213-216
ABSTRACT: Body temperature changes and heat shock protein (HSP-72)
induction in the caudate nucleus were studied in female C57BL/6N mice
pretreated with ibogaine (50 mg/kg) and sacrificed 48 h. after a single
dose of methamphetamine (20 mg/kg). Methamphetamine injection resulted in
hyperthermia and induced HSP-72 expression, whereas treatment with
ibogaine alone produced hypothermia. The ibogaine followed by
methamphetamine injection showed no hyperthermia and decreased HSP-72
expression. These data indicate that pretreatment with ibogaine can
completely block methamphetamine-induced hyperthermia and HSP-72
expression in the striatum.
COMMENTS: pending.

9-1999-1
TITLE: [Pregnancy outcome after ecstasy use; 43 cases followed by the
Teratology Information Service of the National Institute for Public Health
and Environment (RIVM)]
AUTHOR: van Tonningen-van Driel MM; Garbis-Berkvens JM Reuvers-Lodewijks
WE
SOURCE: Ned Tijdschr Geneeskd 1999 Jan 2;143(1):27-31
ABSTRACT: OBJECTIVE: To determine if use of ecstacy during pregnancy has
any harmful effects on pregnancy and the (unborn) child. DESIGN:
Prospective, descriptive. METHODS: After the Teratology Information
Service of the National Institute of Public Health and the Environment.
Bilthoven, the Netherlands, was approached by a physician or midwife for
information, the pregnancies that involved the use of ecstacy were
followed by a follow-up questionnaire one month after the estimated date
of birth. RESULTS: A total of 49 pregnancies were followed. For 43 women,
exposed early in pregnancy, data on course of pregnancy and health of baby
are known. There were 3 elective terminations of pregnancy and 2
spontaneous abortions. There were 40 live-born babies (including one set
of triplets); one of them had a congenital cardiac malformation. Beside
ecstacy the mothers frequently also used other substances potentially
harmful to pregnancy and child. The pregnancies were often unplanned;
previous pregnancies had frequently been terminated. CONCLUSION: The
sample size was too small to draw conclusions. As yet spontaneous
abortions and congenital malformations did not appear to occur more
frequently in pregnancies with use of ecstacy. The lifestyle of the
ecstacy users seemed to be potentially harmful for pregnancy and child.
COMMENTS: pending.



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