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Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Mountain glacier records offer important constraints on the timing and magnitude of climate variability during the last glacial cycle. Existing moraine chronologies from the central Southern Alps indicate maximum ice extent was achieved during marine isotope stages 3–4, followed by repeated advances of similar, but gradually declining extent during marine isotope stage 2, until onset of the glacial termination. Questions remain over the precise role of climate in driving these changes, as most existing moraine chronologies come from large, complex former valley glacier systems, where non-climatic influences such as changing bed topography and proglacial lake formation may have influenced glacier length changes. Here we address this problem via a new cosmogenic 10Be chronology and equilibrium line altitude reconstruction from a cirque glacier situated in Fiordland, New Zealand. Our chronology shows moraine deposition at 32 ± 11 ka, 18.7 ± 0.2 ka, 18.1 ± 0.1 ka, and c. 17.2 ± 0.3 ka. The simple geometry of the former glacier supports the role of climate in driving a net decline of regional ice volume during marine isotope stages 3–2. Close spacing and good preservation of the 19–17 ka moraines permits 2D glacier reconstruction which suggests the equilibrium line altitude remained depressed by c.1130 m (equivalent to 5.8 ± 0.6 °C colder than present) during this interval. Onset of warming after 17.2 ± 0.2 ka is consistent with climate proxy evidence for a sustained southward shift in the southern westerly winds, which may have promoted deglaciation via shifting ocean currents and promoting increases in atmospheric carbon dioxide.

Glaciers will lose mass during the next decades as the climate warms. While the largest uncertainty in this mass loss is the global greenhouse gas emissions pathway, on a local or regional scale there are large uncertainties in some processes that influence glacier response. We explore the competing processes of reduced ablation under debris cover and increased ablation from calving by applying a coupled mass-balance/ice-flow model in the central Southern Alps/Kā Tiritiri o te Moana of New Zealand. Glacier volume loss is assessed over the period from AD 1880 to AD 2099, driven by observed climate data before 2005, and perturbing the modern climate state and imposing representative concentration pathway (RCP) scenarios 2.6–8.5 as expressed by six global circulation models (GCMs) which leads to a regional warming of between 1–4 °C (2006–2099). Key findings are (1) modelled ice volume reduced from 47 km3 to 29 km3 between AD 1880 and 2005; (2) over the period 2006–2099 further volume loss to 24 km3 (19% reduction) is committed under present-day climate; (3) modelled ice volume at AD 2099 is estimated at 2 km3 ± 6 km3 (RCP8.5) to 15 km3 ± 6 km3 (RCP2.6), a reduction of 50–92% relative to present day. The wide range of projected ice volumes reflects the large range of temperature projections between RCP2.6 and RCP8.5. The mode and timing of ice loss provides insight into processes that will drive future glacier behavior. Under RCP2.6 at 2099, the glaciers retain a similar configuration to present, although clean-ice glaciers will retreat significantly, and some debris-covered tongues will disconnect from their accumulation areas. For RCP4.5, RCP6.0 and RCP8.5 the clean-ice glaciers will retreat to become small remnants in the high mountains. Experiments where the debris cover is removed shows a much faster loss of ice, whereas experiments with no lake calving slows ice loss. However, under all but the most moderate warming scenarios, by 2099 the strong climatic forcing overwhelms these processes as there is little ice left at low elevations where debris cover and lake calving occur.

Geological climate archives from the Holocene Epoch provide baseline information concerning natural climate variability. Temperate mountain glacier extent is sensitive to summer air temperature, thus geological records of past glacier length changes are a useful proxy for this climatic variable. Here we present a new cosmogenic 10Be chronology of glacier length changes at Dart Glacier in the Southern Alps, New Zealand. Prominent moraines deposited 321 ± 44 yr ago (n = 11) and 7.8 ± 0.3 ka (n = 5) show glaciers during the Little Ice Age were less extensive than during the early Holocene. This pattern of net Holocene glacier retreat is consistent with emerging data from other catchments in New Zealand and across the southern mid-latitudes. Using the physical framework of a transient global climate model simulation, we suggest that cool summers in the early Holocene were promoted by the local summer insolation minimum, together with low atmospheric greenhouse gas concentrations, causing an early Holocene austral glacial maximum. An insolation-driven reduction in seasonality at southern mid-latitudes may reconcile differences between early Holocene temperature reconstructions where climate proxies have different seasonal sensitivities. We suggest that rising greenhouse gas concentrations after 7 ka caused regional-scale glacier retreat and appear to be the dominant driver of multi-millennial summer temperature trends in the southern mid-latitudes during the present interglacial.

