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The Meduxnekeag watershed is part of the Wulustuk watershed inhabited by the Maliseet people from a very early period. The first traces of human habitation have been dated to a time soon after the glacial ice withdrew, and there is no reason not to believe that the area has not been inhabited ever since. The known Maliseet settlement pattern included the establishment of villages at or near the mouths of major Wulustuk tributary streams; it is very likely that a Maliseet village long preceded the Town of Woodstock at the mouth of the Meduxnekeag and on the island which lay in the St. John off the mouth. As the prime settlement area has since been flooded by the Mactaquac headpond (1967), it is not possible to be certain of the size of the settlement or the length of time it existed, but the earliest surviving written historical records show a Maliseet settlement there in the 17th century.

In any event, the Maliseet residents will not have had a significant shaping effect on the ecology of the watershed or the quality of the water. They may have raised corn and other crops on the offshore island and some of the intervales; they certainly harvested fiddleheads and other edible plants, as well as butternuts; they harvested salmon and other fish; hunted and trapped forest and aquatic animals and birds, and selectively harvested trees – and parts of trees – for raw materials and fuel. They used the Meduxnekeag as a canoe transportation route, but principally within its own watershed: it does not have heavily used portages to other watersheds.

Major changes in the watershed began with the arrival of Loyalist settlers in the mid-1780s. Over the following fifty years, the appearance and ecology of much of the watershed was transformed. Many of the original growth trees were removed, beginning with the most valuable (oldest, largest, straightest) and most accessible (closest to the waterside). The land most suitable for agriculture (best drained, least steep, richest soils) was permanently cleared; virtually all other forest was high-graded for its most valuable trees, excepting only those places which were so remote from water transportation that it was not feasible to get the timber out. Fire, both deliberate and inadvertent, impacted many forested areas. The consequences of this human intervention included both a severe and sudden decline in quality and extent of mature forest; and a negative impact on water quality and aquatic life. Erosion increased, as did the frequency and severity of floods. At the same time, increased hunting, fishing and trapping combined with habitat loss to significantly reduce most animal, fish and bird populations.

This transformation continued throughout the 19th Century as settlement and population expanded: more parts of the watershed forests were permanently converted to agricultural uses; the urban areas expanded; economic changes placed further stresses on the remaining forests (these included a mid-19th century iron mine and smelter just outside the watershed at Upper Woodstock which consumed huge quantities of locally produced hardwood charcoal); a major lumber-milling industry developed on the Meduxnekeag at Woodstock, fed largely with timber from the watershed. In transporting the timber downstream, tributary streams were altered with temporary “driving dams”; boulders were removed or demolished with explosives; debris choked smaller streams; bark and waterlogged branches collected on the bottom of the river damaging spawning habitat and impacting benthic life. Water quality necessarily diminished.

By the early years of the 20th Century, agricultural settlement in the watershed had reached its maximum extent; roads had been established throughout; a railway had reached up the riparian corridor from Woodstock as far as Red Bridge before turning north and rising up out of the watershed on its way to Centreville; the last stands of the surviving old growth trees – the eastern hemlock – were being rapidly cut for their bark to feed the tanneries in Woodstock; dams had been built at several places on the river and its tributaries, interfering with fish migration.

While the New Brunswick portion of the watershed above Woodstock was impacted principally by agriculture and forestry, the upper watershed in Maine added the effects of urban and industrial development including the dumping of untreated municipal and industrial effluent into the river.

These impacts on the Meduxnekeag continued with little abatement until the middle of the 20th Century when agricultural land use began to contract with the abandonment of marginal farmland. Water quality in the Meduxnekeag River probably reached its lowest point about 1960.

By the end of that decade, the construction of the Mactaquac dam on the St. John had produced a headpond flooding the mouth of the Meduxnekeag and its upstream intervales almost as far as the newly constructed Trans-Canada Highway more than two kilometres from the mouth; the railway was abandoned, municipal and industrial effluent in Maine began to be treated and diverted from the river, the water had ceased to be used for the transportation of logs and pulpwood. Water quality slowly began to recover. In the intervening years, this recovery has continued.

Today, the Meduxnekeag in New Brunswick is an important recreational river. Its mouth provides some of the best Small-mouth Bass angling in eastern North America. It supports populations of Brook Trout and Brown Trout. Its intervales are among the best fiddlehead harvesting sites in the province. Jackson Falls on the South Branch, and the North Branch below Briggs's Mill Falls are challenging kayak runs in high water. From the confluence to Woodstock is an easy scenic canoe trip in Spring and Fall.

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