Recent model studies suggest that interannual climatic variability could be confounding the interpretation of glacier fluctuations as climate signals. Paleoclimate interpretations of moraine positions and associated cosmogenic exposure ages may have large uncertainties if the glacier in question was sensitive to interannual variability. Here we address the potential for interannual temperature and precipitation variability to cause large shifts in glacier length during the Holocene. Using a coupled ice-flow and mass-balance model, we simulate the response of Cameron Glacier, a small mountain glacier in New Zealand's Southern Alps, to two types of climate forcing: equilibrium climate and variable climate. Our equilibrium results suggest a net warming trend from the Early Holocene ( 10.69 ± 0.41 ka; 2.7 °C cooler than present) to the Late Holocene (CE 1864; 1.3 °C cooler than present). Interannual climatic variability cannot account for the Holocene glacier fluctuations in this valley. Future studies should consider local environmental characteristics, such as a glacier's climatic setting and topography, to determine the magnitude of glacier length changes caused by interannual variability.

The occurrence of terrestrial palynomorphs in Quaternary marine sedimentary sequences allows for direct land–sea correlations and provides a means for transferring Marine Isotope Stage chronologies to terrestrial records that extend beyond the range of radiocarbon dating. Both of these important applications require an implicit assumption that the lag between pollen release and final deposition on the seafloor – here referred to as source-to-sink residence time – is negligible in relation to the chronological resolution of the sedimentary sequence. Most studies implicitly assume zero lag, and where studies do take palynomorph residence time into account, its magnitude is rarely quantified. In Westland, New Zealand, fluvial transport is the main source of delivery of terrestrial pollen offshore to the adjacent East Tasman Sea. We radiocarbon-dated organic matter carried and deposited by contemporary Westland rivers that drain catchments with varying degrees of disturbance. The ages obtained ranged widely from essentially modern (i.e., − 57 ± 22 cal yr BP) to 3583 ± 188 cal yr BP, suggesting that precisely constraining the residence time in this region is unlikely to be achieved. We also compared the timing of four palynomorph events characterising Westland's late Pleistocene, along with the well-dated Kawakawa/Oruanui Tephra (KOT), between marine core MD06-2991 and four terrestrial records from Westland. Critically, all palynomorph events and the KOT are chronologically indistinguishable with respect to the independently dated marine and terrestrial records, supporting the general principle of transferring the marine chronology onto the terrestrial records in this setting. In other regions, particularly those lacking the high soil production and erosion rates that characterise Westland, we suggest that similar tests of marine residence time should be conducted before assumptions of zero or negligible lag are invoked.

Daily time lapse imagery and pixel tracking was used to monitor and track spatial and temporal changes in sediment-mantled hillslopes, during and immediately after glacier retreat in the Fox Glacier/Te Moeka o Tuawe valley, New Zealand. Observations from 2014 to 2018 of the Fox Glacier and surrounding hillslopes show hillslope failure is primarily coincident with, and triggered by, glacier retreat with rainfall accelerating movement of the hillslope. During glacier retreat, failure of the hillslope primarily occurred through sediment sliding, internal deformation of the sediment and occasional surficial debris falls, flows and avalanches delivering approximately 9.2 M m3 of sediment directly to the underside of the glacier over the study period with a maximum daily averaged movement of 0.4 m per day of the main sediment mass. Following debuttressing, hillslope failure became dominated by localised rainfall-induced debris flows which initiated gullying of the sediment-mantled slope. Ongoing instability of the slope and associated movement is maintained by toe erosion from the Fox River and melting dead ice, while continued rapid failure is facilitated through localised debris flows. The tracking of temporal and spatial changes of sediment-mantled hillslopes during glacier retreat has shown broad-scale hillslope response to occur quickly within days of rainfall or accelerated glacier retreat, particularly during summer. Debris flows, commonly thought to be a dominant erosion process within paraglacial environments, only occur following complete debuttressing and are supply-limited, only occurring after sediment sliding has occurred. Unlike many other case studies, sediment connectivity immediately following glacier retreat is high due to a lack of storage space and high rainfall inducing mass movements, efficiently delivering hillslope sediments to the proglacial stream channel. Attempts to quantify displaced volumes of sediment from paraglacial systems are likely underestimated due to a) a lack of focus on the early and latter stages of debuttressing b) a reliance on debris flows being a primary transport mechanism, and c) sediment being delivered sub-glacially rather than supra-glacially, further enhancing connectivity.

The largest accelerations of glaciers and ice sheets are caused by changes in basal slip. Here we examine glacier speed and rain-induced accelerations using a near-continuous 26-month-long GNSS time series from a large maritime glacier (Tasman Glacier, New Zealand). During periods of high rain-rate we observe short-term increases in 24-hour speeds to up to 15-times background speed. Speeds calculated over 3-hour intervals increase to up to 36-times background speed. Acceleration events correspond with times when bed separation also increases rapidly indicating that the acceleration is associated with the growth of water-filled cavities at the bed. Glacier speeds then decrease prior to the reduction in bed separation, indicating cavity growth, not cavity extent, controls the acceleration. The short-term accelerations are superimposed on longer-term periods of enhanced velocity that persist for days to weeks and decay at similar rates to bed separation estimates and proglacial lake levels. A power-law relationship between observed rain-rate and speed exists at the glacier front and exhibits no apparent upper bound. Overall, we estimate that rain-induced accelerations account for 11–14% of Tasman Glacier's displacement during the observation period. The rain-rate–velocity relationship and the rainfall record since 2001 indicate that rain-induced speed-up events result in interannual variability in glacier displacement of 2%–13%.

Compilation of modern and historical length change records for Franz Josef and Fox Glaciers demonstrates that these glaciers have lost ~ 3 km in length and at least 3–4 km 2 in area since the 1800s, with the greatest overall loss occurring between 1934 and 1983. Within this dramatic and ongoing retreat, both glaciers have experienced periods of re-advance. The record from Franz Josef Glacier is the most detailed, and shows major advances from 1946 to 1951 (340 m), 1965–1967 (400 m), 1983–1999 (1420 m) and 2004–2008 (280 m). At Fox Glacier the record is similar, with advances recorded during 1964–1968 (60 m), 1985–1999 (710 m) and 2004–2008 (290 m). Apart from the latest advance event, the magnitude of advance has been greater at Franz Josef Glacier, suggesting a higher length sensitivity. Analysis of the relationship between glacier length and a reconstructed annual equilibrium line altitude (ELA) record shows that the glaciers react very quickly to ELA variations — with the greatest correlation at 3–4 years' lag. The present (2014) retreat is the fastest retreat in the records of both glaciers. While decadal length fluctuations have been linked to hemispheric ocean–atmosphere variability, the overall reduction in length is a clear sign of twentieth century warming. However, documenting glacier length changes can be challenging; especially when increased surface debris-cover makes identification of the ‘true’ terminus a convoluted process.

Climate proxy records from the middle to high latitude Southern Hemisphere indicate that a Lateglacial (15,000–11,500 years ago) climate reversal, approximately coeval with the Antarctic Cold Reversal (ACR), interrupted a warming trend during deglaciation. In New Zealand, some palaeoclimate proxy records indicate a cool episode during the ACR (ca 14,500–12,500 years ago), while others do not express a significant change in climate. Recently published moraine maps and ages present an opportunity to improve the palaeoclimate interpretation through numerical modelling of glaciers. We use a coupled energy-balance and ice-flow model to quantify palaeoclimate from past glacier extent constrained by mapped and dated moraines in the headwaters of Irishman Stream, a high-elevation catchment in the Southern Alps. First, a suite of steady-state model runs is used to identify the temperature and precipitation forcing required to fit the modelled glacier to well-dated Lateglacial moraine crests. Second, time-dependent glacier simulations forced by a nearby proxy temperature record derived from chironomids are used to assess the fit with the glacial geomorphic record. Steady-state experiments using an optimal parameter set demonstrate that the conditions under which the 13,000 year old moraine formed were 2.3–3.2 °C colder than present with the range in temperature corresponding to a ±20% variance in precipitation relative to the present-day. This reconstructed climate change relative to the present-day corresponds to an equilibrium-line altitude of ca 2000 ± 40 m above sea level (asl), which is ca 400 m lower than present. Time-dependent simulations of glacier length produce ice advance to within 100 m of the 13,000 year old terminal moraine, indicating that the chironomid-based temperature forcing and moraine record provide consistent information about past climate. Our results, together with other climate proxy reconstructions from pollen records and marine sediment cores, support the notion that temperatures during the ACR in New Zealand were ∼2–3 °C cooler than today.

Snow distribution patterns are still poorly understood in steep alpine catchments because of mass redistribution from wind and avalanching. Snow models rarely operate with sufficient resolution, physics or input data to resolve this issue explicitly, and existing sub-grid parameterisations are rarely tested in this type of terrain. To address this issue daily snow cover observations, obtained from a ground-based camera, are combined with a snow melt model to estimate the spatial distribution of snow water equivalent (SWE) in a mountainous alpine catchment. Results show the importance of slope in controlling the spatial distribution of SWE and snow duration. This distribution is linked to the physical process of gravitational transport, where there is removal of snow from steep slopes and preferential deposition on moderate-angle slopes. From a modelling perspective, if sub-grid snow variability is parameterised using a log-normal probability distribution (as is common in hydrological and land-use models) then ignoring steep/shallow slope differences leads to an overestimation of melt at the beginning of the melt season, and a premature end to the snow melt season. When modelling SWE in complex terrain, care should be taken to consider reduced SWE on steep slopes.

A potential complication in using glacier extent to estimate paleoclimatic conditions is the influence of glacier bed evolution on changes in ice extent over time. Here, we examine this issue through model-based reconstructions of the Last Glacial Maximum (LGM) Pukaki glacier, Southern Alps, New Zealand, whose LGM extents are exceptionally well defined by lateral and terminal moraines. Using the well-dated moraine limits as an empirical constraint on maximum ice extents, we employ a one-dimensional glacier flowline model driven by a mass balance model in order to evaluate the influence of climate and glacier bed profile on the extent of the LGM Pukaki glacier. The LGM glacier bed is buried by Lateglacial and post-glacial sediment, so we calculate bed profiles using a modified version of the one-dimensional model and available geologic constraints. A best fit to the moraine record occurs with a LGM temperature of 7–8 °C cooler than present, with precipitation ranging from 80% to 100% of present levels. Modeling of the bed profile evolution indicates that bed changes alone could account for kilometer-scale changes in glacier width and length.

We present a simulation of the New Zealand Southern Alps icefield at the Last Glacial Maximum (LGM, c. 30,000–20,000 calendar years ago (ka)) in an attempt to constrain the climate of that period. We use a 500 m-resolution ice-sheet model parameterised using empirical glaciological, climatological and geological data specific to the model domain to simulate the entire Southern Alps icefield. We find that an LGM cooling of at least 6–6.5 °C is necessary to bring about valley glaciers that extend beyond the mountains. However, climate–topography thresholds related to the elevation and hypsometry of individual catchments control the gradient of the rate of glacier expansion in the domain, and in order to remain within geologically reconstructed LGM limits we find that the LGM cooling was most likely associated with a precipitation regime up to 25% drier than today. Wetter-than-present scenarios give rise to equilibrium line depressions and ice extents that are incompatible with empirical evidence. These results perhaps indicate that either the westerly air masses affecting New Zealand during the LGM were drier than today, or that they were weaker or zonally displaced with respect to present.

Mid-latitude maritime glaciers are responding quickly and directly to climate change. This response is expected to continue, and will result in maritime glaciers making a large contribution to sea level rise over the coming decades. Maritime glaciers in the New Zealand Southern Alps provide an opportunity to learn more about climate–glacier mass balance relationships in a high precipitation setting, and how these relationships might change in the future. Ice core and direct glaciological measurements are used to construct a 24-year record of net accumulation, the longest of its type in New Zealand. We demonstrate that variations in net accumulation on Tasman Glacier are more strongly influenced by temperature than by precipitation. Further, it is temperature during the ablation season that exerts most control. Atmospheric circulation patterns, in particular the state of the El Nino Southern Oscillation (ENSO) and Southern Annular Mode (SAM), were found to influence net accumulation. When the SAM is positive and the ENSO in a La Nina phase, easterly and northerly wind anomalies are enhanced, temperatures increase in the Southern Alps region and more negative glacier mass balances result. Conversely when SAM is negative and ENSO in an El Nino phase, westerly and southerly wind anomalies occur, and temperatures decrease in the Southern Alps region. In this case, glacier mass balance is more likely to be positive. However, relationships between glacier mass balance and these atmospheric circulation modes are not simply linear, with some of the lowest net accumulation years associated with inverse polarity between the SAM and the ENSO.

Understanding the response of relatively small ice masses to climate change on a century-to-century timescale is important because of their significant contribution to sea level change in the recent past, and their likely contribution in the next century. Franz Josef Glacier, with its excellent terminus position record, location in the Southern Hemisphere, and its extreme sensitivity to climatic changes, is a key data point for understanding the magnitude and mechanisms of past and future climate changes. Here, we use a reconstructed mass balance record to drive an ice flow model which simulates the general retreat of the glacier during the 20th century. The model is then used to project future glacier variations, based on regionally downscaled climate change scenarios. The results indicate that, under a mean climate change scenario, the glacier will retreat 5 km and lose 38% of its mass by 2100. Different scenarios give a range of recession from 3.9 to 6.4 km, and a range of volume loss from 26% to 58%. On a global scale, the magnitude of the retreat is at the upper end of the range calculated for other, similar sized, glaciers.

We attempted to determine how accurately members of the public can identify venomous snakes. Six different snakes indigenous to southern California were displayed in cages for 265 people to view at a street fair. These included 4 nonvenomous snakes and 2 venomous snakes. People were asked whether the snake was venomous and the name of the snake, if they knew it. Overall, people recognized whether a snake was venomous or nonvenomous 81% of the time. They were most accurate at identifying rattlesnakes as being venomous (95%) but incorrectly identified nonvenomous snakes as being venomous 25% of the time. Men were more accurate than women, and adults were more accurate than children. Subjects were less well able to identify the exact species of snakes. The results suggest that there may be no need to capture, kill, or bring a snake to the hospital for identification, at least in this geographic area.

The late Holocene retreat of the West Antarctic ice sheet is crucial information for assessing its current dynamics. However, data from this period for parts of the ice sheet where significant change has taken place, mainly the Ross Sea, are very sparse. Some significant dated deposits are from lakes dammed by valley glaciers, themselves dammed by the Ross Ice Sheet. The least age of these deposits is somewhat later than the retreat of the Ross Ice Sheet from the locality on account of the lagged response of the glacier. We present a model of the Hatherton Glacier, which examines its relationship to the Ross ice sheet, using dated margin data from ice-dammed lakes. Problems in modelling are the coupling with the Darwin Glacier, the unknown bed topography and the poorly known surface mass balance, which include blue ice areas. We infer the bed topography by tuning a valley glacier model, and use this model to (i) estimate the thickness of the Last Glacial Maximum (LGM) Ross Ice Sheet; and (ii) estimate the response time of the Hatherton Glacier to changes in the Ross Sea ice sheet. The best fit of the glacier surface profile to the geological data occur if the LGM Ross Ice Sheet elevation is assumed to be 800 m higher than the present-day ice shelf surface. If the decay of the Ross Ice sheet is linear with time, the response time is of the order of several centuries. Step changes in the elevation of the Ross Ice Sheet lead to a response time around one thousand years. The dated deposits in the Hatherton Valley cannot be used directly as dates of Ross Ice Sheet grounding line retreat.

Des-tyrosine-gamma-endorphin (DT gamma E) has been reported to alleviate symptoms of schizophrenia. Attempting to replicate those reports, we administered 1 mg of DT gamma E, i.m., for 8 consecutive days to nine patients meeting the DSM-III criteria for schizophrenia. Patients in this double-blind, crossover, and placebo-controlled study showed a statistically significant, but clinically modest improvement. The improvement was detectable during the first several days of the DT gamma E treatment; the symptoms then returned to baseline level in spite of continued doses of DT gamma E. Testing the metabolism of DT gamma E in the patients' plasma, we found a high rate of formation and of degradation, but the metabolic rates were not related to clinical symptoms.

The subjects were 13 psychiatric inpatients with tardive dyskinesia. Each subject participated in two sessions. Either naloxone (10 mg) or placebo was administered intravenously during each session. In a subset of subjects (n = 7), blood samples for β-endorphin were drawn before and at 30 and 60 minutes after the injection. The Abnormal Involuntary Movement Scale was administered before and at 10, 20, 40, 60, 120, and 360 minutes after the injection. Double-blind procedures were maintained throughout the experiment. Neither naloxone nor placebo had any appreciable effect on the involuntary movements. Naloxone elicited a significant increase in the plasma β-endorphin.